Abstract
Testicular germ cell cancer (TGCC) is one of the most heritable forms of cancer. Previous genome-wide association studies have focused on single nucleotide polymorphisms, largely ignoring the influence of copy number variants (CNVs). Here we present a genome-wide study of CNV on a cohort of 212 cases and 437 controls from Denmark, which was genotyped at ∼1.8 million markers, half of which were non-polymorphic copy number markers. No association of common variants were found, whereas analysis of rare variants (present in less than 1% of the samples) initially indicated a single gene with significantly higher accumulation of rare CNVs in cases as compared to controls, at the gene PTPN1 (P = 3.8 × 10−2, 0.9% of cases and 0% of controls). However, the CNV could not be verified by qPCR in the affected samples. Further, the CNV calling of the array-data was validated by sequencing of the GSTM1 gene, which showed that the CNV frequency was in complete agreement between the two platforms. This study therefore disconfirms the hypothesis that there exists a single CNV locus with a major effect size that predisposes to TGCC. Genome-wide pathway association analysis indicated a weak association of rare CNVs related to cell migration (false-discovery rate = 0.021, 1.8% of cases and 1.1% of controls). Dysregulation during migration of primordial germ cells has previously been suspected to be a part of TGCC development and this set of multiple rare variants may thereby have a minor contribution to an increased susceptibility of TGCCs.
Highlights
Testicular germ cell cancer (TGCC) is the most common malignancy in young men aged 15−45 years
Common variants were defined as copy number variants (CNVs) present in more than 1% of the study population, and rare variants as CNVs present in no more than 1% of the studied subjects
LOCUS ASSOCIATION ANALYSIS In order to identify common CNVs associated with TGCC, binary copy number state frequencies of the case and control cohorts were compared at all loci with CNV frequencies above 1%
Summary
Testicular germ cell cancer (TGCC) is the most common malignancy in young men aged 15−45 years. The familial aggregation of TGCC is one of the highest among cancers. Despite the relatively high degree of heritability, genome-wide familial linkage analyses have not identified any loci predisposing for TGCC, and candidate studies have only found one rare deletion (2–3%) at the Y chromosome that confers a modest 2–3 fold increased risk (Nathanson et al, 2005). Genomewide association studies that search for common single nucleotide variants associated to TGCC have identified susceptibility loci at the genes KITLG, SPRY4, BAK1, DMRT1, TERT, and ATF7IP (Kanetsky et al, 2009; Rapley et al, 2009; Turnbull et al, 2010; Dalgaard et al, 2012). Consistent with the relatively high familial relative risk, this is the largest effect size found for any single loci among cancers. A considerable portion of the heritability remains to be explained
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