Genome Near-Haploidization in CDC73-Wildtype Parathyroid Tumors

Genome Near-Haploidization in CDC73-Wildtype Parathyroid Tumors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Genome Near-Haploidization in CDC73-Wildtype Parathyroid Tumors Maaia Margo Jentus, Filomena Cetani, Marieke Snel, Femke M van Haalen, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7834367/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Recurring parathyroid carcinoma (PC) is foremost associated with germline or somatic CDC73 mutations. We reported three PCs without CDC73 mutations, with massive chromosomal losses, genome near-haploidization with or without endoreduplication/genome doubling. These are characteristic features seen in rare tumor types like oncocytic thyroid carcinoma. We investigated whether similar genomic alterations occur in other parathyroid tumors. We selectively analyzed fourteen parathyroid adenomas (PA, thirteen oncocytic), three atypical parathyroid tumors (APTs, one oncocytic), and one PC, the latter four all negative for CDC73 mutations. Histopathological diagnoses were reviewed according to the WHO classification 2022. All tumors underwent genome-wide SNP array testing with analysis of chromosomal copy number variations (CNVs), imbalances/loss of heterozygosity (LOH). The APTs and PC underwent somatic mutation analysis. Oncocytic PAs exhibited relatively stable genomes with no or minimal chromosomal alterations. Patients with chromosomally altered PA had significantly higher pre-operative serum calcium levels. In contrast, we identified two APTs and one other PC with massive chromosomal losses and genome near-haploidization. Our findings expand the spectrum of chromosomal near-haploidization in APTs and PCs lacking CDC73 mutations. Biological sciences/Cancer Biological sciences/Genetics Biological sciences/Molecular biology Health sciences/Oncology parathyroid carcinoma parathyroid whole chromosome loss molecular analysis endocrine pathology parathyroid neoplasia rare cancer Figures Figure 1 Figure 2 INTRODUCTION The parathyroid glands play a crucial role in calcium homeostasis by tightly regulating the secretion of parathyroid hormone (PTH). Excessive PTH secretion leads to hypercalcemia, and when this occurs independently of physiological feedback mechanisms, it is referred to as autonomous hyperparathyroidism, which can be either primary or tertiary. Autonomous functioning parathyroid glands can exhibit hyperplastic, adenomatous, atypical, or even carcinomatous changes. Among the key genes involved in parathyroid tumorigenesis, MEN1 and CDC73 are the most prominently affected. Inactivating germline mutations in MEN1 and CDC73 lead to MEN1- and HPT-JT syndromes, respectively. The CDC73 gene encodes the parafibromin protein, loss of expression of parafibromin is seen in tumors with CDC73 biallelic inactivation. While CDC73 inactivation and/or parafibromin expression loss is commonly associated with both familial and sporadic parathyroid carcinoma (PC), these can also be seen in (cystic) parathyroid adenomas [ 1 – 4 ]. Loss of parafibromin expression and/or the presence of CDC73 mutations is/are associated with worse disease outcomes in PC and predict(s) aggressive behavior in atypical parathyroid tumors (APTs) [ 5 – 7 ]. MEN1 mutations are present in 11–40% of sporadic PAs and rarely (≤ 10%) observed in sporadic PCs. Other genetic events such as CCND1 amplification and/or mutations in less common genes can be seen in PC [ 8 , 9 ]. Diverse chromosomal copy number alterations in parathyroid lesions are widely reported in the literature and can be considered a hallmark of a subset of these lesions (Tables 1 – 3 include CGH, WES, WGS or SNP-array studies with a genome-wide approach; Supplemental Table 1 includes studies with other methods). Distinct alteration patterns occur in parathyroid adenomas (PAs, Table 1 ) and PCs (Table 2 ) [ 10 – 14 ]. Table 1 Genome-wide studies of chromosomal alterations in parathyroid adenomas utilizing CGH, WES, WGS or SNP-arrays. Study Method n Findings Agarwal et al. [ 13 ] CGH 10 Deletions on chr. 11, 17 (n = 5), and 22 (n = 7). Complex pattern, predominance of losses. Every chr. was involved except chr. 8. Palanisamy et al. [ 15 ] CGH 53 Recurrent gains: chr. 16p (6/53) and 19p (5/53). Frequent losses chr. 11p (14/53), 11q (18/53), chr. 1p, 1q, 6q, 9p, 9q, 13q, and 15q (8–19%). Farnebo et al. [ 16 ] CGH and subsequent MEN1 analysis 26 sporadic PA, in 10 previous head and neck irradiation, and 8 familial cases Sporadic : minimal regions of loss on chr. 11 (38%), 15q (27%), and 1p (19%); gains of chr.19p (15%) and 7 (12%). Irradiation-associated : frequent losses of chr.11q (50%), MEN1 mutations in 4 of 8 cases (50%). Losses of chr. 1p (50%), 11q (50%), 11p (40%), 6q (30%), 18q (30%), and 22q (30%); gain of chr. 19p (30%). Familial : few alterations, gain of chr. 19p as single aberration in 3 tumors. 10/14 PA with involvement of the MEN1 gene locus displayed loss of the entire chr. 11. Loss of chr. 15q in 5 PA. Haven et al. [ 17 ] CGH 4 PA ( CDC73 mutation carriers) No LOH at chr. 1q21–32 observed. One PA: gain of chr. 16 and loss of chr. 13. Other PA: gains of chr. 1q and 17p. Dwight et al. [ 61 ] CGH, LOH and MEN1 mutation analysis 13 sporadic PA 12/13 PA had chromosomal alterations. Partial or total loss of chr. 11 in 4/13 PA. Loss of chr. 13q and whole chr. gain of chr. X in 3/14 PA each. 2/13 PA had losses of chr. 1q and 22q. Losses of chr. 2p, 5q14-q31, 15q and gains of chr. 3, 5, 6p, 7, and 14q were detected once each. Dwight et al. [ 18 ] CGH 10 PA from 5 patients with sporadic multiglandular PHPT Tumors of one patient had no alterations (3/10). 10 PA with chromosomal alteration. Different changes among PA of the same patient, seen in 2 patients. Another two patients with alterations only in one PA of two. Imbalances observed once: gains of chr. 5, 6, 7, 12, 16, 19p; losses of chr. losses 1p,15q, 18, 21q, 22q. Imbalances with losses observed twice: chr. 11, 12q, 13q. LOH observed at chr.11q13 (3/10) and 1p (1/10). Garcia et al. [ 19 ] CGH 14 sporadic conventional PA Chromosomal gains (14/14), losses (3/14). No genomic amplification was observed. One patient: whole chromosome gains of chr. 1, 6p, 7, 8, 9, 10, 12, 16, and whole chr. losses on chr. 11, 12, 13q, 19p. 13/14 PA exhibited > 2 abnormalities. Imbalances with gain were observed 1x (chr. 2p, 3p, 7p, 7q, 8p, 10p, 15q, 16q, 19p, 21q, 22q), 2x (1p, 2q, 5q, 6p, 10q, 12q, 17q, 19q), 3x (1q, 3q, 6q, 9p, 9q, 13q, 14q, 18q, 20q) or 5x (chr. 4q and Xq). Whole chr. gain was observed 1x (chr. 1, 4, 7, 10, 12, 16 and X) and 3x (chr.8 and 9). Imbalances with losses observed 1x (chr. 6, 9pq, 13q, 15q, 18q, 19p, 20p) and 3x (chr. 11q). Whole chr. loss was observed 1x on chr.20 and 2x on. chr 11. No alterations detected on chr. 5p, 12p, 14p, 15p, 17p, 18p, 21p, 22p and Y. Yi et al. [ 32 ] CGH, FISH and TMAs for chr.11 7 Type I PA 9 Type II PA Common finding was deletion of the MEN1 locus or loss of a substantial portion or an entire chr. 11. Loss of 11q23 in slightly less than 50%. The least common finding: translocation of the CCND1 gene. Newey et al. [ 20 ] WES 16 LOH chr.11 (8/16), LOH chr.1, 15 and 18 (3/16), LOH chr. 22 (4/16), LOH chr.13 and 21 (2/16), LOH chr. 2, 3, 4, 5, 7, 8, 9, 10, 17, 19, and X (1/16). Not affected by LOH: chr. 5, 12, 14, 16 and 20. Cromer et al. [ 21 ] WES 8 4/8 PA with a frame shift deletion or nonsense mutation in MEN1 , accompanied by LOH of the other allele. LOH observed once on chr. 1p, 9, 13, 21, 22. No LOH in 3/8 PA. Sulaiman et al. [ 22 ] CGH and SNP microarrays 5 PA, established CDC73 inactivating mutation No significant alterations in 1/5 PA. Deletion of whole chr. 9 (1/5). Gain of entire chr. 16 (n = 2), with gain of entire chr. 17 or 22. No significant aberrations on chr. 1, 11 or 13. Different loss pattern than in unselected tumors. The least extent of CNAs compared to APT and Ca. Chr. chromosome(s), CGH comparative genome hybridization, FISH fluorescence in situ hybridization, HPT hyperparathyroidism, LOH loss of heterozygosity, PA parathyroid adenoma, SNP single nucleotide polymorphism, TMA tissue microarray, WES whole exome sequencing. Table 2 Genome-wide studies of chromosomal alterations in APT and PC utilizing CGH, WES, WGS or SNP-arrays. APT Study Method n Findings Sulaiman et al. [ 22 ] CGH and SNP microarrays 1, established CDC73 inactivating mutation Extensive aberrations affecting almost all chr., large scale gains on chr. 1p, 16, 17, 19, 20 and 22 and loss of chr. 1p. No loss of CDC73 . Jha et al.[ 62 ] WES and FLCN germline sequencing 3 1/3 with FLCN c.1285insC variant, no clear LOH was observed in the tumor, possibly due to normal DNA contamination. PC Study Method n Findings Agarwal et al.[ 13 ] CGH 10 Frequent losses on chr. 1p (4/10) and chr. 17 (3/10), and gains were on chr.5 (3/10). Chr. 2, 9, 10, and 21 were not altered. Haven et al. [ 17 ] CGH 1, CDC73 mutation carrier LOH on chr.1q Kytölä et al. [ 51 ] CGH 29 Losses of chr. 1p and 13q (> 40%), 9p (28%), 6q (24%), and 4q (21%). Gains of chr. 19p (45%), Xq (28%), 9q (24%), 1q (21%), and 16p (21%). A sex-dependent distribution for two common alterations with gain of 1q in females and of Xq in males. Sulaiman et al. [ 22 ] CGH and SNP microarrays 3, with CDC73 inactivating mutations Gross losses of chr. 1p and 13 were associated (p = 0.012) with parathyroid carcinomas as opposed to adenomas. Losses of chromosome 1p, 13, 14, 18 and gains of 1q, 5, 5q, 9, 10, 20, 22. None of the carcinomas exhibited loss on chr. 11. No losses spanning the CDC73 . Costa-Guda et al. [ 14 ] SNP arrays and CGH 16 from 10 patients, 3 with germline HPRT2 mutation. SNP analysis (9 patients) - gains detected once (chr. 3, 11, 11p, 11q, 12, 12p), twice (chr. 5 and 21), three (chr. 1q, 20) and five times (chr.16). Losses detected once (chr. 2, 2q, 4, 8, 8p, 9, 9p, 10, 11, 13q, 14q, 17, 21, 21q, 16p, 16q, 18q), twice (chr. 6, 12, 14 and 15) three (chr. 1p and 18), four (chr.3 and five times (chr.13). cnLOH detected on chr. 3, 1p, 22, 4, and 14. CGH: gains detected once (chr. 5, 5q, 8, 12, 12p, 22), twice (chr. 16, 16p, 20, X) and three times (chr.1). Losses detected once (2q, 6, 12, 12p, 13, 14, 15q, 18, 21), twice (chr. 1p) three (chr. 13q) and four times (chr. 3). Recurrent tumors had partly different pattern than primaries. One of the tumors has shown no alterations in CGH while SNP array was positive. Results of SNP array and CGH were variable. Corver et al. [ 33 ] Genome-wide SNP and flow cytometry DNA content analysis 3 NHG observed in 1 of 3 PCs, also the one lacking a HPRT2/CDC73 mutation. Pandya et al. [ 9 ] WES 17 Recurrent losses of chr.1p (n = 8), 3 (n = 3), and 13 (n = 10) and gains of chr. 1q (n = 6), 16 (n = 9), and 20 (n = 9). Focal recurrent gains 6p11.2, 7q22.1, 10q26.2 and 11q23.2 and losses 1p36.32, 3q29, 6q25.3 and 7p21.3. Detected gain of CCND1 (n = 5), 4 of the 5 cases with no CDC73 mutation. Jha et al. [ 62 ] WES and Sanger sequencing, LOH on FLCN and TP53 17, no germline CDC73 or MEN1 mutations LOH on FLCN in 2 of the 3 patients with germline heterozygous FLCN variants. LOH TP53 in metastases of one patient. Jentus et al. [ 43 ] Genome-wide SNP array and broad somatic mutation analysis (NGS) 2, CDC73 wildtype Near-haploid genome due to massive chromosomal losses in both tumors with LOH of chr. 1, 2, 3, 8, 10, 11, 12, 13, 15, 17, 18, and 22. Detected differences in the two cases were additional loss of chr. 6 and 9, and somatic MEN1 mutation in one tumor. Another tumor showed loss of chr. 4 and 21, and no MEN1 mutations were detected. APT atypical parathyroid tumor, chr. chromosome(s), CGH comparative genome hybridization, FISH fluorescence in situ hybridization, LOH loss of heterozygosity, PC parathyroid carcinoma, SNP single nucleotide polymorphism, WES whole exome sequencing. Table 3 Genome-wide studies of chromosomal alterations in parathyroid hyperplasia utilizing CGH-arrays. Study Method n Findings Imanishi et al. [ 29 ] CGH and genome-wide allelotyping 46 tumors from 28 uremic patients with refractory SHPT or THPT. Eleven tumors (24%) demonstrated clonal chromosomal imbalances. Chromosomal gains were more commonly observed than chromosomal losses. Repeatedly observed gains on chr.7 (4/46), 12 (5/46), and a loss on chr.21 (2/46). Observed once: gains on chr. 1q, 2, 6q, 9p, 9q, 18, 22, X and losses on chr.11, 13q, 22. Afonso et al. [ 24 ] Full text not available. CGH Primary and secondary hyperplasia Substantial number of chromosomal alterations in SHPT. Some of these alterations had been previously reported for PHPT, but the majority were in different regions or in different proportions. Yi et al. [ 32 ] CGH, FISH, and TMA 8 tumors in nonfamilial hyperplasia Genomic changes in PHPT were restricted to 11q13 deletion or loss of chr.11. In SHPT 11q23 deletion was common along with strong CCND1 expression. Dwight et al. [ 61 ] CGH, LOH and MEN1 mutation analysis 12 parathyroid samples of 9 patients with lithium-associated HPT Loss at 1p, 11, 15q, 22q and gain of the X chromosome (4/12). LOH at 11q13 and a somatic MEN1 mutation (c.1193insTAC) in one sample. Fewer genetic alterations than in the sporadic tumors, but the detected changes were similar with both familial and sporadic tumorigenesis. Higher prevalence of multiglandular disease in comparison with idiopathic sporadic patients. Chr. chromosome(s), CGH comparative genome hybridization, FISH fluorescence in situ hybridization, HPT hyperparathyroidism, LOH loss of heterozygosity, SHPT secondary hyperparathyroidism, THPT tertiary hyperparathyroidism, TMA tissue microarray. Although there is no consensus on which type of alteration predominates, PCs exhibit extensive genomic alterations. PAs typically display sparse chromosomal imbalances or LOH [ 13 , 15 – 22 ]. In contrast, APTs (Table 2 ) can exhibit a pattern similar to PCs, with extensive genome wide alterations with multiple LOH events which contribute to their potential aggressive biology [ 22 , 23 ]. Chromosomal imbalances and loss of heterozygosity (LOH) have also been observed in idiopathic primary and uremic secondary hyperplasia (Table 3 ) [ 24 – 28 , 10 , 29 – 32 ]. By comparing patterns, different researchers concluded the existence of independent genesis of PAs and PCs [ 13 , 14 ]. However, only a few studies have utilized genome-wide SNP or WES/WGS analysis to describe the chromosomal alteration patterns in parathyroid neoplasia, with most relying on diverse polymorphic microsatellite marker analyses (Supplemental Table 1) or comparative genome hybridization (CGH) [ 22 , 14 , 33 , 9 , 20 , 21 ]. Notably, Costa-Guda et al. performed both, CGH and SNP microarray (Affymetrix 50k) analyses on a small subset of parathyroid tumors, revealing different results that highlights the limitations of CGH [ 14 ]. CGH is unable to detect allelic differences in cases of duplication of the remaining allele (copy neutral LOH) or the recognition and interpretation of endoreduplication/genome doubling events. Costa-Guda et al. found that loss of chromosome 11q was the most common event in PA but not a recurrent change in PC. Little is known about differences in chromosomal alteration patterns among the diverse histomorphological subtypes of parathyroid lesions, as reports typically focus on classifying diagnoses such as hyperplasia, PA, APT, or PC. Few studies mention specific histological subtypes [ 34 , 25 , 20 ]. Parathyroid lesions can exhibit variants based on the parathyroid cell types, such as transitional, oncocytic and clear cell, though they usually consist of chief cells [ 35 ]. When oncocytic cells constitute more than 75% of the PA, it is referred to as an oncocytic subtype [ 35 ]. Chromosomal aberrations in this subtype are not well studied. Oncocytic PAs are reported to be more symptomatic, associated with higher preoperative calcium levels, and generally larger in size than other histological subtypes [ 36 ]. In oncocytic neoplasms of the neighboring thyroid, the chromosomal copy number alterations serve as a molecular and diagnostic hallmark [ 35 ]. The extent and pattern of these alterations, with sometimes massive chromosomal losses, can even distinguish between benign and malignant cases, guiding follow up discussions in cases with uncertain histology [ 37 ]. CDC73 mutated parathyroid neoplasms are reported to exhibit an oncocytic morphology [ 3 ]. Additionally, sporadic PCs frequently (estimated 41–80% cases) harbor inactivating CDC73 mutations with often LOH as a second hit [ 38 – 41 ]. CDC73- mutated PCs are reported to show increased genomic instability with higher levels of copy number alterations [ 42 ]. Previously, we described one oncocytic PC without a CDC73 mutation, showing massive whole chromosomal losses, genome near haploidization and subsequent genome endoreduplication/genome doubling [ 33 ]. The occurrence of near haploidization and subsequent endoreduplication/genome doubling was proven by the combined use SNP array and flow cytometry DNA content analysis with separation of lesional (cytokeratin positive) and stromal (vimentin positive) cell fractions. In the latter experiment the existence of near haploid and endoreduplicated cytokeratin positive cell subfractions could be shown. Recently, we reported two non-functional CDC73 -wildtype PCs with massive whole chromosomal losses and genome near haploidization [ 43 ]. One of these latter PCs showed endoreduplication. Massive chromosomal losses, genome-wide near-haploidization, and subsequent endoreduplication/genome doubling are observed in various rare tumor types at different frequencies. These tumor types include subsets of adrenal cortical cancers, chondrosarcomas, mesotheliomas, oncocytic thyroid carcinomas, gliomas and corticotroph pituitary neuroendocrine tumors (PitNETs) [ 37 , 33 , 44 – 48 ]. We wondered whether our previously identified PC cases with massive chromosomal losses were incidental findings as a relatively large series (n = 17) of whole exome sequencing did not clearly reveal cases with similar massive whole chromosomal losses [ 9 , 49 ]. As in thyroid neoplasia oncocytic metaplasia with concomitant complex I mitochondrial DNA mutations is highly associated with massive chromosomal loss, we selected a cohort of oncocytic PAs. Furthermore, we studied three APTs and one other PC, all CDC73- wildtype. MATERIALS AND METHODS We reviewed pseudo-anonymized pathology/clinical records of one previously and two recently described CDC73 wild type PCs with a near homozygous genome, with or without subsequent endoreduplication [ 33 , 43 ]. We now also added one similar PC case. Furthermore, three CDC73 wild type APTs were added. Additionally, we added 14 PA cases (13 oncocytic) of which 13 were obtained from the Endocrine Unit (FC and CM) of the University of Pisa. All histopathological diagnoses were reviewed by endocrine pathologists (MJ and HM) in accordance with the WHO classification (5th edition, 2022) [ 35 ]. All cases originated from patients with sporadic parathyroid disease. The patients provided written informed consent for the pseudonymized use of their data. For details, see “Ethics approval and consent”. Molecular analysis All cases were analyzed with genome wide SNP analysis using a custom made and routinely used SNP panel comprising 1500 SNPs ( CNV-Imbalance-LOH analysis) and conducted as previously described [ 37 , 47 ]. Selected cases were accompanied by somatic mutation analysis using diverse NGS panels (OCAplus, RCPL, ENDO32; details are available at https://www.palga.nl/voor-pathologen/moleculaire-bepaling under LUMC). Molecular analyses were performed in the Molecular Diagnostics Unit of the Pathology department (ISO15189 accredited) at the Leiden University Medical Center (LUMC). For molecular testing, total nucleic acid was isolated from formalin-fixed paraffin-embedded (FFPE) tissue after micro-dissection of serial hematoxylin-stained sections and selection of tumor tissue on basis of hematoxylin and eosin-stained diagnostic slides. When tumor cell percentage is sufficiently high (mostly the case in parathyroid neoplasia) imbalances and LOH are identified from the SNP frequency patterns. Imbalances are then characterized by smaller amplitude changes when compared with LOH. Copy number detection by CNV analysis helps to explain the mechanism behind the imbalances/LOH observed, being either chromosomal gains or losses. Subsequently, genotypes were extrapolated. For example, see Fig. 2 . The patterns observed across the patient cohort were scored and the alterations counted. Statistics Due to the limited number of the patients included in the study, there was insufficient statistical power to conduct robust inferential statistical analyses. The study primarily relied on descriptive statistical methods to analyze the data. All statistical analyses were performed using Prism 10.2.3 (GraphPad Software, Inc.). Where applicable, quantitative parameters are presented with minimum, maximum, median, and mean along with standard deviation (SD). Normality was assessed with Kolmogorov-Smirnov and Shapiro-Wilks tests. Unpaired t-tests were used for comparison of two groups in normally distributed variables. The Fisher’s exact test was utilized for contingency analysis. A significance level of P < 0.05 was considered statistically significant. RESULTS An overview of all cases discussed in the current study is depicted in Fig. 1 . In total, tumors of 21 patients were included: 14 PAs (13 oncocytic), three APTs, and four PCs, the latter 7 proven to be CDC73 mutation negative. Ten patients were male and 11 were female, in age range of 38–78 years (mean 61.29 SD 10.4 years, median 61.0). Three PCs were published previously but added for comparison [ 43 , 33 ]. PAs The 14 PA patients consisted of 7 female and 7 male patients. The female patients were significantly older (p = 0.0361) with a mean of 66.86 years (range 42–78, SD 8.92) versus mean 54.71 years (range 38–66, SD 10.29) of male patients. Male patients had significantly higher pre-operative serum calcium levels (p = 0.02) while there was no significant difference in serum PTH levels (p = 0.3). Thirteen of 14 PAs were oncocytic. Eight oncocytic PAs did not show chromosomal alterations. In the remaining 6 PAs a limited and variable number of events were seen. Four out of these 6 PA showed either chromosomal losses or gains, while two PAs (PA11 and PA17) had mixed alterations. Oncocytic PA17 showed imbalance of whole chromosome 8 due to copy number gain (genotype AAB or ABB), LOH (with whole chromosome loss, of chromosome 22 (extrapolated genotype A0 or B0) and gain of whole chromosome X (homozygous state, genotype AA or BB, in a male patient). The latter was also observed in oncocytic PA of male patient 6, which harbored gain of whole chromosome X (genotype AA or BB), LOH with whole chromosome loss (genotype A0 or B0) of chr. 22 and copy neutral LOH of chromosomes 20 and 21 (genotype AA or BB). Oncocytic PA13 showed imbalances of chromosomes 5 and 14 due to copy number gain (genotypes AAB or ABB) and a balanced gain of chromosome 13 (whole chromosome gain, genotype AABB). Chief cell PA11 showed mixed pattern of imbalances with copy number gain on chromosome 8 (genotype AAB or ABB) and copy number loss on chromosomes 11 and 18 (genotypes A0 or A0). Oncocytic PA7 only showed imbalance of chromosome 11 due to copy no loss (genotype A0 or B0). Oncocytic PA15 showed imbalances due to chromosomal loss (genotype A0 or B0) on chromosomes 1 (tips), 7p, 11p, 18p, and 20q. To investigate severity of hyperparathyroidism, we compared PTH and calcium serum values in chromosomal altered adenomas (n = 6, group 1) and those without chromosomal alterations (n = 8, group 2). For two patients pre-operative PTH values were not available (patients 8 and 18, both from group 2). There was no significant difference in PTH serum levels (pmol/L) between the groups (p = 0.2, group 1 mean 33.82; range 11.5–70.0; SD 20.61; group 2 mean 20.48; range 6.9–44.0; SD 12.41). Surprisingly, there was a significant difference in serum calcium levels (mmol/L) between the groups (p = 0.01, group 1 mean 2.98; range 2.77–3.22; SD 0.17; group 2 mean 2.7; range 2.5–2.9; SD 0.13), where patients of group 1 had significantly higher levels of serum calcium. In the two groups there was no significant difference in tumor diameter (p = 0.3) nor sex predilection (p = 0.6). APTs and PCs Chief cell APT1 showed imbalances due to copy number loss of chromosomes 1, 9p, 12q, 13 and 20p (genotypes A0 or B0) (Fig. 2 ). In contrast chief cell APT3 and oncocytic APT10 showed massive chromosomal losses (Fig. 2 ). Unambiguous endoreduplication/genome doubling of APT3 and APT10 was not concluded Novel CDC73 -wildtype PC19 also showed massive chromosomal losses without subsequent endoreduplication/genome doubling. Such genomic characteristics were similarly seen in the previously and recently described CDC73 -wildtype PC4, P20 and PC21, respectively, with subsequent endoreduplication/genome doubling seen in PC20 and PC21 (Fig. 1 ). In PC19 somatic mutations were found in NF1 and TSC1 , with APT10 also carrying a NF1 mutation. MEN1- , hTERT- (PC4) mutations were previously found in PC4 and PTEN , ARID1B , SETD2 , KDM5C in PC20 [ 43 ]. Remaining APT1 & 3 did not show mutations with the tests used. DISCUSSION Previously, we reported one PC with massive chromosomal losses, leading to a near-haploid genome. Subsequent endoreduplication/genome doubling led to a near homozygous genome (NHG). More recently we added two non-functional PCs with similar features [33,43]. In the current study we added three additional parathyroid tumors (2 APTs and one PC) with near-haploidy. All APTs and PCs with near-haploidy and/or NHG were CDC73 -wildtype, whereas inactivation of CDC73 is quite common in these lesions. In the existing literature, recently also comprising whole exome and whole genome analysis, no similar cases with massive chromosomal loss, a subsequent near-haploid genome with or without subsequent endoreduplication/genome doubling, were identified [9,42,50,49]. The absence of similar cases in the literature might thus be explained by the enrichment of CDC73- mutant PC in such studies. Sometimes Comparative Genomic Hybridization was used, a technique in which a near haploid genome with endoreduplication cannot fully be seen [51]. Genome near haploidization is seen in subsets of other tumor types like oncocytic thyroid cancer, chondrosarcomas, adrenal cortical cancers, mesotheliomas, gliomas, and corticotroph PitNETs [37,33,44-48]. The identification near-haploidization has so far not led to successful novel therapies. In oncocytic neoplasms of the thyroid the extent and patterns of chromosomal abnormalities can however distinguish hyperplasia, oncocytic adenomas and oncocytic carcinomas in preoperative cytological material thereby directing subsequent surgical interventions [37,52]. As said, in thyroid neoplasms genome near haploidization is associated with oncocytic features. Oncocytic metaplasia in these tumors is the reflection of the proliferation of abnormal mitochondria in the cytoplasm of the tumor cells. Furthermore, in oncocytic thyroid cancer enrichment of complex I mitochondrial DNA mutations is seen and/or complex I abnormalities at the protein level [53,54]. In the current cohort of parathyroid neoplasia, no or few chromosomal abnormalities were seen in oncocytic PAs and of the more advanced lesions only one APT showed an oncocytic morphology. Thus, the underlying biology leading to massive chromosomal loss might be different in diverse tumor types. In oncocytic thyroid cancer the aberrant production of reactive oxygen species is thought to be an important factor in misalignment of chromosomes during the cell cycle (lagging chromosomes) thereby leading to a gradual loss of chromosomes over time [53,55]. Beside massive chromosomal losses, the mutational landscape of PCs showed mutations in genes such as NF1 , TSC1 , MEN1 , hTERT , PTEN , ARID1B , SETD2 and KDM5C . These mutations have been previously reported in APTs [56]. Among the three selected APTs, two exhibited massive chromosomal losses; however, only in one of these a mutation was detected ( NF1) , while no mutations were found in the other two. The by us first reported PC with a near-haploid genome/NHG was resected with tumor free margins and presented with distant metastasis 14 years after initial resection [33]. The currently presented two APTs with a near-haploid genome/NHG were resected with tumor free margins and did so far not show recurrence (follow up 4-5 years). Of all four now compiled PCs with a near-haploid genome/NHG three were metastatic, and one showed a single local recurrence with the initial resection showing tumor positive resection margins. Extensive chromosomal losses were also previously reported in a PA with no aggressive histological features, and in a PC [20,14]. Unfortunately, additional clinicopathological data could not be accessed. Numerous studies have established that chromosomal copy number variations are common in parathyroid neoplasia, with various attempts made to distinguish benign from malignant processes based on these alterations [11,57,58,12,13,22]. Our findings show that a considerable proportion of (oncocytic) PAs (8/14) had no detectable CNVs aligning with the literature. In this limited number of cases, a significantly higher pre-operative calcium levels were observed in patients with adenomas with chromosomal alterations, without significant differences in pre-operative PTH levels nor in tumor diameter. Significantly higher pre-operative serum calcium levels were observed in male patients with adenomas. Usually (healthy) women tend to have higher serum calcium levels, while in case of PA men reported to have similar or higher serum calcium levels [59,60]. PCs reported in the literature show variable, sometimes minimal and in up to 80% cases even no detectable chromosomal alterations while other authors report more extensive alterations. In detail, we observed LOH (among others) at chromosomes 13 and 1p in all three PCs which were previously reported as a distinguishing feature of PCs [51,22,9]. We found that two of three APTs also exhibit such alteration. The third APT exhibited imbalances due to copy number loss on chromosome 13 and tip of chromosome 1p what could be considered as a pre-LOH state. One of the oncocytic PA also showed loss on the tip of chromosome 1p. Chromosomal losses on chromosome 9, particularly 9p, are more indicative of carcinomas (observed in 3/3 PCs as LOH). The latter data comply with data of Kytola et al. [51] and Sulaiman et al. [22]. This alteration was also observed in all three of our APTs reinforcing the overlap of chromosomal alteration pattern between APTs and PCs. Indeed, no alterations on chromosome 9 were detected in any of the PAs. LOH on chromosome 17 was exclusively seen in PCs (3/3) and in APTs (2/3), further highlighting the similarity of PC and APTs, as previously noted by Agarwal et al [13]. Interestingly, the APT with the least alterations (no NHG) did not show alterations on this chromosome. In conclusion, we compiled CDC73 -wildtype APT and PC cases with remarkable massive chromosomal losses, a subsequent near-haploid genomes (with or without subsequent endoreduplication/genome doubling), as seen in oncocytic thyroid cancer, and other tumors, while this is not observed in oncocytic PAs. Identification of tumors with such remarkable characteristics should eventually lead to the elucidation of a common Achilles’ heel that can be therapeutically targeted in the future. Declarations ETHICS DECLARATIONS Ethics approval and consent Ethical review of the study was waived by the Medical Ethical Review Committee Leiden(W2020.048) and by Local Ethic Committee (CEAVNO - Comitato Etico Area Vasta Nord Ovest, Prot. n° 9989, Pisa 20/02/2019). The patients provided written informed consent for the pseudonymized use of their data. Funding The authors did not receive any financial support for the research, authorship, and/or publication of this article. Conflict of Interest There are no conflicts of interest to declare. CONTRIBUTIONS Conceptualization: Maaia M. Jentus, Filomena Cetani, Claudio Marcocci, Hans Morreau; Methodology: Maaia M. Jentus, Hans Morreau; Formal analysis and investigation: Maaia M. Jentus, Dina Ruano, Hans Morreau; Writing - original draft preparation: Maaia M. Jentus; Writing - review and editing: all authors. Funding acquisition: not applicable; Resources: Filomena Cetani, Marieke Snel, Femke M van Haalen, Natasha M Appelman-Dijkstra, Abbey Schepers, Stijn Crobach, Claudio Marcocci, Liborio Torregrossa; Supervision: Hans Morreau. DATA AVAILABILITY STATEMENT All data are available upon request from the corresponding author. Acknowledgments We want to acknowledge the team of the clinical molecular scientists in pathology of LUMC for support in performing the molecular tests. References Juhlin CC (2024) Not All Parafibromin Deficiency Relates to Parathyroid Carcinoma: The Role of Morphological Assessment. 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08:44:34","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":150883,"visible":true,"origin":"","legend":"","description":"","filename":"4128bc58cedc4ee1a193b4637a35d5861structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7834367/v1/a41b8c830329d38197cf0a47.xml"},{"id":93915334,"identity":"eeaafb72-9076-4c24-9c44-119014b36a38","added_by":"auto","created_at":"2025-10-20 08:44:34","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":166968,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7834367/v1/c8274525925126f6a5c5a60a.html"},{"id":93915320,"identity":"175ef1d1-c665-4239-81b9-b41a6ec3b37c","added_by":"auto","created_at":"2025-10-20 08:44:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":210605,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverview of the cohort with selected clinical characteristics of the patients, parathyroid tumor characteristics, including tumor types and Imbalance-LOH-CNV alterations per chromosomal arm.\u003c/strong\u003e Extrapolated genotypes are indicated, including the presence of a near haploid genome and the mutational landscape. Cases are sorted by dignity and by the number of disrupted chromosomes, from the least number to those mostly affected. Eight of thirteen oncocytic parathyroid adenomas show quiet genomes. The remaining five oncocytic parathyroid adenomas and one chief-cell parathyroid adenoma show limited chromosomal variations as depicted in the results. Two APTs and four PCs show massive chromosomal losses, leading to a near haploid genome with or without subsequent endoreduplication/genome doubling.\u003c/p\u003e\n\u003cp\u003e*previously reported patients [43]\u003c/p\u003e\n\u003cp\u003e**previously reported patient [33].\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7834367/v1/abba3344422885efb2695638.png"},{"id":93915325,"identity":"6872a462-d4d5-4573-ba94-2938163e975d","added_by":"auto","created_at":"2025-10-20 08:44:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":349265,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExample of Imbalance-LOH-CNV plots and comparison of APT1, APT3, APT10, and PC19 (A-D). \u003c/strong\u003eThe upper section of such analysis shows the coverage and performance of all 1500 SNPs used, the middle section represents the CN profiles and the lowest section depicting the allelic frequency for each SNP. Chromosome-wide genotypes were subsequently extrapolated.\u003c/p\u003e\n\u003cp\u003eA. APT1 shows relatively sparse chromosomal alteration in comparison with the other three depicted.\u003c/p\u003e\n\u003cp\u003eB. APT3 shows whole chromosome LOH due to copy number loss of chromosomes 1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 15, 17, 18, and 22. Chromosomes 5, 8, 14, 16, 19, 20, and 21 show a heterozygous state. There is only one chromosome X due to a male sex.\u003c/p\u003e\n\u003cp\u003eC. In APT10 extensive whole chromosomal losses with LOH are seen.\u003c/p\u003e\n\u003cp\u003eD. PC19 shows a comparable pattern of extensive whole chromosome losses, similar to APT3 and APT10.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7834367/v1/1f5b2b30d12a62d8c4382d5f.png"},{"id":93918215,"identity":"7779c502-3c30-40be-aa7e-4b5deb8bb16a","added_by":"auto","created_at":"2025-10-20 09:09:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1220569,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7834367/v1/51238f79-cea7-471f-b82c-4cfcfd571f4e.pdf"},{"id":93915322,"identity":"c07f5fe5-104f-419f-9f1a-1e0b59f7dd57","added_by":"auto","created_at":"2025-10-20 08:44:34","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":114480,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7834367/v1/8c601019e047c9f6cfed6cda.docx"},{"id":93916044,"identity":"d28e9cfe-34f2-418f-be96-5d1a7d18fc85","added_by":"auto","created_at":"2025-10-20 08:52:34","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10022,"visible":true,"origin":"","legend":"","description":"","filename":"Supportingdatavalues.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7834367/v1/d098bc3719804946da82f438.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Genome Near-Haploidization in CDC73-Wildtype Parathyroid Tumors","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe parathyroid glands play a crucial role in calcium homeostasis by tightly regulating the secretion of parathyroid hormone (PTH). Excessive PTH secretion leads to hypercalcemia, and when this occurs independently of physiological feedback mechanisms, it is referred to as autonomous hyperparathyroidism, which can be either primary or tertiary. Autonomous functioning parathyroid glands can exhibit hyperplastic, adenomatous, atypical, or even carcinomatous changes. Among the key genes involved in parathyroid tumorigenesis, \u003cem\u003eMEN1\u003c/em\u003e and \u003cem\u003eCDC73\u003c/em\u003e are the most prominently affected. Inactivating germline mutations in \u003cem\u003eMEN1\u003c/em\u003e and \u003cem\u003eCDC73\u003c/em\u003e lead to MEN1- and HPT-JT syndromes, respectively. The \u003cem\u003eCDC73\u003c/em\u003e gene encodes the parafibromin protein, loss of expression of parafibromin is seen in tumors with \u003cem\u003eCDC73\u003c/em\u003e biallelic inactivation. While \u003cem\u003eCDC73\u003c/em\u003e inactivation and/or parafibromin expression loss is commonly associated with both familial and sporadic parathyroid carcinoma (PC), these can also be seen in (cystic) parathyroid adenomas [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Loss of parafibromin expression and/or the presence of \u003cem\u003eCDC73\u003c/em\u003e mutations is/are associated with worse disease outcomes in PC and predict(s) aggressive behavior in atypical parathyroid tumors (APTs) [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eMEN1\u003c/em\u003e mutations are present in 11\u0026ndash;40% of sporadic PAs and rarely (\u0026le;\u0026thinsp;10%) observed in sporadic PCs. Other genetic events such as \u003cem\u003eCCND1\u003c/em\u003e amplification and/or mutations in less common genes can be seen in PC [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDiverse chromosomal copy number alterations in parathyroid lesions are widely reported in the literature and can be considered a hallmark of a subset of these lesions (Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e include CGH, WES, WGS or SNP-array studies with a genome-wide approach; Supplemental Table\u0026nbsp;1 includes studies with other methods). Distinct alteration patterns occur in parathyroid adenomas (PAs, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and PCs (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) [\u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGenome-wide studies of chromosomal alterations in parathyroid adenomas utilizing CGH, WES, WGS or SNP-arrays.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFindings\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAgarwal et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDeletions on chr. 11, 17 (n\u0026thinsp;=\u0026thinsp;5), and 22 (n\u0026thinsp;=\u0026thinsp;7). Complex pattern, predominance of losses. Every chr. was involved except chr. 8.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePalanisamy et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecurrent gains: chr. 16p (6/53) and 19p (5/53). Frequent losses chr. 11p (14/53), 11q (18/53), chr. 1p, 1q, 6q, 9p, 9q, 13q, and 15q (8\u0026ndash;19%).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFarnebo et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH and subsequent \u003cem\u003eMEN1\u003c/em\u003e analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 sporadic PA, in 10 previous head and neck irradiation, and 8 familial cases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eSporadic\u003c/span\u003e: minimal regions of loss on chr. 11 (38%), 15q (27%), and 1p (19%); gains of chr.19p (15%) and 7 (12%). \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eIrradiation-associated\u003c/span\u003e: frequent losses of chr.11q (50%), \u003cem\u003eMEN1\u003c/em\u003e mutations in 4 of 8 cases (50%). Losses of chr. 1p (50%), 11q (50%), 11p (40%), 6q (30%), 18q (30%), and 22q (30%); gain of chr. 19p (30%). \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eFamilial\u003c/span\u003e: few alterations, gain of chr. 19p as single aberration in 3 tumors. 10/14 PA with involvement of the \u003cem\u003eMEN1\u003c/em\u003e gene locus displayed loss of the entire chr. 11. Loss of chr. 15q in 5 PA.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHaven et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 PA (\u003cem\u003eCDC73\u003c/em\u003e mutation carriers)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo LOH at chr. 1q21\u0026ndash;32 observed. One PA: gain of chr. 16 and loss of chr. 13. Other PA: gains of chr. 1q and 17p.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDwight et al. [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH, LOH and \u003cem\u003eMEN1\u003c/em\u003e mutation analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 sporadic PA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12/13 PA had chromosomal alterations. Partial or total loss of chr. 11 in 4/13 PA. Loss of chr. 13q and whole chr. gain of chr. X in 3/14 PA each. 2/13 PA had losses of chr. 1q and 22q. Losses of chr. 2p, 5q14-q31, 15q and gains of chr. 3, 5, 6p, 7, and 14q were detected once each.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDwight et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 PA from 5 patients with sporadic multiglandular PHPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTumors of one patient had no alterations (3/10). 10 PA with chromosomal alteration. Different changes among PA of the same patient, seen in 2 patients. Another two patients with alterations only in one PA of two. Imbalances observed once: gains of chr. 5, 6, 7, 12, 16, 19p; losses of chr. losses 1p,15q, 18, 21q, 22q. Imbalances with losses observed twice: chr. 11, 12q, 13q. LOH observed at chr.11q13 (3/10) and 1p (1/10).\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGarcia et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 sporadic conventional PA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eChromosomal gains (14/14), losses (3/14). No genomic amplification was observed. One patient: whole chromosome gains of chr. 1, 6p, 7, 8, 9, 10, 12, 16, and whole chr. losses on chr. 11, 12, 13q, 19p. 13/14 PA exhibited\u0026thinsp;\u0026gt;\u0026thinsp;2 abnormalities. Imbalances with gain were observed 1x (chr. 2p, 3p, 7p, 7q, 8p, 10p, 15q, 16q, 19p, 21q, 22q), 2x (1p, 2q, 5q, 6p, 10q, 12q, 17q, 19q), 3x (1q, 3q, 6q, 9p, 9q, 13q, 14q, 18q, 20q) or 5x (chr. 4q and Xq). Whole chr. gain was observed 1x (chr. 1, 4, 7, 10, 12, 16 and X) and 3x (chr.8 and 9). Imbalances with losses observed 1x (chr. 6, 9pq, 13q, 15q, 18q, 19p, 20p) and 3x (chr. 11q). Whole chr. loss was observed 1x on chr.20 and 2x on. chr 11. No alterations detected on chr. 5p, 12p, 14p, 15p, 17p, 18p, 21p, 22p and Y.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYi et al. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH, FISH and TMAs for chr.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 Type I PA\u003c/p\u003e\u003cp\u003e9 Type II PA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCommon finding was deletion of the \u003cem\u003eMEN1\u003c/em\u003e locus or loss of a substantial portion or an entire chr. 11. Loss of 11q23 in slightly less than 50%. The least common finding: translocation of the CCND1 gene.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNewey et al. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLOH chr.11 (8/16), LOH chr.1, 15 and 18 (3/16), LOH chr. 22 (4/16), LOH chr.13 and 21 (2/16), LOH chr. 2, 3, 4, 5, 7, 8, 9, 10, 17, 19, and X (1/16). Not affected by LOH: chr. 5, 12, 14, 16 and 20.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCromer et al. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4/8 PA with a frame shift deletion or nonsense mutation in \u003cem\u003eMEN1\u003c/em\u003e, accompanied by LOH of the other allele. LOH observed once on chr. 1p, 9, 13, 21, 22. No LOH in 3/8 PA.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSulaiman et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH and SNP microarrays\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 PA, established \u003cem\u003eCDC73\u003c/em\u003e inactivating mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo significant alterations in 1/5 PA. Deletion of whole chr. 9 (1/5). Gain of entire chr. 16 (n\u0026thinsp;=\u0026thinsp;2), with gain of entire chr. 17 or 22. No significant aberrations on chr. 1, 11 or 13. Different loss pattern than in unselected tumors. The least extent of CNAs compared to APT and Ca.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eChr. chromosome(s), CGH comparative genome hybridization, FISH fluorescence in situ hybridization, HPT hyperparathyroidism, LOH loss of heterozygosity, PA parathyroid adenoma, SNP single nucleotide polymorphism, TMA tissue microarray, WES whole exome sequencing.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGenome-wide studies of chromosomal alterations in APT and PC utilizing CGH, WES, WGS or SNP-arrays.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eAPT\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFindings\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSulaiman et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH and SNP microarrays\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1, established \u003cem\u003eCDC73\u003c/em\u003e inactivating mutation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExtensive aberrations affecting almost all chr., large scale gains on chr. 1p, 16, 17, 19, 20 and 22 and loss of chr. 1p. No loss of \u003cem\u003eCDC73\u003c/em\u003e.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJha et al.[\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWES and \u003cem\u003eFLCN\u003c/em\u003e germline sequencing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1/3 with FLCN c.1285insC variant, no clear LOH was observed in the tumor, possibly due to normal DNA contamination.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFindings\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAgarwal et al.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFrequent losses on chr. 1p (4/10) and chr. 17 (3/10), and gains were on chr.5 (3/10). Chr. 2, 9, 10, and 21 were not altered.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHaven et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1, \u003cem\u003eCDC73\u003c/em\u003e mutation carrier\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLOH on chr.1q\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKyt\u0026ouml;l\u0026auml; et al. [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLosses of chr. 1p and 13q (\u0026gt;\u0026thinsp;40%), 9p (28%), 6q (24%), and 4q (21%). Gains of chr. 19p (45%), Xq (28%), 9q (24%), 1q (21%), and 16p (21%). A sex-dependent distribution for two common alterations with gain of 1q in females and of Xq in males.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSulaiman et al. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH and SNP microarrays\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3, with \u003cem\u003eCDC73\u003c/em\u003e inactivating mutations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGross losses of chr. 1p and 13 were associated (p\u0026thinsp;=\u0026thinsp;0.012) with parathyroid carcinomas as opposed to adenomas. Losses of chromosome 1p, 13, 14, 18 and gains of 1q, 5, 5q, 9, 10, 20, 22. None of the carcinomas exhibited loss on chr. 11. No losses spanning the \u003cem\u003eCDC73\u003c/em\u003e.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCosta-Guda et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSNP arrays and CGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 from 10 patients, 3 with germline \u003cem\u003eHPRT2\u003c/em\u003e mutation.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSNP analysis (9 patients) - gains detected once (chr. 3, 11, 11p, 11q, 12, 12p), twice (chr. 5 and 21), three (chr. 1q, 20) and five times (chr.16). Losses detected once (chr. 2, 2q, 4, 8, 8p, 9, 9p, 10, 11, 13q, 14q, 17, 21, 21q, 16p, 16q, 18q), twice (chr. 6, 12, 14 and 15) three (chr. 1p and 18), four (chr.3 and five times (chr.13). cnLOH detected on chr. 3, 1p, 22, 4, and 14.\u003c/p\u003e\u003cp\u003eCGH: gains detected once (chr. 5, 5q, 8, 12, 12p, 22), twice (chr. 16, 16p, 20, X) and three times (chr.1). Losses detected once (2q, 6, 12, 12p, 13, 14, 15q, 18, 21), twice (chr. 1p) three (chr. 13q) and four times (chr. 3). Recurrent tumors had partly different pattern than primaries. One of the tumors has shown no alterations in CGH while SNP array was positive. Results of SNP array and CGH were variable.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCorver et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGenome-wide SNP and flow cytometry DNA content analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNHG observed in 1 of 3 PCs, also the one lacking a \u003cem\u003eHPRT2/CDC73\u003c/em\u003e mutation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePandya et al. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWES\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRecurrent losses of chr.1p (n\u0026thinsp;=\u0026thinsp;8), 3 (n\u0026thinsp;=\u0026thinsp;3), and 13 (n\u0026thinsp;=\u0026thinsp;10) and gains of chr. 1q (n\u0026thinsp;=\u0026thinsp;6), 16 (n\u0026thinsp;=\u0026thinsp;9), and 20 (n\u0026thinsp;=\u0026thinsp;9). Focal recurrent gains 6p11.2, 7q22.1, 10q26.2 and 11q23.2 and losses 1p36.32, 3q29, 6q25.3 and 7p21.3. Detected gain of \u003cem\u003eCCND1\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;5), 4 of the 5 cases with no \u003cem\u003eCDC73\u003c/em\u003e mutation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJha et al. [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWES and Sanger sequencing, LOH on \u003cem\u003eFLCN\u003c/em\u003e and \u003cem\u003eTP53\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17, no germline \u003cem\u003eCDC73\u003c/em\u003e or \u003cem\u003eMEN1\u003c/em\u003e mutations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLOH on \u003cem\u003eFLCN\u003c/em\u003e in 2 of the 3 patients with germline heterozygous FLCN variants. LOH \u003cem\u003eTP53\u003c/em\u003e in metastases of one patient.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJentus et al. [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGenome-wide SNP array and broad somatic mutation analysis (NGS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2, \u003cem\u003eCDC73\u003c/em\u003e wildtype\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNear-haploid genome due to massive chromosomal losses in both tumors with LOH of chr. 1, 2, 3, 8, 10, 11, 12, 13, 15, 17, 18, and 22. Detected differences in the two cases were additional loss of chr. 6 and 9, and somatic \u003cem\u003eMEN1\u003c/em\u003e mutation in one tumor. Another tumor showed loss of chr. 4 and 21, and no \u003cem\u003eMEN1\u003c/em\u003e mutations were detected.\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eAPT atypical parathyroid tumor, chr. chromosome(s), CGH comparative genome hybridization, FISH fluorescence in situ hybridization, LOH loss of heterozygosity, PC parathyroid carcinoma, SNP single nucleotide polymorphism, WES whole exome sequencing.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGenome-wide studies of chromosomal alterations in parathyroid hyperplasia utilizing CGH-arrays.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFindings\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImanishi et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH and genome-wide allelotyping\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e46 tumors from 28 uremic patients with refractory SHPT or THPT.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eEleven tumors (24%) demonstrated clonal chromosomal imbalances. Chromosomal gains were more commonly observed than chromosomal losses. Repeatedly observed gains on chr.7 (4/46), 12 (5/46), and a loss on chr.21 (2/46). Observed once: gains on chr. 1q, 2, 6q, 9p, 9q, 18, 22, X and losses on chr.11, 13q, 22.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAfonso et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] Full text not available.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePrimary and secondary hyperplasia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSubstantial number of chromosomal alterations in SHPT. Some of these alterations had been previously reported for PHPT, but the majority were in different regions or in different proportions.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYi et al. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH, FISH, and TMA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 tumors in nonfamilial hyperplasia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGenomic changes in PHPT were restricted to 11q13 deletion or loss of chr.11. In SHPT 11q23 deletion was common along with strong CCND1 expression.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDwight et al. [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCGH, LOH and \u003cem\u003eMEN1\u003c/em\u003e mutation analysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 parathyroid samples of 9 patients with lithium-associated HPT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLoss at 1p, 11, 15q, 22q and gain of the X chromosome (4/12). LOH at 11q13 and a somatic \u003cem\u003eMEN1\u003c/em\u003e mutation (c.1193insTAC) in one sample. Fewer genetic alterations than in the sporadic tumors, but the detected changes were similar with both familial and sporadic tumorigenesis. Higher prevalence of multiglandular disease in comparison with idiopathic sporadic patients.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eChr. chromosome(s), CGH comparative genome hybridization, FISH fluorescence in situ hybridization, HPT hyperparathyroidism, LOH loss of heterozygosity, SHPT secondary hyperparathyroidism, THPT tertiary hyperparathyroidism, TMA tissue microarray.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAlthough there is no consensus on which type of alteration predominates, PCs exhibit extensive genomic alterations. PAs typically display sparse chromosomal imbalances or LOH [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19 CR20 CR21\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In contrast, APTs (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) can exhibit a pattern similar to PCs, with extensive genome wide alterations with multiple LOH events which contribute to their potential aggressive biology [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eChromosomal imbalances and loss of heterozygosity (LOH) have also been observed in idiopathic primary and uremic secondary hyperplasia (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) [\u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30 CR31\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eBy comparing patterns, different researchers concluded the existence of independent genesis of PAs and PCs [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, only a few studies have utilized genome-wide SNP or WES/WGS analysis to describe the chromosomal alteration patterns in parathyroid neoplasia, with most relying on diverse polymorphic microsatellite marker analyses (Supplemental Table\u0026nbsp;1) or comparative genome hybridization (CGH) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Notably, Costa-Guda et al. performed both, CGH and SNP microarray (Affymetrix 50k) analyses on a small subset of parathyroid tumors, revealing different results that highlights the limitations of CGH [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. CGH is unable to detect allelic differences in cases of duplication of the remaining allele (copy neutral LOH) or the recognition and interpretation of endoreduplication/genome doubling events. Costa-Guda et al. found that loss of chromosome 11q was the most common event in PA but not a recurrent change in PC.\u003c/p\u003e\u003cp\u003eLittle is known about differences in chromosomal alteration patterns among the diverse histomorphological subtypes of parathyroid lesions, as reports typically focus on classifying diagnoses such as hyperplasia, PA, APT, or PC. Few studies mention specific histological subtypes [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Parathyroid lesions can exhibit variants based on the parathyroid cell types, such as transitional, oncocytic and clear cell, though they usually consist of chief cells [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. When oncocytic cells constitute more than 75% of the PA, it is referred to as an oncocytic subtype [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Chromosomal aberrations in this subtype are not well studied. Oncocytic PAs are reported to be more symptomatic, associated with higher preoperative calcium levels, and generally larger in size than other histological subtypes [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In oncocytic neoplasms of the neighboring thyroid, the chromosomal copy number alterations serve as a molecular and diagnostic hallmark [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The extent and pattern of these alterations, with sometimes massive chromosomal losses, can even distinguish between benign and malignant cases, guiding follow up discussions in cases with uncertain histology [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. \u003cem\u003eCDC73\u003c/em\u003e mutated parathyroid neoplasms are reported to exhibit an oncocytic morphology [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Additionally, sporadic PCs frequently (estimated 41\u0026ndash;80% cases) harbor inactivating \u003cem\u003eCDC73\u003c/em\u003e mutations with often LOH as a second hit [\u003cspan additionalcitationids=\"CR39 CR40\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. \u003cem\u003eCDC73-\u003c/em\u003emutated PCs are reported to show increased genomic instability with higher levels of copy number alterations [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePreviously, we described one oncocytic PC without a \u003cem\u003eCDC73\u003c/em\u003e mutation, showing massive whole chromosomal losses, genome near haploidization and subsequent genome endoreduplication/genome doubling [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The occurrence of near haploidization and subsequent endoreduplication/genome doubling was proven by the combined use SNP array and flow cytometry DNA content analysis with separation of lesional (cytokeratin positive) and stromal (vimentin positive) cell fractions. In the latter experiment the existence of near haploid and endoreduplicated cytokeratin positive cell subfractions could be shown. Recently, we reported two non-functional \u003cem\u003eCDC73\u003c/em\u003e-wildtype PCs with massive whole chromosomal losses and genome near haploidization [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. One of these latter PCs showed endoreduplication.\u003c/p\u003e\u003cp\u003eMassive chromosomal losses, genome-wide near-haploidization, and subsequent endoreduplication/genome doubling are observed in various rare tumor types at different frequencies. These tumor types include subsets of adrenal cortical cancers, chondrosarcomas, mesotheliomas, oncocytic thyroid carcinomas, gliomas and corticotroph pituitary neuroendocrine tumors (PitNETs) [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan additionalcitationids=\"CR45 CR46 CR47\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe wondered whether our previously identified PC cases with massive chromosomal losses were incidental findings as a relatively large series (n\u0026thinsp;=\u0026thinsp;17) of whole exome sequencing did not clearly reveal cases with similar massive whole chromosomal losses [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. As in thyroid neoplasia oncocytic metaplasia with concomitant complex I mitochondrial DNA mutations is highly associated with massive chromosomal loss, we selected a cohort of oncocytic PAs. Furthermore, we studied three APTs and one other PC, all \u003cem\u003eCDC73-\u003c/em\u003ewildtype.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eWe reviewed pseudo-anonymized pathology/clinical records of one previously and two recently described \u003cem\u003eCDC73\u003c/em\u003e wild type PCs with a near homozygous genome, with or without subsequent endoreduplication [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. We now also added one similar PC case. Furthermore, three \u003cem\u003eCDC73\u003c/em\u003e wild type APTs were added. Additionally, we added 14 PA cases (13 oncocytic) of which 13 were obtained from the Endocrine Unit (FC and CM) of the University of Pisa. All histopathological diagnoses were reviewed by endocrine pathologists (MJ and HM) in accordance with the WHO classification (5th edition, 2022) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. All cases originated from patients with sporadic parathyroid disease. The patients provided written informed consent for the pseudonymized use of their data. For details, see \u0026ldquo;Ethics approval and consent\u0026rdquo;.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eMolecular analysis\u003c/h2\u003e\u003cp\u003eAll cases were analyzed with genome wide SNP analysis using a custom made and routinely used SNP panel comprising 1500 SNPs \u003cb\u003e(\u003c/b\u003eCNV-Imbalance-LOH analysis) and conducted as previously described [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Selected cases were accompanied by somatic mutation analysis using diverse NGS panels (OCAplus, RCPL, ENDO32; details are available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.palga.nl/voor-pathologen/moleculaire-bepaling\u003c/span\u003e\u003cspan address=\"https://www.palga.nl/voor-pathologen/moleculaire-bepaling\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e under LUMC). Molecular analyses were performed in the Molecular Diagnostics Unit of the Pathology department (ISO15189 accredited) at the Leiden University Medical Center (LUMC). For molecular testing, total nucleic acid was isolated from formalin-fixed paraffin-embedded (FFPE) tissue after micro-dissection of serial hematoxylin-stained sections and selection of tumor tissue on basis of hematoxylin and eosin-stained diagnostic slides. When tumor cell percentage is sufficiently high (mostly the case in parathyroid neoplasia) imbalances and LOH are identified from the SNP frequency patterns. Imbalances are then characterized by smaller amplitude changes when compared with LOH. Copy number detection by CNV analysis helps to explain the mechanism behind the imbalances/LOH observed, being either chromosomal gains or losses. Subsequently, genotypes were extrapolated. For example, see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The patterns observed across the patient cohort were scored and the alterations counted.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eDue to the limited number of the patients included in the study, there was insufficient statistical power to conduct robust inferential statistical analyses. The study primarily relied on descriptive statistical methods to analyze the data. All statistical analyses were performed using Prism 10.2.3 (GraphPad Software, Inc.). Where applicable, quantitative parameters are presented with minimum, maximum, median, and mean along with standard deviation (SD). Normality was assessed with Kolmogorov-Smirnov and Shapiro-Wilks tests. Unpaired t-tests were used for comparison of two groups in normally distributed variables. The Fisher\u0026rsquo;s exact test was utilized for contingency analysis. A significance level of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eAn overview of all cases discussed in the current study is depicted in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. In total, tumors of 21 patients were included: 14 PAs (13 oncocytic), three APTs, and four PCs, the latter 7 proven to be \u003cem\u003eCDC73\u003c/em\u003e mutation negative. Ten patients were male and 11 were female, in age range of 38\u0026ndash;78 years (mean 61.29 SD 10.4 years, median 61.0). Three PCs were published previously but added for comparison [\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003ePAs\u003c/h3\u003e\n\u003cp\u003eThe 14 PA patients consisted of 7 female and 7 male patients. The female patients were significantly older (p\u0026thinsp;=\u0026thinsp;0.0361) with a mean of 66.86 years (range 42\u0026ndash;78, SD 8.92) versus mean 54.71 years (range 38\u0026ndash;66, SD 10.29) of male patients. Male patients had significantly higher pre-operative serum calcium levels (p\u0026thinsp;=\u0026thinsp;0.02) while there was no significant difference in serum PTH levels (p\u0026thinsp;=\u0026thinsp;0.3). Thirteen of 14 PAs were oncocytic. Eight oncocytic PAs did not show chromosomal alterations. In the remaining 6 PAs a limited and variable number of events were seen. Four out of these 6 PA showed either chromosomal losses or gains, while two PAs (PA11 and PA17) had mixed alterations. Oncocytic PA17 showed imbalance of whole chromosome 8 due to copy number gain (genotype AAB or ABB), LOH (with whole chromosome loss, of chromosome 22 (extrapolated genotype A0 or B0) and gain of whole chromosome X (homozygous state, genotype AA or BB, in a male patient). The latter was also observed in oncocytic PA of male patient 6, which harbored gain of whole chromosome X (genotype AA or BB), LOH with whole chromosome loss (genotype A0 or B0) of chr. 22 and copy neutral LOH of chromosomes 20 and 21 (genotype AA or BB).\u003c/p\u003e\n\u003cp\u003eOncocytic PA13 showed imbalances of chromosomes 5 and 14 due to copy number gain (genotypes AAB or ABB) and a balanced gain of chromosome 13 (whole chromosome gain, genotype AABB). Chief cell PA11 showed mixed pattern of imbalances with copy number gain on chromosome 8 (genotype AAB or ABB) and copy number loss on chromosomes 11 and 18 (genotypes A0 or A0). Oncocytic PA7 only showed imbalance of chromosome 11 due to copy no loss (genotype A0 or B0). Oncocytic PA15 showed imbalances due to chromosomal loss (genotype A0 or B0) on chromosomes 1 (tips), 7p, 11p, 18p, and 20q.\u003c/p\u003e\n\u003cp\u003eTo investigate severity of hyperparathyroidism, we compared PTH and calcium serum values in chromosomal altered adenomas (n\u0026thinsp;=\u0026thinsp;6, group 1) and those without chromosomal alterations (n\u0026thinsp;=\u0026thinsp;8, group 2). For two patients pre-operative PTH values were not available (patients 8 and 18, both from group 2). There was no significant difference in PTH serum levels (pmol/L) between the groups (p\u0026thinsp;=\u0026thinsp;0.2, group 1 mean 33.82; range 11.5\u0026ndash;70.0; SD 20.61; group 2 mean 20.48; range 6.9\u0026ndash;44.0; SD 12.41). Surprisingly, there was a significant difference in serum calcium levels (mmol/L) between the groups (p\u0026thinsp;=\u0026thinsp;0.01, group 1 mean 2.98; range 2.77\u0026ndash;3.22; SD 0.17; group 2 mean 2.7; range 2.5\u0026ndash;2.9; SD 0.13), where patients of group 1 had significantly higher levels of serum calcium. In the two groups there was no significant difference in tumor diameter (p\u0026thinsp;=\u0026thinsp;0.3) nor sex predilection (p\u0026thinsp;=\u0026thinsp;0.6).\u003c/p\u003e\n\u003ch3\u003eAPTs and PCs\u003c/h3\u003e\n\u003cp\u003eChief cell APT1 showed imbalances due to copy number loss of chromosomes 1, 9p, 12q, 13 and 20p (genotypes A0 or B0) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). In contrast chief cell APT3 and oncocytic APT10 showed massive chromosomal losses (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Unambiguous endoreduplication/genome doubling of APT3 and APT10 was not concluded Novel \u003cem\u003eCDC73\u003c/em\u003e-wildtype PC19 also showed massive chromosomal losses without subsequent endoreduplication/genome doubling. Such genomic characteristics were similarly seen in the previously and recently described \u003cem\u003eCDC73\u003c/em\u003e-wildtype PC4, P20 and PC21, respectively, with subsequent endoreduplication/genome doubling seen in PC20 and PC21 (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). In PC19 somatic mutations were found in \u003cem\u003eNF1\u003c/em\u003e and \u003cem\u003eTSC1\u003c/em\u003e, with APT10 also carrying a \u003cem\u003eNF1\u003c/em\u003e mutation. \u003cem\u003eMEN1-\u003c/em\u003e, \u003cem\u003ehTERT-\u003c/em\u003e (PC4) mutations were previously found in PC4 and \u003cem\u003ePTEN\u003c/em\u003e, \u003cem\u003eARID1B\u003c/em\u003e, \u003cem\u003eSETD2\u003c/em\u003e, \u003cem\u003eKDM5C\u003c/em\u003e in PC20 [\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e]. Remaining APT1 \u0026amp; 3 did not show mutations with the tests used.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003ePreviously, we reported one PC with massive chromosomal losses, leading to a near-haploid genome. Subsequent endoreduplication/genome doubling led to a near homozygous genome (NHG). More recently we added two non-functional PCs with similar features [33,43]. In the current study we added three additional parathyroid tumors (2 APTs and one PC) with near-haploidy. All APTs and PCs with near-haploidy and/or NHG were \u003cem\u003eCDC73\u003c/em\u003e-wildtype, whereas inactivation of \u003cem\u003eCDC73\u003c/em\u003e is quite common in these lesions. In the existing literature, recently also comprising whole exome and whole genome analysis, no similar cases with massive chromosomal loss, a subsequent near-haploid genome with or without subsequent endoreduplication/genome doubling, were identified [9,42,50,49]. The absence of similar cases in the literature might thus be explained by the enrichment of \u003cem\u003eCDC73-\u003c/em\u003emutant PC in such studies. Sometimes Comparative Genomic Hybridization was used, a technique in which a near haploid genome with endoreduplication cannot fully be seen\u0026nbsp;[51]. Genome near haploidization is seen in subsets of other tumor types like oncocytic thyroid cancer, chondrosarcomas, adrenal cortical cancers, mesotheliomas, gliomas, and corticotroph PitNETs\u0026nbsp;[37,33,44-48].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe identification near-haploidization has so far not led to successful novel therapies. In oncocytic neoplasms of the thyroid the extent and patterns of chromosomal abnormalities can however distinguish hyperplasia, oncocytic adenomas and oncocytic carcinomas in preoperative cytological material thereby directing subsequent surgical interventions [37,52]. As said, in thyroid neoplasms genome near haploidization is associated with oncocytic features. Oncocytic metaplasia in these tumors is the reflection of the proliferation of abnormal mitochondria in the cytoplasm of the tumor cells. Furthermore, in oncocytic thyroid cancer enrichment of complex I mitochondrial DNA mutations is seen and/or complex I abnormalities at the protein level [53,54].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the current cohort of parathyroid neoplasia, no or few chromosomal abnormalities were seen in oncocytic PAs and of the more advanced lesions only one APT showed an oncocytic morphology. Thus, the underlying biology leading to massive chromosomal loss might be different in diverse tumor types. In oncocytic thyroid cancer the aberrant production of reactive oxygen species is thought to be an important factor in misalignment of chromosomes during the cell cycle (lagging chromosomes) thereby leading to a gradual loss of chromosomes over time [53,55].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBeside massive chromosomal losses, the mutational landscape of PCs showed mutations in genes such as \u003cem\u003eNF1\u003c/em\u003e, \u003cem\u003eTSC1\u003c/em\u003e, \u003cem\u003eMEN1\u003c/em\u003e, \u003cem\u003ehTERT\u003c/em\u003e, \u003cem\u003ePTEN\u003c/em\u003e, \u003cem\u003eARID1B\u003c/em\u003e, \u003cem\u003eSETD2\u003c/em\u003e and \u003cem\u003eKDM5C\u003c/em\u003e. These mutations have been previously reported in APTs [56]. Among the three selected APTs, two exhibited massive chromosomal losses; however, only in one of these a mutation was detected (\u003cem\u003eNF1)\u003c/em\u003e, while no mutations were found in the other two. The by us first reported PC with a near-haploid genome/NHG was resected with tumor free margins and presented with distant metastasis 14 years after initial resection [33]. The currently presented two APTs with a near-haploid genome/NHG were resected with tumor free margins and did so far not show recurrence (follow up 4-5 years). Of all four now compiled PCs with a near-haploid genome/NHG three were metastatic, and one showed a single local recurrence with the initial resection showing tumor positive resection margins. Extensive chromosomal losses were also previously reported in a PA with no aggressive histological features, and in a PC [20,14]. Unfortunately, additional clinicopathological data could not be accessed.\u003c/p\u003e\n\u003cp\u003eNumerous studies have established that chromosomal copy number variations are common in parathyroid neoplasia, with various attempts made to distinguish benign from malignant processes based on these alterations [11,57,58,12,13,22]. Our findings show that a considerable proportion of (oncocytic) PAs (8/14) had no detectable CNVs aligning with the literature. In this limited number of cases, a significantly higher pre-operative calcium levels were observed in patients with adenomas with chromosomal alterations, without significant differences in pre-operative PTH levels nor in tumor diameter. Significantly higher pre-operative serum calcium levels were observed in male patients with adenomas. Usually (healthy) women tend to have higher serum calcium levels, while in case of PA men reported to have similar or higher serum calcium levels [59,60]. PCs reported in the literature show variable, sometimes minimal and in up to 80% cases even no detectable chromosomal alterations while other authors report more extensive alterations. In detail, we observed LOH (among others) at chromosomes 13 and 1p in all three PCs which were previously reported as a distinguishing feature of PCs [51,22,9]. We found that two of three APTs also exhibit such alteration. The third APT exhibited imbalances due to copy number loss on chromosome 13 and tip of chromosome 1p what could be considered as a pre-LOH state. One of the oncocytic PA also showed loss on the tip of chromosome 1p. Chromosomal losses on chromosome 9, particularly 9p, are more indicative of carcinomas (observed in 3/3 PCs as LOH). The latter data comply with data of Kytola et al. [51] and Sulaiman et al. [22]. This alteration was also observed in all three of our APTs reinforcing the overlap of chromosomal alteration pattern between APTs and PCs. Indeed, no alterations on chromosome 9 were detected in any of the PAs. LOH on chromosome 17 was exclusively seen in PCs (3/3) and in APTs (2/3), further highlighting the similarity of PC and APTs, as previously noted by Agarwal et al [13]. Interestingly, the APT with the least alterations (no NHG) did not show alterations on this chromosome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, we compiled \u003cem\u003eCDC73\u003c/em\u003e-wildtype APT and PC cases with remarkable massive chromosomal losses, a subsequent near-haploid genomes (with or without subsequent endoreduplication/genome doubling), as seen in oncocytic thyroid cancer, and other tumors, while this is not observed in oncocytic PAs. Identification of tumors with such remarkable characteristics should eventually lead to the elucidation of a common \u003cem\u003eAchilles’ heel\u003c/em\u003e that can be therapeutically targeted in the future.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICS DECLARATIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical review of the study was waived by the Medical Ethical Review Committee Leiden(W2020.048) and by Local Ethic Committee (CEAVNO - Comitato Etico Area Vasta Nord Ovest, Prot. n\u0026deg; 9989, Pisa 20/02/2019).\u0026nbsp;The patients provided written informed consent for the pseudonymized use of their data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive any financial support for the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Maaia M. Jentus,\u0026nbsp;Filomena Cetani, Claudio Marcocci, Hans Morreau; Methodology: Maaia M. Jentus, Hans Morreau; Formal analysis and investigation: Maaia M. Jentus, Dina Ruano, Hans Morreau; Writing - original draft preparation: Maaia M. Jentus; Writing - review and editing: all authors. Funding acquisition: not applicable; Resources:\u0026nbsp;Filomena Cetani, Marieke Snel, Femke M van Haalen,\u0026nbsp;Natasha M Appelman-Dijkstra,\u0026nbsp;Abbey Schepers, Stijn Crobach, Claudio Marcocci,\u0026nbsp;Liborio Torregrossa; Supervision: Hans Morreau.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are available upon request from the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe want to acknowledge the team of the clinical molecular scientists in pathology of LUMC for support in performing the molecular tests. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eJuhlin CC (2024) Not All Parafibromin Deficiency Relates to Parathyroid Carcinoma: The Role of Morphological Assessment. 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Scientific Reports 13(1):8310. https://doi.org/10.1038/s41598-023-34800-w\u003c/li\u003e\n \u003cli\u003eYavropoulou MP, Anastasilakis AD, Panagiotakou A, Kassi E, Makras P (2020) Gender Predilection in Sporadic Parathyroid Adenomas. Int J Mol Sci 21(8). https://doi.org/10.3390/ijms21082964\u003c/li\u003e\n \u003cli\u003eDwight T, Kyt\u0026ouml;l\u0026auml; S, Teh BT, Theodosopoulos G, Richardson AL, Philips J, Twigg S, Delbridge L, Marsh DJ, Nelson AE, Larsson C, Robinson BG (2002) Genetic analysis of lithium-associated parathyroid tumors. Eur J Endocrinol 146(5):619-627. https://doi.org/10.1530/eje.0.1460619\u003c/li\u003e\n \u003cli\u003eJha S, Welch J, Tora R, Lack J, Warner A, Del Rivero J, Sadowski SM, Nilubol N, Schmidt LS, Linehan WM, Weinstein LS, Simonds WF, Agarwal SK (2023) Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors. J Clin Endocrinol Metab 108(10):2686-2698. https://doi.org/10.1210/clinem/dgad136\u003cstrong\u003e\u003cbr\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"parathyroid carcinoma, parathyroid, whole chromosome loss, molecular analysis, endocrine pathology, parathyroid neoplasia, rare cancer","lastPublishedDoi":"10.21203/rs.3.rs-7834367/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7834367/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRecurring parathyroid carcinoma (PC) is foremost associated with germline or somatic \u003cem\u003eCDC73 \u003c/em\u003emutations. We reported three PCs without \u003cem\u003eCDC73\u003c/em\u003e mutations, with massive chromosomal losses, genome near-haploidization with or without endoreduplication/genome doubling. These are characteristic features seen in rare tumor types like oncocytic thyroid carcinoma. We investigated whether similar genomic alterations occur in other parathyroid tumors. We selectively analyzed fourteen parathyroid adenomas (PA, thirteen oncocytic), three atypical parathyroid tumors (APTs, one oncocytic), and one PC, the latter four all negative for \u003cem\u003eCDC73\u003c/em\u003emutations. Histopathological diagnoses were reviewed according to the WHO classification 2022. All tumors underwent genome-wide SNP array testing with analysis of chromosomal copy number variations (CNVs), imbalances/loss of heterozygosity (LOH). The APTs and PC underwent somatic mutation analysis.\u003c/p\u003e\n\u003cp\u003eOncocytic PAs exhibited relatively stable genomes with no or minimal chromosomal alterations. Patients with chromosomally altered PA had significantly higher pre-operative serum calcium levels. In contrast, we identified two APTs and one other PC with massive chromosomal losses and genome near-haploidization. Our findings expand the spectrum of chromosomal near-haploidization in APTs and PCs lacking \u003cem\u003eCDC73 \u003c/em\u003emutations.\u003c/p\u003e","manuscriptTitle":"Genome Near-Haploidization in CDC73-Wildtype Parathyroid Tumors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-20 08:44:29","doi":"10.21203/rs.3.rs-7834367/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-22T07:18:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-20T20:15:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-06T08:54:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"299507104233180781781338444414755008818","date":"2026-04-02T12:34:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"190822592594815722768437932990961112776","date":"2026-04-01T17:40:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-28T13:14:42+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-26T18:02:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"31280458908600824047976180623667859239","date":"2026-02-24T09:05:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"156071239704462134693721631057062059697","date":"2026-02-19T16:51:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66241635668634949531351130240793699467","date":"2026-02-19T09:19:49+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-17T08:57:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-10T11:20:45+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-20T09:57:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-16T17:10:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-10-16T17:06:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d0a771a4-d90b-4288-ab62-ffa4b6d9abce","owner":[],"postedDate":"October 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56508925,"name":"Biological sciences/Cancer"},{"id":56508926,"name":"Biological sciences/Genetics"},{"id":56508927,"name":"Biological sciences/Molecular biology"},{"id":56508928,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-05-08T06:25:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-20 08:44:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7834367","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7834367","identity":"rs-7834367","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}