Mangantig Ernest, MacGregor Stuart, Iles Mark M, Scolyer Richard A, Cust Anne E, Hayward Nicholas K, Montgomery Grant W, Duffy David L, Thompson John F, Henders Anjali, Bowdler Lisa, Rowe Casey, Cadby Gemma, Mann Graham J, Whiteman David C, Long Georgina V, Ward Sarah V, Khosrotehrani Kiarash, Barrett Jennifer H, Law Matthew H
Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Pulau Pinang, Malaysia.
Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia.
Hum Mol Genet. 2021 Jan 6;29(21):3578-3587. doi: 10.1093/hmg/ddaa222.
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.
已发现种系基因变异，这些变异使个体和家族易患黑色素瘤。肿瘤厚度是临床局限性原发性黑色素瘤患者预后的最强预测指标。我们试图确定肿瘤厚度的变异是否存在遗传基因贡献。如果得到证实，这将为寻找影响肿瘤厚度的特定基因变异提供依据。为了解决这个问题，我们使用测量了原发性皮肤黑色素瘤厚度的非亲属患者，估计了全基因组遗传变异（基于变异的遗传力）对肿瘤厚度变异的贡献比例。作为次要分析，我们对肿瘤厚度进行了全基因组关联研究（GWAS）。分析使用了10604名原发性皮肤黑色素瘤患者，这些患者来自从普通人群、初级保健和黑色素瘤治疗中心招募的8个队列的9个GWAS数据集。在进行质量控制并筛选出具有研究表型的非亲属个体后，8125名患者被用于初步分析，以检验肿瘤厚度是否具有遗传性。对8505名个体（47.6%为女性）的扩展集进行了次要GWAS荟萃分析。分析针对参与者的年龄、性别、队列和血统进行了调整。我们发现，肿瘤厚度变异的26.6%（标准误11.9%，P = 0.0128）可归因于全基因组遗传变异。虽然需要重复验证，但11号染色体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肿瘤厚度相关的基因变异，这将有助于识别影响黑色素瘤生长和侵袭的宿主生物学过程。
