Inherited genetic variants associated with occurrence of multiple primary melanoma.
Inherited genetic variants associated with occurrence of multiple primary melanoma.
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DOI：
10.1158/1055-9965.epi-14-1426
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
GEM Study Group
中科院分区：
文献类型：
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作者：
Gibbs DC;Orlow I;Kanetsky PA;Luo L;Kricker A;Armstrong BK;Anton-Culver H;Gruber SB;Marrett LD;Gallagher RP;Zanetti R;Rosso S;Dwyer T;Sharma A;La Pilla E;From L;Busam KJ;Cust AE;Ollila DW;Begg CB;Berwick M;Thomas NE;GEM Study Group
最近的研究，包括全基因组关联研究，已经确定了几个假定的黑色素瘤低外显率易感性位点。我们试图在国际人群基因、环境和黑色素瘤 (GEM) 研究中确定它们对多原发性黑色素瘤遗传易感性的普遍性。 GEM 是一项病例对照研究，纳入了 1,206 例多原发性黑色素瘤病例和 2,469 例首次原发性黑色素瘤参与者作为对照组。我们研究了来自先前报道与黑色素瘤相关的 21 个不同遗传区域的 47 个单核苷酸多态性 (SNP) 发生多发性原发性黑色素瘤的几率。 OR 和 95% CI 使用根据基线特征（年龄、性别、按性别划分的年龄和研究中心）进行调整的逻辑回归模型来确定。我们研究了单变量模型并建立了多变量模型来评估 SNP 的独立效应。 6 个基因邻域（TERT/CLPTM1L、TYRP1、MTAP、TYR、NCOA6 和 MX2）中的 11 个 SNP 和 PARP1 单倍型与多发性原发性黑色素瘤相关。在仅包含单变量建模中最具统计学意义的发现并针对色素表型、背痣和基线特征进行调整的多变量模型中，我们发现 TERT/CLPTM1L rs401681 (P = 0.004)、TYRP1 rs2733832 (P = 0.006)、MTAP rs1335510 (P = 0.0005)、 TYR rs10830253 (P = 0.003) 和 MX2 rs45430 (P = 0.008) 与多原发性黑色素瘤显着相关，而 NCOA6 rs4911442 接近显着性 (P = 0.06)。 GEM 研究为这些遗传区域与黑色素瘤风险的相关性提供了额外的证据，并估计了观察到的遗传效应对随后原发性黑色素瘤发展的影响程度。
Recent studies including genome-wide association studies have identified several putative low-penetrance susceptibility loci for melanoma. We sought to determine their generalizability to genetic predisposition for multiple primary melanoma in the international population-based Genes, Environment, and Melanoma (GEM) Study. GEM is a case-control study of 1,206 incident cases of multiple primary melanoma and 2,469 incident first primary melanoma participants as the control group. We investigated the odds of developing multiple primary melanoma for 47 single nucleotide polymorphisms (SNP) from 21 distinct genetic regions previously reported to be associated with melanoma. ORs and 95% CIs were determined using logistic regression models adjusted for baseline features (age, sex, age by sex interaction, and study center). We investigated univariable models and built multivariable models to assess independent effects of SNPs. Eleven SNPs in 6 gene neighborhoods (TERT/CLPTM1L, TYRP1, MTAP, TYR, NCOA6, and MX2) and a PARP1 haplotype were associated with multiple primary melanoma. In a multivariable model that included only the most statistically significant findings from univariable modeling and adjusted for pigmentary phenotype, back nevi, and baseline features, we found TERT/CLPTM1L rs401681 (P = 0.004), TYRP1 rs2733832 (P = 0.006), MTAP rs1335510 (P = 0.0005), TYR rs10830253 (P = 0.003), and MX2 rs45430 (P = 0.008) to be significantly associated with multiple primary melanoma while NCOA6 rs4911442 approached significance (P = 0.06). The GEM study provides additional evidence for the relevance of these genetic regions to melanoma risk and estimates the magnitude of the observed genetic effect on development of subsequent primary melanoma.