Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas.
Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas.
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DOI：
10.1093/jnci/djab167
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发表时间：
2022-02-07
期刊：
影响因子：
--
通讯作者：
Stern MH
中科院分区：
文献类型：
--
作者：
Mobuchon L;Derrien AC;Houy A;Verrier T;Pierron G;Cassoux N;Milder M;Deleuze JF;Boland A;Scelo G;Cancel-Tassin G;Cussenot O;Rodrigues M;Noirel J;Machiela MJ;Stern MH
葡萄膜黑色素瘤（UM）是一种罕见的眼部恶性肿瘤，主要见于欧洲血统人群。携带单体 3 (M3) 的 UM 经常主要在肝脏中复发，而携带二体性 3 (D3) 的 UM 与更有利的结果相关。在这里，我们在一项大型全基因组关联研究 (GWAS) 中探讨了 UM 遗传易感因素，该研究对 1142 名欧洲 UM 患者和 882 名健康对照进行了研究。我们将 2 个独立的数据集（全局筛选阵列）与先前发布的 UM 中的 GWAS（Omni5 阵列）中描述的数据集结合起来，分别进行估算并随后合并。根据 3 号染色体状态对患者进行分层，并测试确定的 UM 风险位点与 M3 或 D3 亚组的差异关联。所有统计检验都是双面的。我们概括了之前在 CLPTM1L 上确定的 5 号染色体上的风险位点（rs421284：比值比 [OR] = 1.58，95% 置信区间 [CI] = 1.35 至 1.86；P = 1.98 × 10-8），并确定了 2 个与眼睛色素沉着有关的额外风险位点：6 号染色体上的 IRF4 位点（rs12203592：OR = 1.76，95% CI = 1.44 至 2.16；P = 3.55 × 10-8）和 15 号染色体上的 HERC2 基因座（rs12913832：OR = 0.57，95% CI = 0.48 至 0.67； P = 1.88 × 10-11)。研究发现，IRF4 rs12203592 单核苷酸多态性与 D3 UM 亚型的风险完全相关（ORD3 = 2.73，95% CI = 1.87 至 3.97；P = 1.78 × 10-7），HERC2 rs12913832 单核苷酸多态性与 D3 UM 亚型的风险完全相关。 M3 UM 亚型（ORM3 = 2.43，95% CI = 1.79 至 3.29；P = 1.13 × 10-8）。然而，CLPTM1L 风险位点在两个亚组中具有同样的统计显着性。这项工作确定了另外 2 个 UM 风险位点，这些位点因其在色素沉着中的作用而闻名。重要的是，我们证明UM肿瘤生物学和转移潜力受到患者遗传背景的影响。
Uveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. UMs carrying a monosomy 3 (M3) frequently relapse mainly in the liver, whereas UMs with disomy 3 (D3) are associated with more favorable outcome. Here, we explored the UM genetic predisposition factors in a large genome-wide association study (GWAS) of 1142 European UM patients and 882 healthy controls . We combined 2 independent datasets (Global Screening Array) with the dataset described in a previously published GWAS in UM (Omni5 array), which were imputed separately and subsequently merged. Patients were stratified according to their chromosome 3 status, and identified UM risk loci were tested for differential association with M3 or D3 subgroups. All statistical tests were 2-sided. We recapitulated the previously identified risk locus on chromosome 5 on CLPTM1L (rs421284: odds ratio [OR] =1.58, 95% confidence interval [CI] = 1.35 to 1.86; P = 1.98 × 10-8) and identified 2 additional risk loci involved in eye pigmentation: IRF4 locus on chromosome 6 (rs12203592: OR = 1.76, 95% CI = 1.44 to 2.16; P = 3.55 × 10-8) and HERC2 locus on chromosome 15 (rs12913832: OR= 0.57, 95% CI = 0.48 to 0.67; P = 1.88 × 10-11). The IRF4 rs12203592 single-nucleotide polymorphism was found to be exclusively associated with risk for the D3 UM subtype (ORD3 = 2.73, 95% CI = 1.87 to 3.97; P = 1.78 × 10-7), and the HERC2 rs12913832 single-nucleotide polymorphism was exclusively associated with risk for the M3 UM subtype (ORM3 = 2.43, 95% CI = 1.79 to 3.29; P = 1.13 × 10-8). However, the CLPTM1L risk locus was equally statistically significant in both subgroups. This work identified 2 additional UM risk loci known for their role in pigmentation. Importantly, we demonstrate that UM tumor biology and metastatic potential are influenced by patients’ genetic backgrounds.
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DOI：
10.1126/science.1194472
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Harbour JW;Onken MD;Roberson ED;Duan S;Cao L;Worley LA;Council ML;Matatall KA;Helms C;Bowcock AM
通讯作者：
Bowcock AM
影响因子：
9.8
作者：
Royer-Bertrand, Beryl;Torsello, Matteo;Rivolta, Carlo
通讯作者：
Rivolta, Carlo
影响因子：
30.8
作者：
Harbour, J. William;Roberson, Elisha D. O.;Anbunathan, Hima;Onken, Michael D.;Worley, Lori A.;Bowcock, Anne M.
通讯作者：
Bowcock, Anne M.
影响因子：
11.5
作者：
Field, Matthew G.;Kuznetsov, Jeffim N.;Harbour, J. William
通讯作者：
Harbour, J. William
影响因子：
4.6
作者：
Ferguson, Robert;Vogelsang, Matjaz;Kirchhoff, Tomas
通讯作者：
Kirchhoff, Tomas