The Y Deletion gr/gr and Susceptibility to Testicular Germ Cell Tumor

Abstract

Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region--known as the "gr/gr" deletion--has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3-3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5-6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6-5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72-3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT.

Male infertility: Pathogenesis and clinical diagnosis

“…61 In the same study the authors also demonstrated that the deletion affects the spermatogenic potential even in the normal range. gr/ gr deletion has also been reported as a potential risk factor for testicular germ cell tumours, 62 however, this data needs further confirmation in an ethnically and geographically matched casecontrol study setting.…”

Familial testicular cancer: Interest in genetic testing among high-risk family members

“…13 Six years later, a major FTC susceptibility gene has yet to be identified, despite substantial additional research. 15,16 The most recent genome-wide linkage analysis reported by the ITCLC did not provide additional support for the hypothesized Xq27 locus, and yielded only modestly interesting LOD scores at other autosomal candidate loci. In this regard, FTC may more closely resemble familial prostate cancer where there is a demonstrated interest in genetic testing, [17][18][19][20] with numerous candidate susceptibility loci having been identified, but to date no major susceptibility genes have been discovered to account for the majority of familial cases.…”

Genetic aspects of testicular germ cell tumors

“…A two fold increased risk of TGCT for "gr/gr" deletion carriers in 1807 affected subjects has been observed with an even higher-three fold-increase in familial cases. 43 In contrast to what would be expected, the authors found that probands from TGCT families exhibiting maternal lineage were at greater risk than those exhibiting paternal lineage. The association between "gr/gr" deletion and TGCT was not confirmed in a separate UK study 42 and an Italian study.…”

“…37 In general, the analysis of a very large group of subjects might be more appropriate for detecting genetic predispositions acting at low penetrance than smaller studies, however the situation is more complex for the Y chromosome than for the rest of the genome because of potential biases such as population stratification. 44 Ethnic and geographic matching of cases and controls is fundamental when searching for Y related factors and the multicenter study, 43 although very large, contained only 15% of cases and 23% of unaffected males from designed epidemiologic case-control studies. Moreover, since both gr/gr deletions and familial cases are rare the strength of the large multicenter study is still limited and would require further confirmation.…”