The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors. Seven MITF-E318K carriers were identified, spanning every group except the pediatric patients. Three carriers showed mutated CDKN2A, five displayed MC1R variants, while the sporadic carrier revealed no variants. Germline/tumor whole exome sequencing for this carrier revealed germline variants of unknown significance in ATM and FANCI genes and, in four BRAF-V600E metastases, somatic loss of the MITF wild-type allele, amplification of MITF-E318K and deletion of a 9p21.3 chromosomal region including CDKN2A and MTAP. In silico analysis of tumors from MITF-E318K melanoma carriers in the TCGA Pan-Cancer-Atlas dataset confirmed the association with BRAF mutation and 9p21.3 deletion revealing a common genetic pattern. MTAP was the gene deleted at homozygous level in the highest number of patients. These results support the utility of both germline and tumor genome analysis to define tumor groups providing enhanced information for clinical strategies and highlight the importance of melanoma prevention programs for MITF-E318K patients.

中文翻译：

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黑色素瘤患者与 MITF-E318K 种系突变相关的遗传变异和体细胞改变

MITF-E318K 变体与皮肤黑色素瘤的遗传易感性有关。我们在以医院为基础的 248 名黑色素瘤患者系列中探讨了 MITF-E318K 的发生及其与 CDKN2A 和 MC1R 基因种系状态的关联，这些患者包括多发性、家族性、儿科、散发性和与其他肿瘤相关的黑色素瘤。确定了 7 名 MITF-E318K 携带者，涵盖除儿科患者外的每一组。三个携带者显示突变的 CDKN2A，五个显示 MC1R 变体，而散发性携带者没有显示变体。该载体的种系/肿瘤全外显子组测序揭示了 ATM 和 FANCI 基因中未知意义的种系变体，在四个 BRAF-V600E 转移中，MITF 野生型等位基因的体细胞丢失、MITF-E318K 的扩增和 9p21 的缺失。在TCGA Pan-Cancer-Atlas 数据集中对来自 MITF-E318K 黑色素瘤携带者的肿瘤进行计算机分析证实了与 BRAF 突变和 9p21.3 缺失的关联，揭示了一种共同的遗传模式。MTAP 是在最多患者中以纯合水平缺失的基因。这些结果支持利用种系和肿瘤基因组分析来定义肿瘤组，为临床策略提供增强的信息，并强调黑色素瘤预防计划对 MITF-E318K 患者的重要性。