A physical analysis of the Y chromosome shows no additional deletions, other than Gr/Gr, associated with testicular germ cell tumour

Abstract

Testicular germ cell tumour (TGCT) is the most common malignancy in men aged 15 -45 years. A small deletion on the Y chromosome known as 'gr/gr' was shown to be associated with a two-fold increased risk of TGCT, increasing to three-fold in cases with a family history of TGCT. Additional deletions of the Y chromosome, known as AZFa, AZFb and AZFc, are described in patients with infertility; however, complete deletions of these regions have not been identified in TGCT patients. We screened the Y chromosome in a series of TGCT cases to evaluate if additional deletions of Y were implicated in TGCT susceptibility. Single copy Y chromosome STS markers with an average inter-marker spacing of 128 kb were examined in constitutional DNA of 271 index TGCT patients. Three markers showed evidence of deletions, sY1291, indicative of 'gr/gr' (eight out of 271; 2.9%), Y-DAZ3 contained within 'gr/gr' (21 out of 271; 7.7%) and a single deletion of the marker G66152 was identified in one TGCT case. No other markers demonstrated deletions. While several regions of the Y chromosome are known to be deleted and associated with infertility, our study provides no evidence to suggest regions of Y deletion, other than 'gr/gr', are associated with susceptibility to TGCT in UK patients. Testicular germ cell tumour (TGCT) is the most common cancer 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 racial and ethnic groups (Ferlay et al, 2004). The highest incidence of the disease occurs in men of European descent and the lowest in African and Asian groups (Ferlay et al, 2004). Risk factors for TGCT include a family history of disease (Forman et al, 1992;Heimdal et al, 1996;Westergaard et al, 1996;Sonneveld et al, 1999;Hemminki and Li, 2004), a previously diagnosed germ cell tumour (Osterlind et al, 1991; Wanderas et al, 1997), a history of undescended testis (UDT) (Brown et al, 1987;Swerdlow et al, 1997), infertility (Petersen et al, 1998;Moller and Skakkebaek, 1999;Jacobsen et al, 2001;Richiardi et al, 2004), atrophy (Harland et al, 1998) and gonadal dysgenesis (Verp and Simpson, 1987).Family history is one of the strongest of the underlying risk factors. Multiple studies have documented that brothers and fathers of patients with TGCT have a 8 -12-fold and 4 -6-fold risk, respectively (Forman et al, 1992;Heimdal et al, 1996;Westergaard et al, 1996;Sonneveld et al, 1999;Hemminki and Li, 2004). These relative risks are higher than for most other cancer types, which rarely exceed 4 (Hemminki et al, 2001) and suggest that there is a substantial contribution to the disease risk from underlying susceptibility genes.Despite the high familial risk, the underlying genetic susceptibility to the TGCT remains unclear. A recent genome-wide linkage search on 237 TGCT pedigrees, the largest series of TGCT families examined to date, identified several 'regions of interest' on chromosomes 2p33, 3p12, 3q26, 12q13 -q21, 18q21 -q23 and Xq27. Each region demonstrated a HLOD ...

An oncofetal and developmental perspective on testicular germ cell cancer

“…Indeed, 25% of GCC susceptibility could be attributed to genetic factors according to an elegant epidemiological study by Czene and coworkers [129]. In targeted studies specific genomic risk loci/Single Nucleotide Polymorphisms (SNPs) were identified at the Y chromosome (gr/gr microdeletion) [130,131] and in the FSH [132]/androgen receptors [133]. Risk loci were also found in PTEN [134] and loci related to genes involved in steroid hormone metabolism [135,136], cAMP signaling [137], insulin like growth factor signaling [138], DNA damage response [139,140], estrogen metabolism/signaling [141][142][143], gonadotropin regulation [144], TP53-KITL interaction [145], sex determination [146] and prostate/colorectal/breast cancer (8q24 locus) [147].…”

BAX-mediated cell death affects early germ cell loss and incidence of testicular teratomas in Dnd1 mice

“…The variable penetrance of the tumor phenotype in Ter mice of different genetic backgrounds faithfully mimics the etiology of germ cell tumors in humans. Germ cell tumors are the most common form of cancer in men between the ages of 15 and 34, and are highly correlated with ethnicity and other complex genetic influences (Brown et al, 1987; Brown et al, 1986; Hussain et al, 2008; Linger et al, 2007). …”

Regulation of male germ cell cycle arrest and differentiation by DND1 is modulated by genetic background

“…Based on the comparison between three genetic backgrounds, we suggest that mitotic arrest is a threshold effect influenced by the levels of multiple factors that vary between strains, including positive and negative regulators of the cell cycle and possibly miRNAs. The variability that we see among genetic backgrounds reflects the etiology of the human disease, where the incidence of germ cell tumors is correlated with ethnicity and other complex genetic factors that have not been completely explained (Brown et al, 1987; Brown et al, 1986;Hussain et al, 2008;Linger et al, 2007;Looijenga, 2009;Oosterhuis and Looijenga, 2005).…”