PDF(Pubmed)
Abstract：
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.
摘要：
MITF-E318K变体与皮肤黑素瘤的遗传易感性有关。我们讨论了MITF-E318K的发生及其与CDKN2A和MC1R基因的种系状态的关联，在基于医院的248例黑色素瘤患者中，包括多个队列，家族性,儿科,与其他肿瘤相关的散发性和黑色素瘤。确定了7名MITF-E318K携带者，跨越除儿科患者以外的每一组。三个携带者显示突变的CDKN2A，五种显示的MC1R变体，而零星的携带者没有发现变异。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异，在四个BRAF-V600E转移中，MITF野生型等位基因的体细胞丢失，MITF-E318K的扩增和包括CDKN2A和MTAP的9p21.3染色体区域的缺失。TCGAPan-Cancer-Atlas数据集中MITF-E318K黑色素瘤携带者的肿瘤的计算机模拟分析证实了与BRAF突变和9p21.3缺失的关联，揭示了共同的遗传模式。MTAP是在最高数量的患者中以纯合水平缺失的基因。这些结果支持种系和肿瘤基因组分析的实用性，以定义肿瘤组，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。
