Integrated case-control and somatic-germline interaction analyses of melanoma susceptibility genes.
Integrated case-control and somatic-germline interaction analyses of melanoma susceptibility genes.
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黑色素瘤易感基因的综合病例对照和体细胞-种系相互作用分析。
DOI：
10.1016/j.bbadis.2018.01.007
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Huff,ChadD
中科院分区：
文献类型：
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作者：
Yu,Yao;Hu,Hao;Chen,Jiun-Sheng;Hu,Fulan;Fowler,Jerry;Scheet,Paul;Zhao,Hua;Huff,ChadD
虽然许多基因与黑色素瘤的易感性有关，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的研究。为了更好地表征生殖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病例对照和体细胞-生殖系相互作用研究，研究对象包括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对跨平台技术分层进行了对照，并使用VAAST 2进行了基于基因的关联测试。四个已建立的黑色素瘤易感基因获得了名义上的统计学意义，分别是MC1R(p = .0014)、Mitf(p = .0165)、BRCA2(p = .0206)和MTAP(p = .0393)。我们还观察到FANCA(p = .002)与FANCA的关联，该基因以前与黑色素瘤的生存有关。BRCA2的关联信号主要由可能的基因干扰(LGD)变异驱动，优势比(OR)为5.62(95%可信区间(CI)1.03-30.1)。相反，MC1R和MITF的关联信号主要是由预测的致病错义变异驱动的，估计MC1R和MITF的OR值分别为1.4到3.0和4.1。MTAP在病例中显示出超过LGD和预测的损害性错义变异，OR值分别为5.62和3.72，尽管这两个类别都不显著。对于已知或预测具有破坏性变异的个体，四个基因中的两个，MC1R(p = .005)和MTAP(p = .035)的发病年龄显著较低。在对生殖系携带者状态和重叠拷贝数改变的分析中，我们没有观察到证据支持在四个基因中的任何一个中存在两次致癌模型。尽管MC1R携带者在四种分子肿瘤亚型中的比例很高，但在三种野生型肿瘤中，这些个体占紫外线(UV)辐射突变特征的69%(p = .040)，突显出MC1R功能丧失变异的个体对紫外线暴露的敏感性增加。
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), andMTAP(p = .0393). We also observed a suggestive association forFANCA(p = .002), a gene previously implicated in melanoma survival. The association signal forBRCA2was 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 forMC1RandMITFwere driven primarily by predicted pathogenic missense variants, with estimated ORs of 1.4 to 3.0 forMC1Rand 4.1 forMITF.MTAPexhibited 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) andMTAP(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. AlthoughMC1Rcarriers 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 inMC1R.