Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
Center for Immunotherapy & Precision Immuno-Oncology, Cleveland Clinic Foundation, Cleveland, Ohio.
J Am Acad Dermatol. 2024 Aug;91(2):265-272. doi: 10.1016/j.jaad.2023.11.070. Epub 2024 Mar 20.
Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers.
To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma.
Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets.
Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study.
Cohorts with varying degrees of selection, some retrospective.
Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.
先前的研究估计，只有少数患有黑色素瘤（2%-2.5%）的个体存在种系癌症易感性，但最近的一项双胞胎研究表明，黑色素瘤是所有癌症中遗传性最高的。
确定遗传性黑色素瘤的发病率，并确定可能增加黑色素瘤风险的癌症易感性基因谱。
对 400 名患有黑色素瘤且有个人或家族癌症病史的个体进行了>80 种癌症易感性基因的种系检测。对另外 3 个肿瘤学和皮肤科数据集进行了种系数据的比较分析。
在 15.3%（61 名）患有黑色素瘤的个体中发现了种系致病性/可能致病性（P/LP）变异。大多数变异（41，67%）涉及与黑色素瘤无关的基因（BLM、BRIP1、CHEK2、MLH1、MSH2、PMS2、RAD51C）。三分之一（20，33%）是先前与家族性黑色素瘤相关的基因（BAP1、BRCA2、CDKN2A、MITF、TP53）。近一半（30，46.9%）的 P/LP 变异发生在同源修复缺陷基因中。验证队列显示，来自非选择性肿瘤队列的 P/LP 率为 10.6%，来自精选商业检测队列的 P/LP 率为 15.8%，来自高度精选的皮肤科研究的 P/LP 率为 14.5%。
队列具有不同程度的选择性，有些是回顾性的。
黑色素瘤患者的种系易感性很常见，在 10.6%至 15.8%的患者中可诊断出具有临床可操作性的发现。
