Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
Biochim Biophys Acta Mol Basis Dis. 2018 Jun;1864(6 Pt B):2247-2254. doi: 10.1016/j.bbadis.2018.01.007. Epub 2018 Jan 6.
While a number of genes have been implicated in melanoma susceptibility, the role of protein-coding variation in melanoma development and progression remains underexplored. To better characterize the role of germline coding variation in melanoma, we conducted a whole-exome case-control and somatic-germline interaction study involving 322 skin cutaneous melanoma cases from The Cancer Genome Atlas and 3607 controls of European ancestry. We controlled for cross-platform technological stratification using XPAT and conducted gene-based association tests using VAAST 2. Four established melanoma susceptibility genes achieved nominal statistical significance, MC1R (p = .0014), MITF (p = .0165) BRCA2 (p = .0206), and MTAP (p = .0393). We also observed a suggestive association for FANCA (p = .002), a gene previously implicated in melanoma survival. The association signal for BRCA2 was driven primarily by likely gene disrupting (LGD) variants, with an Odds Ratio (OR) of 5.62 (95% Confidence Interval (CI) 1.03-30.1). In contrast, the association signals for MC1R and MITF were driven primarily by predicted pathogenic missense variants, with estimated ORs of 1.4 to 3.0 for MC1R and 4.1 for MITF. MTAP exhibited an excess of both LGD and predicted damaging missense variants among cases, with ORs of 5.62 and 3.72, respectively, although neither category was significant. For individuals with known or predicted damaging variants, age of disease onset was significantly lower for two of the four genes, MC1R (p = .005) and MTAP (p = .035). In an analysis of germline carrier status and overlapping copy number alterations, we observed no evidence to support a two-hit model of carcinogenesis in any of the four genes. Although MC1R carriers were represented proportionally among the four molecular tumor subtypes, these individuals accounted for 69% of ultraviolet (UV) radiation mutational signatures among triple-wild type tumors (p = .040), highlighting the increased sensitivity to UV exposure among individuals with loss-of-function variants in MC1R.
虽然有许多基因与黑色素瘤易感性有关，但蛋白质编码变异在黑色素瘤发生和发展中的作用仍未得到充分探索。为了更好地描述种系编码变异在黑色素瘤中的作用，我们进行了一项全外显子组病例对照和体细胞-种系相互作用研究，涉及来自癌症基因组图谱的 322 例皮肤黑色素瘤病例和 3607 例欧洲血统对照。我们使用 XPAT 控制跨平台技术分层，并使用 VAAST 2 进行基于基因的关联测试。四个已确立的黑色素瘤易感性基因达到了名义统计学意义，即 MC1R（p=0.0014）、MITF（p=0.0165）、BRCA2（p=0.0206）和 MTAP（p=0.0393）。我们还观察到 FANCA（p=0.002）的提示性关联，该基因先前与黑色素瘤存活有关。BRCA2 的关联信号主要由可能的基因破坏（LGD）变异驱动，比值比（OR）为 5.62（95%置信区间（CI）为 1.03-30.1）。相比之下，MC1R 和 MITF 的关联信号主要由预测的致病性错义变异驱动，MC1R 的估计 OR 为 1.4 至 3.0，而 MITF 的 OR 为 4.1。MTAP 在病例中表现出 LGD 和预测的破坏性错义变异的过度表达，OR 分别为 5.62 和 3.72，尽管这两个类别都没有显著意义。对于已知或预测的破坏性变异携带者，两种基因（MC1R 和 MTAP）的疾病发病年龄明显较低（p=0.005 和 p=0.035）。在对种系携带状态和重叠拷贝数改变的分析中，我们没有发现任何证据支持任何四个基因的致癌作用的双打击模型。尽管 MC1R 携带者在四个分子肿瘤亚型中所占比例相当，但这些个体在三重野生型肿瘤中占紫外线（UV）辐射突变特征的 69%（p=0.040），这突出了 MC1R 功能丧失变异个体对 UV 暴露的敏感性增加。
