Abstract

Germline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness.To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness.The analyses utilized 10 604 individuals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated individuals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 individuals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry.We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P < 5 × 10⁻⁸) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.

中文翻译：

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生殖系变异与诊断时原发性黑色素瘤肿瘤厚度增加有关

摘要

已经鉴定出生殖系遗传变异，这会使个人和家庭容易患上黑色素瘤。肿瘤厚度是临床局部原发性黑色素瘤患者预后的最强预测因子。我们试图确定是否存在对肿瘤厚度变化的遗传性贡献。如果得到证实，这将证明寻找影响肿瘤厚度的特定遗传变异是合理的。为了解决这个问题，我们使用具有测量的原发性皮肤黑色素瘤的无关患者估计了归因于全基因组遗传变异（基于变异的遗传力）的肿瘤厚度变异的比例厚度。作为次要分析，我们进行了肿瘤厚度的全基因组关联研究（GWAS）。分析利用了从普通人群、初级保健和黑色素瘤治疗中心招募的八个队列的九个 GWAS 数据集提取的 10604 名原发性皮肤黑色素瘤患者。在对具有研究表型的无关个体进行质量控制和过滤后，8125 名患者被用于初步分析以测试肿瘤厚度是否可遗传。对 8505 名个体（47.6% 女性）的扩展集进行了二次 GWAS 荟萃分析。根据参与者的年龄、性别、队列和血统调整分析 对 8505 名个体（47.6% 女性）的扩展集进行了二次 GWAS 荟萃分析。根据参与者的年龄、性别、队列和血统调整分析 对 8505 名个体（47.6% 女性）的扩展集进行了二次 GWAS 荟萃分析。根据参与者的年龄、性别、队列和血统调整分析. 我们发现 肿瘤厚度的26.6% (SE 11.9%, P = 0.0128) 变异可归因于全基因组遗传变异。虽然需要复制，但染色体 11 位点与肿瘤厚度相关（P  < 5 × 10 ^-8）。我们的工作表明，足够大的数据集将能够发现与更大的肿瘤厚度相关的遗传变异，这将导致识别影响黑色素瘤生长和侵袭的宿主生物过程。