葡萄膜黑色素瘤（UM）和非肢端皮肤黑色素瘤（CM）是不同的实体，具有不同的遗传景观，尽管两者都起源于黑色素细胞。然而，它们之间存在相似之处，即它们最常影响欧洲血统的人，并且 BAP1、POT1 和 CDKN2A 的高外显率种系变异已被证明易患 UM 和 CM。本研究旨在进一步探索受 UM 和 CM 影响的患者的种系变异，揭示导致这些疾病的潜在遗传机制。我们利用外显子组测序分析了 83 名被诊断患有 UM 和 CM 的澳大利亚患者的种系 DNA 样本。 8 名 (10%) 患者被发现携带已知黑色素瘤易感基因 POT1、MITF、OCA2、SLC45A2 和 TYR 的致病性突变。三名 (4%) 患者携带先前与其他癌症综合征相关的基因（ATR、BRIP1 和 MSH6）的致病性变异，另外三名患者携带隐性癌症基因（着色性干皮病和范可尼贫血）的单等位基因致病性变异，表明表型外显率降低这些人可能有助于 UM 和 CM 的发展。这些发现强调需要进一步研究这些基因在黑色素瘤易感性中的作用。© 2024 作者。色素细胞

Uveal melanoma (UM) and nonacral cutaneous melanoma (CM) are distinct entities with varied genetic landscapes despite both arising from melanocytes. There are, however, similarities in that they most frequently affect people of European ancestry, and high penetrance germline variants in BAP1, POT1 and CDKN2A have been shown to predispose to both UM and CM. This study aims to further explore germline variants in patients affected by both UM and CM, shedding light on the underlying genetic mechanism causing these diseases. Using exome sequencing we analysed germline DNA samples from a cohort of 83 Australian patients diagnosed with both UM and CM. Eight (10%) patients were identified that carried pathogenic mutations in known melanoma predisposition genes POT1, MITF, OCA2, SLC45A2 and TYR. Three (4%) patients carried pathogenic variants in genes previously linked with other cancer syndromes (ATR, BRIP1 and MSH6) and another three cases carried monoallelic pathogenic variants in recessive cancer genes (xeroderma pigmentosum and Fanconi anaemia), indicating that reduced penetrance of phenotype in these individuals may contribute to the development of both UM and CM. These findings highlight the need for further studies characterising the role of these genes in melanoma susceptibility.© 2024 The Author(s). Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.