David Y Chen, Leslie A Sutton, Sai Mukund Ramakrishnan, Eric J Duncavage, Sharon E Heath, Leigh A Compton, Christopher A Miller, Timothy J Ley
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引用次数: 0
摘要
人们越来越认识到,表观遗传调控因子的改变是肿瘤发生的早期事件;因此,表观遗传调控因子的获得性或遗传性变异患者罹患多种类型癌症的风险可能会增加。由 DNA 甲基转移酶基因 DNMT3A 的种系致病变异引起的 DNMT3A 过度生长综合征(DOS)与易患造血和神经元恶性肿瘤有关。据描述,DNMT3A 缺乏会促进小鼠角质细胞的增殖。虽然 DNA 甲基化模式的改变在黑色素瘤中已得到广泛认可,但 DNA 甲基转移酶在黑色素瘤发病机制中的作用尚不明确。我们报告了一例患有种系DNMT3A功能缺失突变的成年DOS患者的病例,该患者早发黑色素瘤并伴有区域淋巴结转移性疾病。原发肿瘤的外显子组测序在显性肿瘤克隆中发现了一个额外的获得性错义 DNMT3A 突变,这表明 DNMT3A 功能缺失与该肿瘤的发病有关。
Melanoma in a patient with DNMT3A overgrowth syndrome.
Alterations in epigenetic regulators are increasingly recognized as early events in tumorigenesis; thus, patients with acquired or inherited variants in epigenetic regulators may be at increased risk for developing multiple types of cancer. DNMT3A overgrowth syndrome (DOS), caused by germline pathogenic variants in the DNA methyltransferase gene DNMT3A, has been associated with a predisposition toward development of hematopoietic and neuronal malignancies. DNMT3A deficiency has been described to promote keratinocyte proliferation in mice. Although altered DNA methylation patterns are well-recognized in melanoma, the role of DNA methyltransferases in melanoma pathogenesis is not clear. We report the case of an adult DOS patient with a germline DNMT3A loss-of-function mutation, who developed an early-onset melanoma with regional lymph node metastatic disease. Exome sequencing of the primary tumor identified an additional acquired, missense DNMT3A mutation in the dominant tumor clone, suggesting that the loss of DNMT3A function was relevant for the development of this tumor.
期刊介绍:
Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.