A genome-wide association study of testicular germ cell tumor

Abstract

We conducted a genome-wide association study for testicular germ cell tumor (TGCT), genotyping 307,666 SNPs in 730 cases and 1,435 controls from the UK and replicating associations in a further 571 cases and 1,806 controls. We found strong evidence for susceptibility loci on chromosome 5 (per allele OR = 1.37 (95% CI = 1.19-1.58), P = 3 × 10 −13 ), chromosome 6 (OR = 1.50 (95% = CI = 1.28-1.75), P = 10 −13 ) and chromosome 12 (OR = 2.55 (95% CI = 2.05-3.19), P = 10 −31 ). KITLG, encoding the ligand for the receptor tyrosine kinase KIT, which has previously been implicated in the pathogenesis of TGCT and the biology of germ cells, may explain the association on chromosome 12.Testicular germ cell tumor (TGCT) is the most common malignancy in men aged 15-45 years. The worldwide incidence of the disease is 7.5 per 100,000, but the rates vary considerably between countries and ancestry groups1. Known risk factors include a family history of the disease, previous germ cell tumor, subfertility, undescended testis (UDT)2 and testicular microlithiasis3, the presence of small foci of intratesticular calcification. There are two main subclasses of TGCT: seminomas show histological features of primordial germ cells, whereas nonseminomas show varying degrees of differentiation toward embryonal and extraembryonal structures. Some tumors show features of both classes. TGCTs are believed to arise from progenitor germ cells through a preinvasive phase of intratubular germ cell neoplasia (ITGCN)4. The peak incidence of nonseminomas is between the ages of 20 and 30 Several studies have estimated the risk to brothers and fathers of individuals with TGCT to be eight-to tenfold and four-to sixfold, respectively7, much higher than the familial risks for most other cancer classes, which are generally approximately twofold8. However, most families with multiple cases of TGCT include only two affected individuals, usually sibpairs, and extended pedigrees with several cases are exceedingly rare9. A genome-wide genetic linkage study of 179 families by an international consortium did not provide strong evidence for the location of a gene predisposing to TGCT9. However, candidate association studies have indicated that deletions on the Y chromosome that are also associated with infertility are implicated in TGCT susceptibility10.We carried out a genome-wide association study for TGCT susceptibility alleles using subjects with TGCT from the UK and the Illumina 370K array. Table 2 online). SNPs on chromosomes 5, 6 and 12 showed convincing evidence of association after replication (Table 1).The strongest evidence was obtained for rs995030 and rs1508595, which are located within the same LD block on chromosome 12. SNPs located in adjacent LD blocks showed much weaker evidence of association, suggesting that the causative variant resides within this block. In a multiple regression analysis, there was evidence that both rs995030 and rs1508595 are independently associated with disease risk (P = 0.03 in stage 2, P = 0.0006 overall, compare...

Transgenerational epigenetic effects of theApobec1cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

“…Testicular cancer is the most common malignancy affecting young men (3), more than 90% of testicular cancers result from TGCTs (4), TGCTs rank third in heritability among all cancers (5), and family history is the strongest known risk factor with a two-to sixfold increase among sons and a 5-to 19-fold increase among brothers of affected individuals (6)(7)(8)(9). Despite the strong evidence for heritability, the only TGCT susceptibility factors identified in genome-wide association studies are the gr/gr deletion on the Y chromosome and autosomal variants in KITLG, SPRY4, BAK1, and DMRT1, which together account for less than 10% of risk (10)(11)(12)(13)(14). The substantial difference in prevalence between sons and brothers of cases and the epidemiological evidence for maternal estrogens, birth order, birth weight, and other factors (15)(16)(17) together raise the possibility that maternal conditions, epigenetic effects, and perhaps unconventional modes of inheritance also contribute to TGCT risk (18).…”

Variants in KITLG predispose to testicular germ cell cancer independently from spermatogenic function

“…Another possibility is related to the presence of possible confounding risk factors. In fact, both GWAS included subjects with familial history of TGCT and personal history of cryptorchidism (Kanetsky et al 2009, Rapley et al 2009), which represent to date the most important clinical risk factor for TGCT with a relative risk of 4.8 (Dieckmann & Pichlmeier 2004). On the contrary, they did not consider another important risk factor for TGCT, infertility, or low sperm count.…”

“…More recently, four genome-wide association studies (GWAS) from UK and USA have reported association of TGCTs with six new loci (KITLG, SPRY4, BAK1, DMRT1, TERT, and ATF7IP; Kanetsky et al 2009, Rapley et al 2009, Turnbull et al 2010. The strongest association for TGCT susceptibility was found for SNPs in KITLG (ligand for the membrane-bound receptor tyrosine kinase KIT) gene with a O2.5-fold increased risk of disease per major allele (Kanetsky et al 2009, Rapley et al 2009, which is the highest reported for any cancer to date (Chanock 2009). The KITLG-KIT system regulates the survival, proliferation, and migration of primordial germ cells (PGCs; Runyan et al 2006, Boldajipour & Raz 2007, the cells from which spermatogonia and spermatocytes develop and from which TGCT is believed to arise.…”

“…In fact, analysis of KITLG variation in TGCT men with a history of infertility, even if suggested, was not tested in GWAS (Kanetsky et al 2009, Rapley et al 2009). We therefore analyzed the association between previously identified SNPs in KITLG (Kanetsky et al 2009, Rapley et al 2009) and TGCT cases and controls with normal and disrupted spermatogenesis.…”

The pursuit of genome-wide association studies: where are we now?

“…The KILTG gene encodes the ligand for the membrane receptor tyrosine kinase (c-KIT), and both the somatic and germline mutations in the KIT/ KILTG pathway have been well-linked to testicular cancer. 101,102 The results are notable because it is rare to find common risk alleles (in the context of SNPs) with ORs larger than 2, not only in cancers but also in other complex diseases.…”