Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours

Abstract

Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations. The incidence of TGCT has risen dramatically over the last century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT.

Familial risk in testicular cancer as a clue to a heritable and environmental aetiology

“…The higher familial risk for testicular cancer among brothers than father -son pairs may suggest the involvement of a recessive mode of inheritance or an X-linked susceptibility locus in the aetiology of testicular cancer, consistent with the segregation analysis and the gene-mapping findings (Heimdal et al, 1997;Rapley et al, 2000). Such results would point to the importance of the maternal lineage of inheritance and perhaps also maternally exerted environmental factors.…”

Intragenomic conflict and cancer

“…Some forms of cancer have been found to be associated with genetic variation of X-linked genes (e.g., (74,75)). This makes sense in light of Hurst's (57) view of the X and Y chromosome as involved in a biochemical tug of war, in which there is a 'stalemate', with each party producing factors that counter the factors produced by the opponent.…”

Somatic mutations of KIT in familial testicular germ cell tumours

“…TGCT has been one of the highest familial relative risks of any cancer syndrome with reported increased risks of 8 -10-fold to brothers and 4 -6-fold to fathers (Forman et al, 1992;Heimdal et al, 1996). We previously described linkage of familial testicular cancer to a locus (TGCT1) at Xq27 (Rapley et al, 2000). This locus was particularly strongly associated with families characterised by at least one case of bilateral testicular cancer.…”