Genetic associations of the interleukin locus at 1q32.1 with clinical outcomes of cutaneous melanoma.
Genetic associations of the interleukin locus at 1q32.1 with clinical outcomes of cutaneous melanoma.
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DOI：
10.1136/jmedgenet-2014-102832
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发表时间：
2015-04
影响因子：
4
通讯作者：
Kirchhoff T
中科院分区：
文献类型：
--
作者：
Rendleman J;Vogelsang M;Bapodra A;Adaniel C;Silva I;Moogk D;Martinez CN;Fleming N;Shields J;Shapiro R;Berman R;Pavlick A;Polsky D;Shao Y;Osman I;Krogsgaard M;Kirchhoff T
由于黑色素瘤的高免疫原性，免疫途径中的种系遗传变异与黑色素瘤预后的相关性已被研究。然而，有限的候选选择、不充分的力量或缺乏独立的验证阻碍了这些先前发现的重复性，阻碍了个性化临床应用于黑色素瘤预测。我们的目的是评估免疫调节途径中的遗传变异在预测黑色素瘤临床结果中的预后作用。我们对1022例黑色素瘤患者的44个免疫调节基因中的72个标签单核苷酸多态(SNPs)进行了基因分型，并进行了COX回归分析，以检验SNPs与黑色素瘤无复发(RFS)和总生存期(OS)的关系。我们使用精细定位策略进一步研究了最显著的相关性，并对75例黑色素瘤患者的亚群中的CD4+T细胞进行了功能分析。在白介素10染色体1q32.1(杂合子HR0.58，95%可信区间0.39至0.86；p=0.0006)上发现了与黑色素瘤OS最显著的关联，该变异先前被证明与自身免疫性疾病有关。位于1q32.1的多个额外的SNP在名义上也与OS相关，证实了该基因座中至少有两个独立的关联信号。此外，我们还发现rs3024493与下调CD4+T细胞分泌白介素10(IL10)有关。我们在1q32.1发现了IL10与黑色素瘤生存的新关联，表明该基因座可被认为是一种新的黑色素瘤预后生物标记物，具有帮助黑色素瘤患者治疗的潜力。我们的发现也进一步支持了IL10在刺激抗肿瘤免疫反应中的另一种作用。
Due to high melanoma immunogenicity, germline genetic variants in immune pathways have been studied for association with melanoma prognosis. However, limited candidate selection, inadequate power, or lack of independent validation have hampered the reproducibility of these prior findings, preventing personalised clinical applicability in melanoma prognostication. Our objective was to assess the prognostic utility of genetic variants in immunomodulatory pathways for prediction of melanoma clinical outcomes. We genotyped 72 tag single nucleotide polymorphisms (SNPs) in 44 immunomodulatory genes in a population sample of 1022 melanoma patients and performed Cox regression analysis to test the association between SNPs and melanoma recurrence-free (RFS) and overall survival (OS). We have further investigated the most significant associations using a fine mapping strategy and followed with functional analyses in CD4+ T cells in a subset of 75 melanoma patients. The most significant associations were found with melanoma OS for rs3024493 in IL10 at chromosome 1q32.1 (heterozygous HR 0.58, 95% CI 0.39 to 0.86; p = 0.0006), a variant previously shown to be linked with autoimmune conditions. Multiple additional SNPs at 1q32.1 were also nominally associated with OS confirming at least two independent association signals in this locus. In addition, we found rs3024493 associated with the downregulation of interleukin 10 (IL10) secretion in CD4+ T cells. We discovered novel associations of IL10 with melanoma survival at 1q32.1, suggesting this locus should be considered as a novel melanoma prognostic biomarker with potential for aiding melanoma patient management. Our findings also provide further support for an alternative role of IL10 in stimulation of anti-tumour immune response.
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影响因子：
3.4
作者：
Dennis KL;Blatner NR;Gounari F;Khazaie K
通讯作者：
Khazaie K
影响因子：
--
作者：
Bradford, Porcia T.;Goldstein, Alisa M.;McMaster, Mary L.;Tucker, Margaret A.
通讯作者：
Tucker, Margaret A.
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
2.2
作者：
Martínez-Escribano, JA;Moya-Quiles, MR;Alvarez-López, MR
通讯作者：
Alvarez-López, MR
影响因子：
2.4
作者：
Nemunaitis, J;Fong, T;Ando, D
通讯作者：
Ando, D