A germline SETD2 variant and malignant phyllodes tumor: extending the spectrum of SETD2-related tumor predisposition

A germline SETD2 variant and malignant phyllodes tumor: extending the spectrum of SETD2-related tumor predisposition | 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 A germline SETD2 variant and malignant phyllodes tumor: extending the spectrum of SETD2-related tumor predisposition Noriko Goda, Ayumi Kawamata, Daiki Okamoto, Tomoyuki Yoshiyama, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7804267/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Feb, 2026 Read the published version in Current Genetic Medicine Reports → Version 1 posted You are reading this latest preprint version Abstract The SETD2 gene, located on chromosome 3p21.31, encodes a histone methyltransferase responsible for trimethylation of histone H3 at lysine 36 (H3K36me3), a key epigenetic modification involved in transcriptional regulation and DNA repair. Germline SETD2 variants are known to cause SETD2-related disorders characterized by neurodevelopmental delay, intellectual disability, and variable growth abnormalities. Although the neurodevelopmental spectrum of these disorders has been well established, tumor predisposition among affected individuals remains incompletely defined. We report a 34-year-old woman with neurodevelopmental delay, intellectual disability, hypertrichosis, and café-au-lait–like pigmentation who developed a giant malignant phyllodes tumor of the breast and multiple uterine leiomyomas. Her mother had a history of vestibular schwannoma and exhibited similar physical and neurodevelopmental features. Germline testing for RASopathy-related genes was negative, while whole-exome sequencing identified a heterozygous SETD2 likely pathogenic variant (NM_014159.7:c.2557_2558del; p.Lys853Alafs*5), which was absent from population databases. According to standardized guidelines, this variant met criteria PVS1 and PM2 and was classified as “likely pathogenic.” Despite surgery, radiotherapy, and systemic chemotherapy with doxorubicin and ifosfamide, the disease progressed rapidly, resulting in death. This case broadens the oncologic spectrum of SETD2-related disorders and suggests a potential link between SETD2 germline alterations and phyllodes tumorigenesis. Greater clinical awareness and further studies are warranted to establish appropriate cancer surveillance strategies for affected individuals. SETD2 germline variant malignant phyllodes tumor neurodevelopmental disorder tumor predisposition Figures Figure 1 Figure 2 Figure 3 Introduction The SETD2 gene, located on chromosome 3p21.31, encodes the sole histone methyltransferase responsible for catalyzing trimethylation of histone H3 at lysine 36 (H3K36me3)【1】. This histone modification is essential for transcriptional fidelity, alternative splicing, and DNA double-strand break repair【2,3】. Loss of SETD2 function disrupts genomic integrity and contributes to tumorigenesis【4】. Somatic mutations in SETD2 have been identified in renal cell carcinoma, pediatric high-grade gliomas, and acute leukemias【5–7】, while functional studies indicate that SETD2 alterations promote tumor progression through genomic instability and altered chromatin accessibility【8,9】. In recent years, germline variants in SETD2 have been associated with neurodevelopmental phenotypes collectively referred to as SETD2-related disorders, encompassing Luscan–Lumish syndrome (LLS; MIM# 616831)【9–11,13–15】. These conditions are characterized by developmental delay, intellectual disability, and variable growth abnormalities, including both overgrowth and, in some cases, short stature. Although the neurodevelopmental features of SETD2-related disorders are increasingly recognized, tumor predisposition among affected individuals has only recently gained attention. Reported neoplasms include Wilms tumor, osteosarcoma, brain tumors, and hematologic malignancies【12–15,16,21】. Moreover, recent epigenomic studies have identified distinctive DNA methylation episignatures in SETD2-related disorders, some of which were associated with tumor development【14】. Malignant phyllodes tumor (MPT) of the breast is a rare fibroepithelial neoplasm, accounting for fewer than 1% of all breast tumors【17,18】. Approximately 10–30% of phyllodes tumors are classified as malignant, with risks of local recurrence and distant metastasis【17,18】. Genomic profiling has revealed a characteristic mutational landscape involving MED12, TERT promoter, TP53, RB1, and EGFR. Notably, somatic SETD2 mutations have been reported in a subset of phyllodes tumors, with frequencies ranging from approximately 9% to 20%, depending on the cohort【19–21,25】. With respect to hereditary predisposition, malignant phyllodes tumor is generally regarded as a sporadic neoplasm, and its relationship with inherited cancer syndromes remains poorly defined. Rare cases have described phyllodes tumors in individuals with Li–Fraumeni syndrome (TP53 germline variants) or other hereditary cancer predisposition conditions【17,18】. Germline SETD2 variants have been implicated in neurodevelopmental syndromes with tumor susceptibility【12–16,21】, and their possible contribution to phyllodes tumorigenesis warrants consideration. Here, we describe a female patient carrying a germline SETD2 likely pathogenic variant who developed a malignant phyllodes tumor of the breast and multiple uterine leiomyomas. This unusual presentation further expands the clinical and oncologic spectrum of SETD2-associated disorders. Case Presentation The patient first presented to our institution at the age of 34 years. On admission, her height was 144 cm and her weight was 44 kg. She exhibited thick eyebrows, generalized truncal hypertrichosis (Fig. 1 a), and faint café-au-lait–like pigmentation (Fig. 1 b). On clinical contact, long-standing developmental delay and intellectual disability were apparent. After graduating from a local public high school, she had never been employed and had lived at home with limited social interactions outside her family. Despite these features, she had never undergone formal medical or specialist evaluation for her neurodevelopmental or physical abnormalities. During our interactions, she was able to respond appropriately to closed questions requiring a “yes” or “no” answer but experienced difficulty responding to open-ended questions. She was capable of performing basic self-care and operating a smartphone. However, her behavior also exhibited immaturity not typical for her chronological age, such as keeping and affectionately caring for her favorite mascot toy. She presented with a giant breast mass measuring approximately 30 cm in diameter (Fig. 1 c,d). Until the tumor reached this size, she had never consulted a medical professional. Computed tomography (CT) revealed no distant metastases. A core needle biopsy established the diagnosis of malignant phyllodes tumor of the breast, and she subsequently underwent surgical excision. CT also revealed multiple large uterine leiomyomas (Fig. 1 e,f), which were surgically resected by the gynecology team following the breast surgery. Histopathological examination confirmed malignant phyllodes tumor of the breast and benign uterine leiomyomas. Her family history was notable (Fig. 2 ). Her elder sister had died in her twenties of a cerebrovascular disorder, although the details remained unclear. Her mother had a history of vestibular schwannoma treated surgically, with residual tumor requiring follow-up in our neurosurgery department. In addition, a maternal relative reportedly had an intellectual disability. Her mother also shared strikingly similar physical and neurodevelopmental features to those observed in the patient. Given her clinical features and family history, we considered a hereditary tumor predisposition syndrome. With informed consent, we first performed germline testing for RASopathy-associated genes, which revealed no pathogenic variants. Subsequent whole-exome sequencing identified a heterozygous SETD2 likely pathogenic variant (NM_014159.7:c.2557_2558del; p.Lys853Alafs*5), representing a two–base pair deletion(Fig. 3 ). This variant was absent from population databases, including gnomAD v4.1.0 ( https://gnomad.broadinstitute.org/ ), ToMMo 54KJPN ( https://jmorp.megabank.tohoku.ac.jp/ ), HGVD ( https://www.hgvd.genome.med.kyoto-u.ac.jp/ ), and ClinVar ( https://www.ncbi.nlm.nih.gov/clinvar/ ). According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the variant met criteria PVS1 and PM2 and was therefore classified as “likely pathogenic.” Because no other cancer-predisposing genetic alterations were identified, this variant was considered to explain her neurodevelopmental and physical characteristics as well as her tumor profile. Following breast surgery, the patient underwent regular follow-up with physical examinations and CT scans every six months. At the age of 38 years, multiple bone metastases were detected, and recurrent malignant phyllodes tumor was diagnosed. Despite radiotherapy and systemic chemotherapy with doxorubicin and ifosfamide, her disease showed poor response, and multiple bone and lung metastases followed a rapidly progressive course. She died of progressive disease shortly thereafter. Discussion This case highlights a patient with neurodevelopmental features suggestive of an underlying hereditary disorder who presented with a giant malignant phyllodes tumor. Initially, a RASopathy was suspected, but targeted testing for RASopathy-associated genes yielded negative results. Broader germline testing using whole-exome sequencing subsequently identified a SETD2 germline pathogenic variant, providing a unifying explanation for her neurodevelopmental phenotype and tumor predisposition. The SETD2 gene, located on chromosome 3p21.31, encodes the only known histone methyltransferase responsible for catalyzing trimethylation of histone H3 at lysine 36 (H3K36me3)【1】. This epigenetic modification regulates transcriptional fidelity, alternative splicing, and DNA damage repair【2,3】. Loss of SETD2 function results in genomic instability and aberrant transcriptional regulation, thereby contributing to oncogenesis【4】. In addition to these canonical roles, SETD2 loss alters chromatin accessibility and affects global histone methylation dynamics【23,24】. Germline variants in SETD2 have been associated with a spectrum of neurodevelopmental phenotypes collectively referred to as SETD2-related disorders【9–11,13–15】. These disorders are characterized by developmental delay, intellectual disability, and variable growth abnormalities, including both overgrowth and, in some cases, short stature. Although initially delineated as Luscan–Lumish syndrome, recent studies have emphasized phenotypic heterogeneity and the need for a broader classification【13–15】. Importantly, accumulating evidence indicates that SETD2 germline variants may also confer susceptibility to various tumors, including Wilms tumor, osteosarcoma, brain tumors, and hematologic malignancies【12–15,16,21】. Phyllodes tumors are rare fibroepithelial neoplasms of the breast, accounting for fewer than 1% of all breast tumors【17,18】. Approximately 10–30% are classified as malignant, with a risk of local recurrence and distant metastasis【17,18】. Recent genomic studies have defined the mutational landscape of malignant phyllodes tumors, identifying recurrent alterations in MED12, TERT promoter, TP53, RB1, and EGFR【19–21】. Somatic SETD2 mutations have been reported in 9–20% of phyllodes tumors, depending on the cohort【19–21,25】. Although these are typically tumor-acquired alterations, our case raises the possibility that a germline SETD2 variant may contribute to the pathogenesis of malignant phyllodes tumor. The tumor predisposition spectrum of SETD2-related disorders remains incompletely characterized. While sarcomas, brain tumors, and hematologic malignancies have been described, phyllodes tumors have not been consistently reported in this context. This case therefore contributes to the evolving understanding of SETD2-associated tumorigenesis. At present, no standardized surveillance protocols exist for individuals with SETD2-related disorders. Surveillance strategies might reasonably focus on sarcomas, brain tumors, and hematologic malignancies; however, whether breast neoplasms such as phyllodes tumors should also be included requires further case accumulation. In addition, awareness and understanding of cancer surveillance needs may be limited among affected patients and families, underscoring the importance of ongoing genetic counseling. Several limitations should be acknowledged. First, this is a single case report, and it remains unclear whether the patient’s malignant phyllodes tumor truly arose as a consequence of her SETD2 variant, or whether these represent coincidental events, with delayed presentation of a sporadic tumor due to underlying developmental disability. Second, although the variant was identified in the germline, cascade testing of family members was not performed, and co-segregation analysis is therefore lacking. Such data would have strengthened the interpretation of pathogenicity. Third, comprehensive tumor profiling—such as methylation analysis or comprehensive genomic profiling—was not performed due to limitations in informed consent and the patient’s rapid clinical decline. Consequently, functional evidence linking the germline SETD2 variant to her tumor remains unavailable. Conclusion In summary, this case illustrates the occurrence of a malignant phyllodes tumor in a patient harboring a germline SETD2 likely pathogenic variant in the context of neurodevelopmental features. These findings expand the oncologic spectrum of SETD2-related disorders, highlight their potential tumor predisposition, and underscore the need for further investigation into appropriate cancer surveillance strategies for affected individuals. Declarations Funding This study was partially supported by KAKENHI (grant Numbers 24K10940) from the Japan Society for the Promotion of Science; a grant (grant number JP23ek0109637) and Initiative on Rare and Undiagnosed Diseases (grant number 24ek0109760h0001) from the Japan Agency for Medical Research and Development (AMED); and a grant from the Ministry of Health, Labor, and Welfare Japan (24FC1003). Author information Authors and Affiliations Department of Breast Surgery, NHO Kure Medical Center, Japan 3 − 1 Aoyama-cho, Kure City, Hiroshima Prefecture, 737 − 0023, Japan. Noriko Goda, Ayumi Kawamata, Daiki Okamoto and Tomoyuki Yoshiyama. Department of Genomics, Tokyo Women's Medical University, Japan 8 − 1 Kawadacho, Shinjuku-ku, Tokyo 162–8666, Japan Toshiyuki Yamamoto Contributions NG, TYo, AK and DO treated the patients and summarized the clinical course. TH provided genetic counseling to the patient and family. NG and DO described and summarized the patient's clinical course. NG, TYo and HN conceived and designed the report. TYa performed NGS initial analysis. NG was responsible for the initial writing of the manuscript. NG and TYa produced the figures. All authors have read, edited, and approved the final manuscript. Corresponding author Correspondence to Noriko Goda. Ethics declarations Ethical Compliance and Informed Consent This research is in accordance with ethical standards established in the Declaration of Helsinki (1964), its subsequent revisions, and Resolution 466/2012 of the Brazilian National Health Council. The project was approved by the Research Ethics Committee of the Tokyo Women's Medical University. Informed consent was obtained from the patient's parents, who also authorized the publication of photographs. Conflicts of interest The authors declare no competing interests. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References Li J, Duns G, Westers H, et al. SETD2 : an epigenetic modifier with tumor suppressor functionality. Oncotarget. 2016;7:50719–34. Pfister SX, Ahrabi S, Zalmas LP, et al. SETD2 -dependent histone H3K36 trimethylation is required for homologous recombination repair. Cell Rep. 2014;7:2006–18. Carvalho S, Raposo AC, Martins FB, et al. Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics. Nucleic Acids Res. 2013;41:2881–93. Zhu X, He F, Zeng H, et al. Identification of functional cooperative mutations of SETD2 in human cancer. Nat Commun. 2014;5:5286. Dalgliesh GL, Furge K, Greenman C, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010;463:360–3. Fontebasso AM, Schwartzentruber J, Khuong-Quang DA, et al. Mutations in SETD2 in pediatric high-grade gliomas. Nat Genet. 2013;45:422–6. Skucha A, Ebner J, Grebien F. Roles of SETD2 in leukemia. Int J Mol Sci. 2019;20:1029. Ho TH, Park IY, Zhao H, et al. High expression of histone methyltransferase SETD2 in RCC is associated with poor prognosis. Oncotarget. 2016;7:50804–14. Luscan A, Laurendeau I, Malan V, et al. Mutations in SETD2 cause a novel overgrowth condition. J Med Genet. 2014;51:512–7. Lumish HS, Wynn J, Devinsky O, et al. SETD2 -related overgrowth syndrome: Luscan–Lumish syndrome. Am J Med Genet A. 2017;173:1923–8. Sobreira N, et al. Clinical delineation of Luscan–Lumish syndrome associated with SETD2 variants. Genet Med. 2019;21:298–305. Zhang J, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373:2336–46. Perenthaler E, Yousefi S, Niggl E, et al. SETD2 germline variants and their role in human disease. Hum Mutat. 2022;43:1147–62. Lee JS, Sobreira N, Won D, et al. DNA methylation episignatures for SETD2 -related disorders. Hum Mol Genet. 2023;32:3123–34. Lucain E, et al. SETD2 germline variants define a novel syndromic phenotype with tumor predisposition. Am J Med Genet A. 2025;197:e64043. Brohl AS, Patidar R, Turner CE, et al. Germline variants in SETD2 in pediatric and young adult cancers. Cancer Genet. 2017;216–217:37–42. Tan BY, Acs G, Apple SK, et al. Phyllodes tumours of the breast: a consensus review. Histopathology. 2016;68:5–21. Lakhani SR, Ellis IO, Schnitt SJ, et al. WHO Classification of Tumours of the Breast. 4th ed. Lyon: IARC; 2012. Liu J, Shen D, Hu N, et al. Mod Pathol. 2016;29:450–9. Tsang JYS, Ni YB, Chan SK, et al. Histopathology. 2021;78(6):930–40. Ye J, et al. Mod Pathol. 2024;37:1000–12. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Genet Med. 2015;17(5):405–24. Yang L, et al. Semin Cancer Biol. 2020;57:45–54. Neri F, et al. Nat Rev Genet. 2022;23:651–67. Rosenberger LH et al. Genomic landscape of malignant phyllodes tumors reveals multiple targetable opportunities. Mod Pathol. 2024; in press. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Feb, 2026 Read the published version in Current Genetic Medicine Reports → 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":472096,"visible":true,"origin":"","legend":"\u003cp\u003eClinical and radiological findings of the patient.\u003cbr\u003e\na) Facial appearance showing thick eyebrows and facial hair.\u003cbr\u003e\nb) Faint café-au-lait–like pigmentation on the back.\u003cbr\u003e\nc) A giant right breast mass measuring approximately 30 cm in diameter. The patient had not sought medical consultation until the tumor reached this size.\u003cbr\u003e\nd) Computed tomography (CT) scout image of the breast tumor.\u003cbr\u003e\ne) CT image demonstrating a uterine leiomyoma larger than 15 cm (arrow).\u003cbr\u003e\nf) Sagittal magnetic resonance imaging (MRI) scan of the uterine leiomyoma (arrow).\u003c/p\u003e","description":"","filename":"Fig.1a.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7804267/v1/0767e3bc9d51936516190844.jpg"},{"id":97985893,"identity":"e4bc7175-4386-4811-9ba5-a9a2e17fc41b","added_by":"auto","created_at":"2025-12-11 13:43:45","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":58360,"visible":true,"origin":"","legend":"\u003cp\u003ePedigree of the patient’s family.\u003c/p\u003e\n\u003cp\u003eThe patient’s elder sister died in her twenties of a cerebrovascular disorder (details unknown). The patient’s mother had a history of vestibular schwannoma treated surgically and shared similar physical and neurodevelopmental features. In addition, a maternal relative was reported to have intellectual disability.\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7804267/v1/322391571c77c3c20736a541.jpg"},{"id":98424150,"identity":"9f784b32-1b09-455c-ae8f-35b0fec2e0fe","added_by":"auto","created_at":"2025-12-17 16:33:00","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":74851,"visible":true,"origin":"","legend":"\u003cp\u003ePresentation of the identified variant. Integrative Genomics Viewer (IGV; https://igv.org/) shows that approximately half of the reads show a two-base pair deletion.\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7804267/v1/fc7a3df0a53c64228867ab3c.jpg"},{"id":103765416,"identity":"1c11ccd1-4895-40da-b988-d8e26a07897e","added_by":"auto","created_at":"2026-03-02 16:00:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":927788,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7804267/v1/941f9871-72c8-4d8f-bb34-f81a89ed5e8f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A germline SETD2 variant and malignant phyllodes tumor: extending the spectrum of SETD2-related tumor predisposition","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe SETD2 gene, located on chromosome 3p21.31, encodes the sole histone methyltransferase responsible for catalyzing trimethylation of histone H3 at lysine 36 (H3K36me3)【1】. This histone modification is essential for transcriptional fidelity, alternative splicing, and DNA double-strand break repair【2,3】. Loss of SETD2 function disrupts genomic integrity and contributes to tumorigenesis【4】. Somatic mutations in SETD2 have been identified in renal cell carcinoma, pediatric high-grade gliomas, and acute leukemias【5–7】, while functional studies indicate that SETD2 alterations promote tumor progression through genomic instability and altered chromatin accessibility【8,9】.\u003c/p\u003e\u003cp\u003eIn recent years, germline variants in SETD2 have been associated with neurodevelopmental phenotypes collectively referred to as SETD2-related disorders, encompassing Luscan–Lumish syndrome (LLS; MIM# 616831)【9–11,13–15】. These conditions are characterized by developmental delay, intellectual disability, and variable growth abnormalities, including both overgrowth and, in some cases, short stature. Although the neurodevelopmental features of SETD2-related disorders are increasingly recognized, tumor predisposition among affected individuals has only recently gained attention. Reported neoplasms include Wilms tumor, osteosarcoma, brain tumors, and hematologic malignancies【12–15,16,21】. Moreover, recent epigenomic studies have identified distinctive DNA methylation episignatures in SETD2-related disorders, some of which were associated with tumor development【14】.\u003c/p\u003e\u003cp\u003eMalignant phyllodes tumor (MPT) of the breast is a rare fibroepithelial neoplasm, accounting for fewer than 1% of all breast tumors【17,18】. Approximately 10–30% of phyllodes tumors are classified as malignant, with risks of local recurrence and distant metastasis【17,18】. Genomic profiling has revealed a characteristic mutational landscape involving MED12, TERT promoter, TP53, RB1, and EGFR. Notably, somatic SETD2 mutations have been reported in a subset of phyllodes tumors, with frequencies ranging from approximately 9% to 20%, depending on the cohort【19–21,25】.\u003c/p\u003e\u003cp\u003eWith respect to hereditary predisposition, malignant phyllodes tumor is generally regarded as a sporadic neoplasm, and its relationship with inherited cancer syndromes remains poorly defined. Rare cases have described phyllodes tumors in individuals with Li–Fraumeni syndrome (TP53 germline variants) or other hereditary cancer predisposition conditions【17,18】. Germline SETD2 variants have been implicated in neurodevelopmental syndromes with tumor susceptibility【12–16,21】, and their possible contribution to phyllodes tumorigenesis warrants consideration.\u003c/p\u003e\u003cp\u003eHere, we describe a female patient carrying a germline SETD2 likely pathogenic variant who developed a malignant phyllodes tumor of the breast and multiple uterine leiomyomas. This unusual presentation further expands the clinical and oncologic spectrum of SETD2-associated disorders.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eThe patient first presented to our institution at the age of 34 years. On admission, her height was 144 cm and her weight was 44 kg. She exhibited thick eyebrows, generalized truncal hypertrichosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea), and faint café-au-lait–like pigmentation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). On clinical contact, long-standing developmental delay and intellectual disability were apparent. After graduating from a local public high school, she had never been employed and had lived at home with limited social interactions outside her family. Despite these features, she had never undergone formal medical or specialist evaluation for her neurodevelopmental or physical abnormalities. During our interactions, she was able to respond appropriately to closed questions requiring a “yes” or “no” answer but experienced difficulty responding to open-ended questions. She was capable of performing basic self-care and operating a smartphone. However, her behavior also exhibited immaturity not typical for her chronological age, such as keeping and affectionately caring for her favorite mascot toy.\u003c/p\u003e\u003cp\u003eShe presented with a giant breast mass measuring approximately 30 cm in diameter (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec,d). Until the tumor reached this size, she had never consulted a medical professional. Computed tomography (CT) revealed no distant metastases. A core needle biopsy established the diagnosis of malignant phyllodes tumor of the breast, and she subsequently underwent surgical excision. CT also revealed multiple large uterine leiomyomas (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee,f), which were surgically resected by the gynecology team following the breast surgery. Histopathological examination confirmed malignant phyllodes tumor of the breast and benign uterine leiomyomas.\u003c/p\u003e\u003cp\u003eHer family history was notable (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Her elder sister had died in her twenties of a cerebrovascular disorder, although the details remained unclear. Her mother had a history of vestibular schwannoma treated surgically, with residual tumor requiring follow-up in our neurosurgery department. In addition, a maternal relative reportedly had an intellectual disability. Her mother also shared strikingly similar physical and neurodevelopmental features to those observed in the patient.\u003c/p\u003e\u003cp\u003eGiven her clinical features and family history, we considered a hereditary tumor predisposition syndrome. With informed consent, we first performed germline testing for RASopathy-associated genes, which revealed no pathogenic variants. Subsequent whole-exome sequencing identified a heterozygous SETD2 likely pathogenic variant (NM_014159.7:c.2557_2558del; p.Lys853Alafs*5), representing a two–base pair deletion(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This variant was absent from population databases, including gnomAD v4.1.0 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gnomad.broadinstitute.org/\u003c/span\u003e\u003cspan address=\"https://gnomad.broadinstitute.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e), ToMMo 54KJPN (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://jmorp.megabank.tohoku.ac.jp/\u003c/span\u003e\u003cspan address=\"https://jmorp.megabank.tohoku.ac.jp/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e), HGVD (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.hgvd.genome.med.kyoto-u.ac.jp/\u003c/span\u003e\u003cspan address=\"https://www.hgvd.genome.med.kyoto-u.ac.jp/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e), and ClinVar (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/clinvar/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/clinvar/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e). According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the variant met criteria PVS1 and PM2 and was therefore classified as “likely pathogenic.” Because no other cancer-predisposing genetic alterations were identified, this variant was considered to explain her neurodevelopmental and physical characteristics as well as her tumor profile.\u003c/p\u003e\u003cp\u003eFollowing breast surgery, the patient underwent regular follow-up with physical examinations and CT scans every six months. At the age of 38 years, multiple bone metastases were detected, and recurrent malignant phyllodes tumor was diagnosed. Despite radiotherapy and systemic chemotherapy with doxorubicin and ifosfamide, her disease showed poor response, and multiple bone and lung metastases followed a rapidly progressive course. She died of progressive disease shortly thereafter.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case highlights a patient with neurodevelopmental features suggestive of an underlying hereditary disorder who presented with a giant malignant phyllodes tumor. Initially, a RASopathy was suspected, but targeted testing for RASopathy-associated genes yielded negative results. Broader germline testing using whole-exome sequencing subsequently identified a SETD2 germline pathogenic variant, providing a unifying explanation for her neurodevelopmental phenotype and tumor predisposition.\u003c/p\u003e\u003cp\u003eThe SETD2 gene, located on chromosome 3p21.31, encodes the only known histone methyltransferase responsible for catalyzing trimethylation of histone H3 at lysine 36 (H3K36me3)【1】. This epigenetic modification regulates transcriptional fidelity, alternative splicing, and DNA damage repair【2,3】. Loss of SETD2 function results in genomic instability and aberrant transcriptional regulation, thereby contributing to oncogenesis【4】. In addition to these canonical roles, SETD2 loss alters chromatin accessibility and affects global histone methylation dynamics【23,24】.\u003c/p\u003e\u003cp\u003eGermline variants in SETD2 have been associated with a spectrum of neurodevelopmental phenotypes collectively referred to as SETD2-related disorders【9\u0026ndash;11,13\u0026ndash;15】. These disorders are characterized by developmental delay, intellectual disability, and variable growth abnormalities, including both overgrowth and, in some cases, short stature. Although initially delineated as Luscan\u0026ndash;Lumish syndrome, recent studies have emphasized phenotypic heterogeneity and the need for a broader classification【13\u0026ndash;15】. Importantly, accumulating evidence indicates that SETD2 germline variants may also confer susceptibility to various tumors, including Wilms tumor, osteosarcoma, brain tumors, and hematologic malignancies【12\u0026ndash;15,16,21】.\u003c/p\u003e\u003cp\u003ePhyllodes tumors are rare fibroepithelial neoplasms of the breast, accounting for fewer than 1% of all breast tumors【17,18】. Approximately 10\u0026ndash;30% are classified as malignant, with a risk of local recurrence and distant metastasis【17,18】. Recent genomic studies have defined the mutational landscape of malignant phyllodes tumors, identifying recurrent alterations in MED12, TERT promoter, TP53, RB1, and EGFR【19\u0026ndash;21】. Somatic SETD2 mutations have been reported in 9\u0026ndash;20% of phyllodes tumors, depending on the cohort【19\u0026ndash;21,25】. Although these are typically tumor-acquired alterations, our case raises the possibility that a germline SETD2 variant may contribute to the pathogenesis of malignant phyllodes tumor.\u003c/p\u003e\u003cp\u003eThe tumor predisposition spectrum of SETD2-related disorders remains incompletely characterized. While sarcomas, brain tumors, and hematologic malignancies have been described, phyllodes tumors have not been consistently reported in this context. This case therefore contributes to the evolving understanding of SETD2-associated tumorigenesis. At present, no standardized surveillance protocols exist for individuals with SETD2-related disorders. Surveillance strategies might reasonably focus on sarcomas, brain tumors, and hematologic malignancies; however, whether breast neoplasms such as phyllodes tumors should also be included requires further case accumulation. In addition, awareness and understanding of cancer surveillance needs may be limited among affected patients and families, underscoring the importance of ongoing genetic counseling.\u003c/p\u003e\u003cp\u003eSeveral limitations should be acknowledged. First, this is a single case report, and it remains unclear whether the patient\u0026rsquo;s malignant phyllodes tumor truly arose as a consequence of her SETD2 variant, or whether these represent coincidental events, with delayed presentation of a sporadic tumor due to underlying developmental disability. Second, although the variant was identified in the germline, cascade testing of family members was not performed, and co-segregation analysis is therefore lacking. Such data would have strengthened the interpretation of pathogenicity. Third, comprehensive tumor profiling\u0026mdash;such as methylation analysis or comprehensive genomic profiling\u0026mdash;was not performed due to limitations in informed consent and the patient\u0026rsquo;s rapid clinical decline. Consequently, functional evidence linking the germline SETD2 variant to her tumor remains unavailable.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, this case illustrates the occurrence of a malignant phyllodes tumor in a patient harboring a germline SETD2 likely pathogenic variant in the context of neurodevelopmental features. These findings expand the oncologic spectrum of SETD2-related disorders, highlight their potential tumor predisposition, and underscore the need for further investigation into appropriate cancer surveillance strategies for affected individuals.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis study was partially supported by KAKENHI (grant Numbers 24K10940) from the Japan Society for the Promotion of Science; a grant (grant number JP23ek0109637) and Initiative on Rare and Undiagnosed Diseases (grant number 24ek0109760h0001) from the Japan Agency for Medical Research and Development (AMED); and a grant from the Ministry of Health, Labor, and Welfare Japan (24FC1003).\u003c/p\u003e\u003cp\u003eAuthor information\u003c/p\u003e\u003cp\u003eAuthors and Affiliations\u003c/p\u003e\u003cp\u003eDepartment of Breast Surgery, NHO Kure Medical Center, Japan\u003c/p\u003e\u003cp\u003e3\u0026thinsp;\u0026minus;\u0026thinsp;1 Aoyama-cho, Kure City, Hiroshima Prefecture, 737\u0026thinsp;\u0026minus;\u0026thinsp;0023, Japan.\u003c/p\u003e\u003cp\u003eNoriko Goda, Ayumi Kawamata, Daiki Okamoto and Tomoyuki Yoshiyama.\u003c/p\u003e\u003cp\u003eDepartment of Genomics, Tokyo Women's Medical University, Japan\u003c/p\u003e\u003cp\u003e8\u0026thinsp;\u0026minus;\u0026thinsp;1 Kawadacho, Shinjuku-ku, Tokyo 162\u0026ndash;8666, Japan\u003c/p\u003e\u003cp\u003eToshiyuki Yamamoto\u003c/p\u003e\u003cp\u003eContributions\u003c/p\u003e\u003cp\u003eNG, TYo, AK and DO treated the patients and summarized the clinical course. TH provided genetic counseling to the patient and family. NG and DO described and summarized the patient's clinical course. NG, TYo and HN conceived and designed the report. TYa performed NGS initial analysis. NG was responsible for the initial writing of the manuscript. NG and TYa produced the figures. All authors have read, edited, and approved the final manuscript.\u003c/p\u003e\u003cp\u003eCorresponding author\u003c/p\u003e\u003cp\u003eCorrespondence to Noriko Goda.\u003c/p\u003e\u003cp\u003eEthics declarations\u003c/p\u003e\u003cp\u003eEthical Compliance and Informed Consent\u003c/p\u003e\u003cp\u003eThis research is in accordance with ethical standards established in the Declaration of Helsinki (1964), its subsequent revisions, and Resolution 466/2012 of the Brazilian National Health Council. The project was approved by the Research Ethics Committee of the Tokyo Women's Medical University. Informed consent was obtained from the patient's parents, who also authorized the publication of photographs.\u003c/p\u003e\u003cp\u003eConflicts of interest\u003c/p\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003cp\u003eHuman and Animal Rights and Informed Consent\u003c/p\u003e\u003cp\u003eThis article does not contain any studies with human or animal subjects performed by any of the authors.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLi J, Duns G, Westers H, et al. \u003cem\u003eSETD2\u003c/em\u003e: an epigenetic modifier with tumor suppressor functionality. Oncotarget. 2016;7:50719\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePfister SX, Ahrabi S, Zalmas LP, et al. \u003cem\u003eSETD2\u003c/em\u003e-dependent histone H3K36 trimethylation is required for homologous recombination repair. 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Mod Pathol. 2016;29:450\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTsang JYS, Ni YB, Chan SK, et al. Histopathology. 2021;78(6):930\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYe J, et al. Mod Pathol. 2024;37:1000\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRichards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Genet Med. 2015;17(5):405\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang L, et al. Semin Cancer Biol. 2020;57:45\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNeri F, et al. Nat Rev Genet. 2022;23:651\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRosenberger LH et al. Genomic landscape of malignant phyllodes tumors reveals multiple targetable opportunities. Mod Pathol. 2024; in press.\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":true,"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":"SETD2, germline variant, malignant phyllodes tumor, neurodevelopmental disorder, tumor predisposition","lastPublishedDoi":"10.21203/rs.3.rs-7804267/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7804267/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe SETD2 gene, located on chromosome 3p21.31, encodes a histone methyltransferase responsible for trimethylation of histone H3 at lysine 36 (H3K36me3), a key epigenetic modification involved in transcriptional regulation and DNA repair. Germline SETD2 variants are known to cause SETD2-related disorders characterized by neurodevelopmental delay, intellectual disability, and variable growth abnormalities. Although the neurodevelopmental spectrum of these disorders has been well established, tumor predisposition among affected individuals remains incompletely defined.\u003c/p\u003e\u003cp\u003eWe report a 34-year-old woman with neurodevelopmental delay, intellectual disability, hypertrichosis, and caf\u0026eacute;-au-lait\u0026ndash;like pigmentation who developed a giant malignant phyllodes tumor of the breast and multiple uterine leiomyomas. Her mother had a history of vestibular schwannoma and exhibited similar physical and neurodevelopmental features. Germline testing for RASopathy-related genes was negative, while whole-exome sequencing identified a heterozygous SETD2 likely pathogenic variant (NM_014159.7:c.2557_2558del; p.Lys853Alafs*5), which was absent from population databases. According to standardized guidelines, this variant met criteria PVS1 and PM2 and was classified as \u0026ldquo;likely pathogenic.\u0026rdquo; Despite surgery, radiotherapy, and systemic chemotherapy with doxorubicin and ifosfamide, the disease progressed rapidly, resulting in death.\u003c/p\u003e\u003cp\u003eThis case broadens the oncologic spectrum of SETD2-related disorders and suggests a potential link between SETD2 germline alterations and phyllodes tumorigenesis. Greater clinical awareness and further studies are warranted to establish appropriate cancer surveillance strategies for affected individuals.\u003c/p\u003e","manuscriptTitle":"A germline SETD2 variant and malignant phyllodes tumor: extending the spectrum of SETD2-related tumor predisposition","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-11 13:43:36","doi":"10.21203/rs.3.rs-7804267/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":"521919be-6c3f-4f88-8413-9fe472c69442","owner":[],"postedDate":"December 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T16:00:11+00:00","versionOfRecord":{"articleIdentity":"rs-7804267","link":"https://doi.org/10.1007/s40142-026-00241-w","journal":{"identity":"current-genetic-medicine-reports","isVorOnly":false,"title":"Current Genetic Medicine Reports"},"publishedOn":"2026-02-26 15:57:12","publishedOnDateReadable":"February 26th, 2026"},"versionCreatedAt":"2025-12-11 13:43:36","video":"","vorDoi":"10.1007/s40142-026-00241-w","vorDoiUrl":"https://doi.org/10.1007/s40142-026-00241-w","workflowStages":[]},"version":"v1","identity":"rs-7804267","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7804267","identity":"rs-7804267","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}