The relationship between the gain of X chromosome, the loss of Y chromosome and Trisomy 7 in Grade 4 Astrocytoma Tumours

The relationship between the gain of X chromosome, the loss of Y chromosome and Trisomy 7 in Grade 4 Astrocytoma Tumours | 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 Case Report The relationship between the gain of X chromosome, the loss of Y chromosome and Trisomy 7 in Grade 4 Astrocytoma Tumours Priya Kadam, Irrum Aneela, Mr Chandrasekaran Kaliaperumal This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6558589/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A male in his early twenties, who was usually fit and well, underwent a biopsy of a brain tumour (WHO Grade 4 Astrocytoma) that revealed an XX biological sex chromosome pattern rather than the expected XY. The patient identified as male, denied prior hormonal treatment for gender reassignment and had no female sexual characteristics. The patient had a partial debulking of a large midline frontal tumour with Neurosurgery and was referred to Oncology. Further microarray genetics revealed a trisomy 7 pattern, which may be associated with mosaicism of sex chromosomes in brain tissue, including the loss of Y or gain of X. Interestingly, a ‘gain of X’ has not been explored as readily as the loss of Y alongside trisomy 7 and in the context of astrocytoma. We discuss the aetiopathogenesis, genetics and management of this rarity. The purpose of this article is to discuss the Loss of Y and gain of X in association with trisomy 7 and its relevance to an intracerebral tumour (Astrocytoma- WHO Grade 4) ( 29 ). Trisomy 7 Mosaicism Astrocytoma Loss of Y gain of X Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Gliomas comprise nearly one-third of newly diagnosed brain tumours in adolescents and young adults ( 1 ). Anaplastic Astrocytoma and glioblastoma present with a high rate of recurrence and poor prognosis, with an average life expectancy of 14 to 16 months ( 2 ). Although some risk factors for developing glioma such as ionizing radiation and genetic syndromes (Neurofibromatosis type I, Lynch syndrome and Li-Fraumeni) have been identified, no one cause of tumour emergence is known ( 3 ). The pathogenesis of glioma has been linked to deregulation of major signalling pathways including 1p/19q deletion and the cyclin -dependent kinase inhibitor 2A (p16) gene ( 4 ). Mutations in tumour suppressor genes such as p53 and Neurofibromatosis type 1 are also heavily involved ( 4 ). Identification of specific tumour markers such as IDH1 and 1p/19q deletion, through cellular analysis can inform prognosis and management. Astrocytoma tumour cells are influenced by hormonal changes in the body, including upregulation in oestrogen receptor signalling. Oestrogens can bind to nuclear or membrane receptors and potentially stimulate many different interconnected signalling pathways, leading to complex cascades and potential tumour growth ( 3 ). The hormone sensitive astrocytoma tissue may be linked with changes in X chromosome expression, although studies are inconclusive. Genetic background: Mosaicism Mosaicism, changes within the chromosomal composition of cells, occurs in both healthy and malignant brain tissues. Tumour cells are more vulnerable to changes in their cellular composition, owing to mutations affecting growth, for example mutations p53 and braf ( 4 ). Changes in tumour cellular composition may involve alterations in the biological sex chromosomes, X and Y. The loss of both Y and X chromosomes have been found in astrocytoma tumour cells, but rarely reported as a ‘loss of Y and/or gain of X’. Loss of Y Loss of Y (LOY) has been thought of as both a natural karyotype for ageing and a vector for pro cancerous growth ( 14 ). The presence of Y may infer protective cellular effect, as its loss correlates with general genome wide instability for pro-oncogenesis. LOY is particularly prevalent in patients with renal carcinomas and rarely found in gliomas ( 14 ). LOY specifically is associated with poorer prognosis in male patients with glioblastoma, specifically if there is an absence of SRY gene ( 5 ). LOY also associated with dysregulation of T cells in prostate cancer, which may cause immunosuppression ( 24 ). Gain of X Gain of X chromosome has been found in cancerous cells, but again not readily in the glioma cell line. The gain of X is associated with oncogenesis, but it is unclear if this is found in female cells rather than male. Similarly to the LOY mosaicism being the most common clonal mosaicism ( 6 ), X mosaicism is also common and increases with age ( 13 ). Substantial numbers of adult cells possess these chromosomal alterations, which have been postulated to occur due to the lack of regulation in cellular protective mechanisms as age increases. Trisomy 7 Trisomy 7 is a common finding in tumours, both benign and malignant owing to its irregularities in mitotic processes. Trisomy 7 is also found in non-cancerous diseases such as rheumatoid and osteoarthritis ( 26 ). The most commonly amplified gene in glioblastomas is the gene coding for the EGFR on chromosome 7 , correlating with trisomy 7 in glioblastomas ( 27 ). The most common chromosomal abnormality in diffuse astrocytoma of WHO grade II is trisomy 7 ( 24 ). Research infers that the cells having loss of one sex chromosome or trisomy 7 have a proliferative advantage ( 19 ). Trisomy 7 correlates with shorter survival of astrocytoma grade II patients, therefore establishing the presence of the marker early is important for prognosis ( 25 ). Trisomy 7 correlates with Loss of Y chromosome in neoplasms of the renal cortex, and with cancer mutations in MET proto- oncogene. Case presentation A 23-year-old fit and well Asian gentleman presented to A + E with an episode of collapse. He had been experiencing headaches and three weeks of visual disturbance in the left eye, loss of appetite and vomiting in the lead up to the collapse. An MRI head was performed and demonstrated a midline frontal space occupying lesion with a cyst extending posteriorly compressing the lateral ventricles causing hydrocephalus (Fig. 1 ). An MRI post contrast confirmed a large heterogenous midline tumour of the frontal lobe. Examination revealed no focal neurological deficits. Following a multi-disciplinary oncology meeting, he underwent a neuro-navigation guided bifrontal craniotomy and a partial debulking of the large midline frontal tumour in addition to an insertion of a frontal ventricular assisted device. The biopsy of the tumour revealed an undifferentiated cell with high grade features, which was confirmed as a WHO Grade 4 Astrocytoma upon histology. Molecular analysis of the tumour was performed as a part of the histopathology for characterisation and to guide further management. Histopathology: Molecular and Cellular The patient’s blood sample analysis demonstrated a male pattern represented by ten X chromosome specific markers, Y chromosome specific SRY, AMEL alleles and DYS448 markers. Microarray investigation of the DNA from the astrocytoma cells found a complex picture, including XX chromosomes, gain and loss of function mutations and trisomy 7. An overall diagnosis of astrocytoma, Isocitrate dehydrogenase (IDH) mutant, CNS WHO grade 4; MGMT-methylated (26.7%) was made. Literature review of molecular analysis: Although there was a loss of Y found in the tumour cells, the SRY gene was present in blood markers. Literature suggests that if SRY gene was absent , this would lead to a poorer prognosis ( 5 ) which is not applicable in this case. The pro-oncogene TP53 is more frequently mutated in LOY tumours, which is a possibility for one of the astrocytoma growth pathways. Similarly, this astrocytoma with IDH mutant status and 1p/19q codeletion is associated with a p53 mutation ( 9 ). Overall, MGMT- Methylated astrocytoma taken together with the IDH-1 mutant result, alongside age < 50 and good resection margin in surgery, is a favourable prognosis. Radiotherapy and chemotherapy are likely to be offered as next steps in management ( 2 , 8 , 9 ). One study found favourable prognostic value of IDH1 mutation and MGMT methylation in patients with anaplastic astrocytoma treated with Radiotherapy plus concomitant and adjuvant Temzolomide ( 28 ). Interestingly, IDH wildtype GBM has high frequency chromosome 7 gain due to increase in tyrosine kinases signalling (MET gain and BRAF gain) and loss of cell cycle inhibitors compared with IDH mutated ( 11 ). However, our case was a IDH mutated type. Management: This gentleman received chemoradiotherapy 6000 cGY in 30 fractions over a 6-week period with Temzolomide, along with Dexamethasone. He was followed up by the Neuro- Oncology team and remained well during this period. Follow up: Following his treatment, MRI scans demonstrated stable appearances of his tumour and response to adjuvant chemoradiotherapy. During this time, he was clinically stable with good cognitive function. MRI head T1 post contrast demonstrated good resection margins of astrocytoma (Figs. 2 and 3 ). Sadly the patient died less than one year on following surgery and completion of chemotherapy. Discussion Mosaicism of sex chromosomes in Astrocytoma have not been studied as readily as in other forms of cancer. Abnormalities in X and Y are varied and may or may not lead to cancerous growth through alternative molecular and cellular pathways. Evidence suggests that sex chromosomes undergo mosaic events more often than autosomes ( 13 ). It is likely that different phenotypes are linked with different patterns of X mosaicism. Chromosomal abnormalities may not be limited to gain of a full X chromosome, as gain of X chromosome arms alone have been associated with cancers ( 8 ). Higher prevalence of chromosome arm aneuploidy was found in lower grade astrocytoma recurrence, compared with higher grade astrocytoma ( 9 ). High frequency gains of one arm of X have been associated with hepatoblastoma, whilst extra X have been found in acute lymphoblastic leukaemia ( 8 ). Contrary to previous thought, gain of X may not be associated with cancerous growth. Tumour cells are known to have differences in their chromosomal markers and cellular composition, and we may question whether the gain of X is purely an anomaly and not associated with neoplastic change ( 10 ). In females, one X chromosome is naturally silenced ( 12 ) to compensate for dosage differences between the sexes as males carry only one X ( 18 ). In this case, gain of X may be acquired in an inactive form and not have an influence on tumour growth ( 13 ). Overriding X silencing, even in male cancer can lead to oncogenesis ( 12 ). Specifically, this overriding is proposed to lead to glioma development through loss of regulation of the Xist (RNA X-inactive specific transcript gene) due to abnormalities ( 15 ). Literature does not elude to the conclusion that a ‘loss of y means a ‘gain of X’, in the context of Astrocytoma and trisomy 7. Although gain of X and LOY are involved in the evolution of cancer, they are separate processes. Absence of Y leads to genomic instability and potential vulnerability to cancerous growth ( 14 ), whereas gain of X is usually associated with upregulation of oncogenesis. It is important to note that these findings have not been demonstrated in Astrocytoma these tumour cohort have not been included in LOY studies due to the low proportions of LOY ( 14 ). Research also suggests that the XX clones in malignant gliomas from men are the consequence of LOY with X isodisomy, a non-random sequence of sex chromosome changes ( 10 ). These sex chromosome changes have an impact on brain anatomy and development of intellectual disorders ( 16 ). Furthermore, X isodisomy may unmask recessive diseases by allowing transmission of two affected gene copies from a heterozygous parent carrier ( 17 ). It may be plausible that the gain of X could be associated with isodisomy, though this is unclear at present. Astrocytoma and hormones Astrocytoma are known as a hormone sensitive tumour, but interestingly as astrocytoma increase in grade, the prevalence of oestrogen receptors decrease. Oestrogen receptor expression may be unrelated to upregulation of oncogenesis, and the relationship of oestrogen and cellular growth may be more complex than originally thought ( 30 ). Trisomy 7 Glioma frequently exhibit trisomy 7 ( 19 ) and gain of 7q early in the astrocytoma development in adult patients has been proposed ( 22 ). Literature suggests that the combination of trisomy 7 and loss of gonosomes in glioma is not a neoplastic specific finding, but instead represents the affinity for brain tissue to acquire and lose chromosomes ( 20 ). Similarly, when aneuploidy of autosome 7 and sex chromosomes were studied in glioblastoma using FISH, researchers found that chromosomal abnormalities do not appear to be characteristic of a glioblastoma subtype ( 21 ). Conversely, studies looking at chromosome centromere probes suggest that there is a complex chromosome pattern of aberrations in astrocytoma ( 23 ) which may affect biological processes. There are fewer studies examining WHO-grade 4 Astrocytoma specifically, and fewer still looking at the relationship between gain of X and trisomy 7. Conclusion WHO grade 4 Astrocytoma with a cellular composition XX in a biological XY young male is a rarity and has not been reported before in a young fit and well male previously. LOY increases with age and is underreported in Astrocytoma. The functional consequence of chromosomal mosaicism remains to be determined. LOY and gain of X are suggested to be separate rather than simultaneous processes. Both Loss of Y and gain of X can lead to pro-oncogenesis, akin to two sides of the same coin. Further research is required to investigate the incidence of gain of X in astrocytoma tumour, and indeed if X gain may be active in the oncogenic process or ‘inactive bystander in this Chromosomal business’. Learning points Abnormalities in biological sex chromosomes X and Y may occur in Astrocytoma and be distinct to the biological sex of the individual found in a blood test. There is more than one mechanism for cellular cancerous growth, and the Y chromosome may infer protection from oncogenesis and therefore a loss of Y favours mutation whereas a gain of X chromosome favours oncogenesis on the other hand ( Fig. 4 ). From a clinical perspective, having specifics of tumour markers may be useful for discussion with genetics teams and contribute to a prognosis. Abbreviations LOY – Loss of Y chromosome. MGMT- O-6-methylguanine -DNA methyltransferase enzyme. Methylation of MGMT- Silences transcription of the MGMT enzyme which would repair DNA damage. P53 – P 53 mutation, pro-oncogenesis. Trisomy 7 – Three copies of chromosome 7. XIST- X- Inactive specific transcript Hepatoblastoma- A rare form of liver cancer, the majority affecting young children. Acute lymphoblastic leukaemia – a type of blood cancer, originating from lymphocytes. SRY- sex determining region of Y chromosome. AMEL allele- Amelogenin gene which exists both on X and Y chromosomes, determines biological sex in humans. The locus is different on X and Y, to determine the sex. DYS448- allele location on Y chromosome. It is a prenatal test to determine biological sex. 1p/19q codeletion – combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 MET – Mesenchymal epithelial transition factor receptor BRAF – proto-oncogene B Raf FISH – fluorescence in situ hybrid. Declarations Acknowledgments We are indebted to the patient involved in this article for consenting and for sharing the medical information. We are also thankful to his family for consenting to share his story after he passed away. We are very grateful to the Neuro-Oncology team in the Department of Clinical neuroscience (DCN), Royal Infirmary of Edinburgh (Tessa- Jowell Centre of Excellence); Neuro-pathology team in the RIE, DCN Anaesthetic and theatre team and the Neurosurgical ward staff in the DCN. Authorship declarations No AI was utilised in the writing of this article. There are no competing/conflicts of interest to declare. There are no funding sources to declare. Informed consent was gained from both patient and family. No experimental data or animal studies were used in this article. Author contributions Mr Chandrasekaran Kaliaperumal – supervision, visualisation, conception, review and editing. Dr Priya Kadam – writing, editing, review, visualisation, researching. Dr Irrum Aneela- supervision, support and collaboration References Diwanji TP, Engelman A, Snider JW, MohindraP. 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Tavares CB, Gomes-Braga Fd, Costa-Silva DR, Escórcio-Dourado CS, Borges US, Conde-Junior AM, Barros-Oliveira Mda C, Sousa EB, Barros Lda R, Martins LM, Facina G, da-Silva BB. Expression of estrogen and progesterone receptors in astrocytomas: a literature review. Clinics (Sao Paulo). 2016;71(8):481–6. doi: 10.6061/clinics/2016(08)12 . PMID: 27626480; PMCID: PMC4975780. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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flowchart highlighting mutated cellular processes in astrocytoma\u003c/u\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6558589/v1/9dfb722ed60e0af40aafbc47.png"},{"id":83784817,"identity":"3db7cb71-89df-4549-afe0-1f91b54e588e","added_by":"auto","created_at":"2025-06-02 16:32:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":52491,"visible":true,"origin":"","legend":"\u003cp\u003eAn MRI axial section T1 post contrast scan monstrating large heterogenous frontal midline tumour\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6558589/v1/d16ba44c8e6a0d33483b840a.png"},{"id":83785641,"identity":"8feab04e-dffa-451a-bc0e-d262911c4d74","added_by":"auto","created_at":"2025-06-02 16:48:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":99437,"visible":true,"origin":"","legend":"\u003cp\u003eMRI axial T1 post contrast scan demonstrating reduction in midline tumour.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6558589/v1/79c416e1db90a94357bded44.png"},{"id":83784821,"identity":"adab33cd-792b-4330-a1e1-d97b1543f9f8","added_by":"auto","created_at":"2025-06-02 16:32:27","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":105185,"visible":true,"origin":"","legend":"\u003cp\u003eMRI sagittal T1 post contrast reduction in midline tumour.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6558589/v1/88857f7261a426a15926e4e9.png"},{"id":95524513,"identity":"f546cdce-cdbf-4674-a555-df2002c05201","added_by":"auto","created_at":"2025-11-10 10:02:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":737260,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6558589/v1/4f5712ec-5518-4e51-a47f-925b13ec089a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The relationship between the gain of X chromosome, the loss of Y chromosome and Trisomy 7 in Grade 4 Astrocytoma Tumours","fulltext":[{"header":"Background","content":"\u003cp\u003eGliomas comprise nearly one-third of newly diagnosed brain tumours in adolescents and young adults (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Anaplastic Astrocytoma and glioblastoma present with a high rate of recurrence and poor prognosis, with an average life expectancy of 14 to 16 months (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Although some risk factors for developing glioma such as ionizing radiation and genetic syndromes (Neurofibromatosis type I, Lynch syndrome and Li-Fraumeni) have been identified, no one cause of tumour emergence is known (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe pathogenesis of glioma has been linked to deregulation of major signalling pathways including 1p/19q deletion and the cyclin -dependent kinase inhibitor 2A (p16) gene (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Mutations in tumour suppressor genes such as p53 and Neurofibromatosis type 1 are also heavily involved (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Identification of specific tumour markers such as IDH1 and 1p/19q deletion, through cellular analysis can inform prognosis and management.\u003c/p\u003e \u003cp\u003eAstrocytoma tumour cells are influenced by hormonal changes in the body, including upregulation in oestrogen receptor signalling. Oestrogens can bind to nuclear or membrane receptors and potentially stimulate many different interconnected signalling pathways, leading to complex cascades and potential tumour growth (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The hormone sensitive astrocytoma tissue may be linked with changes in X chromosome expression, although studies are inconclusive.\u003c/p\u003e \u003cp\u003eGenetic background:\u003c/p\u003e\n\u003ch3\u003eMosaicism\u003c/h3\u003e\n\u003cp\u003eMosaicism, changes within the chromosomal composition of cells, occurs in both healthy and malignant brain tissues. Tumour cells are more vulnerable to changes in their cellular composition, owing to mutations affecting growth, for example mutations p53 and braf (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eChanges in tumour cellular composition may involve alterations in the biological sex chromosomes, X and Y. The loss of both Y and X chromosomes have been found in astrocytoma tumour cells, but rarely reported as a \u0026lsquo;loss of Y \u003cem\u003eand/or\u003c/em\u003e gain of X\u0026rsquo;.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eLoss of Y\u003c/h2\u003e \u003cp\u003eLoss of Y (LOY) has been thought of as both a natural karyotype for ageing and a vector for pro cancerous growth (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The presence of Y may infer protective cellular effect, as its loss correlates with general genome wide instability for pro-oncogenesis. LOY is particularly prevalent in patients with renal carcinomas and rarely found in gliomas (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). LOY specifically is associated with poorer prognosis in male patients with glioblastoma, specifically if there is an absence of SRY gene (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). LOY also associated with dysregulation of T cells in prostate cancer, which may cause immunosuppression (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eGain of X\u003c/h3\u003e\n\u003cp\u003eGain of X chromosome has been found in cancerous cells, but again not readily in the glioma cell line. The gain of X is associated with oncogenesis, but it is unclear if this is found in female cells rather than male.\u003c/p\u003e \u003cp\u003eSimilarly to the LOY mosaicism being the most common clonal mosaicism (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), X mosaicism is also common and increases with age (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Substantial numbers of adult cells possess these chromosomal alterations, which have been postulated to occur due to the lack of regulation in cellular protective mechanisms as age increases.\u003c/p\u003e\n\u003ch3\u003eTrisomy 7\u003c/h3\u003e\n\u003cp\u003eTrisomy 7 is a common finding in tumours, both benign and malignant owing to its irregularities in mitotic processes. Trisomy 7 is also found in non-cancerous diseases such as rheumatoid and osteoarthritis (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe most commonly amplified gene in \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eglioblastomas\u003c/span\u003e is the gene coding for the \u003cem\u003eEGFR\u003c/em\u003e on \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003echromosome 7\u003c/span\u003e, correlating with \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003etrisomy\u003c/span\u003e 7 in glioblastomas (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe most common chromosomal abnormality in diffuse astrocytoma of WHO grade II is trisomy 7 (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Research infers that the cells having loss of one sex chromosome or trisomy 7 have a proliferative advantage (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Trisomy 7 correlates with shorter survival of astrocytoma grade II patients, therefore establishing the presence of the marker early is important for prognosis (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTrisomy 7 correlates with Loss of Y chromosome in neoplasms of the renal cortex, and with cancer mutations in MET proto- oncogene.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 23-year-old fit and well Asian gentleman presented to A\u0026thinsp;+\u0026thinsp;E with an episode of collapse. He had been experiencing headaches and three weeks of visual disturbance in the left eye, loss of appetite and vomiting in the lead up to the collapse. An MRI head was performed and demonstrated a midline frontal space occupying lesion with a cyst extending posteriorly compressing the lateral ventricles causing hydrocephalus (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAn MRI post contrast confirmed a large heterogenous midline tumour of the frontal lobe. Examination revealed no focal neurological deficits. Following a multi-disciplinary oncology meeting, he underwent a neuro-navigation guided bifrontal craniotomy and a partial debulking of the large midline frontal tumour in addition to an insertion of a frontal ventricular assisted device.\u003c/p\u003e \u003cp\u003eThe biopsy of the tumour revealed an undifferentiated cell with high grade features, which was confirmed as a WHO Grade 4 Astrocytoma upon histology. Molecular analysis of the tumour was performed as a part of the histopathology for characterisation and to guide further management.\u003c/p\u003e\n\u003ch3\u003eHistopathology:\u003c/h3\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMolecular and Cellular\u003c/h2\u003e \u003cp\u003eThe patient\u0026rsquo;s blood sample analysis demonstrated a male pattern represented by ten X chromosome specific markers, Y chromosome specific SRY, AMEL alleles and DYS448 markers.\u003c/p\u003e \u003cp\u003eMicroarray investigation of the DNA from the astrocytoma cells found a complex picture, including XX chromosomes, gain and loss of function mutations and trisomy 7.\u003c/p\u003e \u003cp\u003eAn overall diagnosis of astrocytoma, Isocitrate dehydrogenase (IDH) mutant, CNS WHO grade 4; MGMT-methylated (26.7%) was made.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLiterature review of molecular analysis:\u003c/h3\u003e\n\u003cp\u003eAlthough there was a loss of Y found in the tumour cells, the SRY gene was present in blood markers. Literature suggests that if \u003cem\u003eSRY gene was absent\u003c/em\u003e, this would lead to a poorer prognosis (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) which is not applicable in this case.\u003c/p\u003e \u003cp\u003eThe pro-oncogene TP53 is more frequently mutated in LOY tumours, which is a possibility for one of the astrocytoma growth pathways. Similarly, this astrocytoma with IDH mutant status and 1p/19q codeletion is associated with a p53 mutation (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOverall, MGMT- Methylated astrocytoma taken together with the IDH-1 mutant result, alongside age\u0026thinsp;\u0026lt;\u0026thinsp;50 and good resection margin in surgery, is a favourable prognosis. Radiotherapy and chemotherapy are likely to be offered as next steps in management (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne study found favourable prognostic value of IDH1 mutation and MGMT methylation in patients with anaplastic astrocytoma treated with Radiotherapy plus concomitant and adjuvant Temzolomide (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInterestingly, IDH wildtype GBM has high frequency chromosome 7 gain due to increase in tyrosine kinases signalling (MET gain and BRAF gain) and loss of cell cycle inhibitors compared with IDH mutated (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, our case was a IDH mutated type.\u003c/p\u003e \u003cp\u003eManagement:\u003c/p\u003e \u003cp\u003eThis gentleman received chemoradiotherapy 6000 cGY in 30 fractions over a 6-week period with Temzolomide, along with Dexamethasone. He was followed up by the Neuro- Oncology team and remained well during this period.\u003c/p\u003e \u003cp\u003eFollow up:\u003c/p\u003e \u003cp\u003eFollowing his treatment, MRI scans demonstrated stable appearances of his tumour and response to adjuvant chemoradiotherapy. During this time, he was clinically stable with good cognitive function. MRI head T1 post contrast demonstrated good resection margins of astrocytoma (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSadly the patient died less than one year on following surgery and completion of chemotherapy.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMosaicism of sex chromosomes in Astrocytoma have not been studied as readily as in other forms of cancer. Abnormalities in X and Y are varied and may or may not lead to cancerous growth through alternative molecular and cellular pathways. Evidence suggests that sex chromosomes undergo mosaic events more often than autosomes (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt is likely that different phenotypes are linked with different patterns of X mosaicism. Chromosomal abnormalities may not be limited to gain of a full X chromosome, as gain of X chromosome arms alone have been associated with cancers (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Higher prevalence of chromosome arm aneuploidy was found in lower grade astrocytoma recurrence, compared with higher grade astrocytoma (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). High frequency gains of one arm of X have been associated with hepatoblastoma, whilst extra X have been found in acute lymphoblastic leukaemia (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eContrary to previous thought, gain of X may \u003cem\u003enot\u003c/em\u003e be associated with cancerous growth. Tumour cells are known to have differences in their chromosomal markers and cellular composition, and we may question whether the gain of X is purely an anomaly and not associated with neoplastic change (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn females, one X chromosome is naturally silenced (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) to compensate for dosage differences between the sexes as males carry only one X (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In this case, gain of X may be acquired in an \u003cem\u003einactive form\u003c/em\u003e and not have an influence on tumour growth (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Overriding X silencing, even in male cancer can lead to oncogenesis (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Specifically, this overriding is proposed to lead to glioma development through loss of regulation of the Xist (RNA X-inactive specific transcript gene) due to abnormalities (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eLiterature does not elude to the conclusion that a \u0026lsquo;loss of y means a \u0026lsquo;gain of X\u0026rsquo;, in the context of Astrocytoma and trisomy 7. Although gain of X and LOY are involved in the evolution of cancer, they are separate processes. Absence of Y leads to genomic instability and potential vulnerability to cancerous growth (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), whereas gain of X is usually associated with upregulation of oncogenesis. It is important to note that these findings have not been demonstrated in Astrocytoma these tumour cohort have not been included in LOY studies due to the low proportions of LOY (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eResearch also suggests that the XX clones in malignant gliomas from men are the consequence of LOY with X isodisomy, a non-random sequence of sex chromosome changes (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). These sex chromosome changes have an impact on brain anatomy and development of intellectual disorders (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Furthermore, X isodisomy may unmask recessive diseases by allowing transmission of two affected gene copies from a heterozygous parent carrier (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). It may be plausible that the gain of X could be associated with isodisomy, though this is unclear at present.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAstrocytoma and hormones\u003c/h2\u003e \u003cp\u003eAstrocytoma are known as a hormone sensitive tumour, but interestingly as astrocytoma increase in grade, the prevalence of oestrogen receptors decrease. Oestrogen receptor expression may be unrelated to upregulation of oncogenesis, and the relationship of oestrogen and cellular growth may be more complex than originally thought (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTrisomy 7\u003c/h2\u003e \u003cp\u003eGlioma frequently exhibit trisomy 7 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) and gain of 7q early in the astrocytoma development in adult patients has been proposed (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Literature suggests that the combination of trisomy 7 and loss of gonosomes in glioma is not a neoplastic specific finding, but instead represents the affinity for brain tissue to acquire and lose chromosomes (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Similarly, when aneuploidy of autosome 7 and sex chromosomes were studied in glioblastoma using FISH, researchers found that chromosomal abnormalities do not appear to be characteristic of a glioblastoma subtype (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Conversely, studies looking at chromosome centromere probes suggest that there is a complex chromosome pattern of aberrations in astrocytoma (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) which may affect biological processes.\u003c/p\u003e \u003cp\u003eThere are fewer studies examining WHO-grade 4 Astrocytoma specifically, and fewer still looking at the relationship between gain of X and trisomy 7.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWHO grade 4 Astrocytoma with a cellular composition XX in a biological XY young male is a rarity and has not been reported before in a young fit and well male previously. LOY increases with age and is underreported in Astrocytoma.\u003c/p\u003e \u003cp\u003eThe functional consequence of chromosomal mosaicism remains to be determined. LOY and gain of X are suggested to be separate rather than simultaneous processes. Both Loss of Y and gain of X can lead to pro-oncogenesis, akin to two sides of the same coin.\u003c/p\u003e \u003cp\u003eFurther research is required to investigate the incidence of gain of X in astrocytoma tumour, and indeed if X gain may be active in the oncogenic process or \u0026lsquo;inactive bystander in this Chromosomal business\u0026rsquo;.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLearning points\u003c/h2\u003e \u003cp\u003eAbnormalities in biological sex chromosomes X and Y may occur in Astrocytoma and be distinct to the biological sex of the individual found in a blood test.\u003c/p\u003e \u003cp\u003eThere is more than one mechanism for cellular cancerous growth, and the Y chromosome may infer protection from oncogenesis and therefore a loss of Y favours mutation whereas a gain of X chromosome favours oncogenesis on the other hand \u003cem\u003e(\u003c/em\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cem\u003e).\u003c/em\u003e\u003c/p\u003e \u003cp\u003eFrom a clinical perspective, having specifics of tumour markers may be useful for discussion with genetics teams and contribute to a prognosis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eLOY – Loss of Y\u0026nbsp;chromosome.\u003c/p\u003e\n\u003cp\u003eMGMT- O-6-methylguanine -DNA methyltransferase enzyme.\u003c/p\u003e\n\u003cp\u003eMethylation of MGMT- Silences transcription of the MGMT enzyme which would repair DNA\u0026nbsp;damage.\u003c/p\u003e\n\u003cp\u003eP53 – P 53\u0026nbsp;mutation,\u0026nbsp;pro-oncogenesis.\u003c/p\u003e\n\u003cp\u003eTrisomy 7 – Three copies of chromosome 7.\u003c/p\u003e\n\u003cp\u003eXIST-\u0026nbsp;X- Inactive specific transcript\u003c/p\u003e\n\u003cp\u003eHepatoblastoma- A rare form of liver cancer, the majority affecting young children.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcute lymphoblastic leukaemia – a type of blood cancer, originating from lymphocytes.\u003c/p\u003e\n\u003cp\u003eSRY- sex determining region of Y chromosome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAMEL allele- Amelogenin gene which exists both on X and Y chromosomes, determines biological sex in humans. The locus is different on X and Y, to determine the sex.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDYS448- allele location on Y chromosome. It is a prenatal test to determine biological sex.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1p/19q codeletion – combined loss of the short arm of chromosome 1 and\u0026nbsp;the long arm of chromosome 19\u003c/p\u003e\n\u003cp\u003eMET – Mesenchymal epithelial transition factor receptor\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBRAF\u0026nbsp;– proto-oncogene B Raf\u003c/p\u003e\n\u003cp\u003eFISH – fluorescence in situ\u0026nbsp;hybrid.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAcknowledgments\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are indebted to the patient\u0026nbsp;involved\u0026nbsp;in this\u0026nbsp;article for consenting and for sharing the medical information. We are also thankful to his family for consenting to share his story after he passed away. We are very grateful to the Neuro-Oncology team in the\u0026nbsp;Department of Clinical\u0026nbsp;neuroscience (DCN),\u0026nbsp;Royal\u0026nbsp;Infirmary\u0026nbsp;of Edinburgh\u0026nbsp;(Tessa- Jowell Centre of Excellence); Neuro-pathology team in the RIE, DCN\u0026nbsp;Anaesthetic and theatre team and the\u0026nbsp;Neurosurgical\u0026nbsp;ward staff in the DCN.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship declarations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo AI was utilised in the writing of this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are no competing/conflicts of interest to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are no funding sources to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent was gained from both patient and family.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo experimental data or animal studies were used in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMr Chandrasekaran Kaliaperumal – supervision, visualisation, conception, review and editing.\u003c/p\u003e\n\u003cp\u003eDr Priya Kadam – writing, editing, review, visualisation, researching.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDr Irrum Aneela- supervision, support and collaboration\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDiwanji TP, Engelman A, Snider JW, MohindraP. 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PMID: 27626480; PMCID: PMC4975780.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Trisomy 7, Mosaicism, Astrocytoma, Loss of Y, gain of X","lastPublishedDoi":"10.21203/rs.3.rs-6558589/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6558589/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA male in his early twenties, who was usually fit and well, underwent a biopsy of a brain tumour (WHO Grade 4 Astrocytoma) that revealed an XX biological sex chromosome pattern rather than the expected XY. The patient identified as male, denied prior hormonal treatment for gender reassignment and had no female sexual characteristics.\u003c/p\u003e \u003cp\u003eThe patient had a partial debulking of a large midline frontal tumour with Neurosurgery and was referred to Oncology. Further microarray genetics revealed a trisomy 7 pattern, which may be associated with mosaicism of sex chromosomes in brain tissue, including the loss of Y or gain of X.\u003c/p\u003e \u003cp\u003eInterestingly, a \u0026lsquo;gain of X\u0026rsquo; has not been explored as readily as the loss of Y alongside trisomy 7 and in the context of astrocytoma.\u003c/p\u003e \u003cp\u003eWe discuss the aetiopathogenesis, genetics and management of this rarity.\u003c/p\u003e \u003cp\u003eThe purpose of this article is to discuss the Loss of Y and gain of X in association with trisomy 7 and its relevance to an intracerebral tumour (Astrocytoma- WHO Grade 4) (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e","manuscriptTitle":"The relationship between the gain of X chromosome, the loss of Y chromosome and Trisomy 7 in Grade 4 Astrocytoma Tumours","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-02 16:32:23","doi":"10.21203/rs.3.rs-6558589/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e56fde07-98fb-4f24-a4f1-356f3b70cff7","owner":[],"postedDate":"June 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-07T05:38:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-02 16:32:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6558589","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6558589","identity":"rs-6558589","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}