Testicular germ cell tumors (TGCTs) are the most common types of testicular cancer as well as the most common tumor in men aged 15 – 34. Despite their prevalence, the genetic control of susceptibility is poorly understood. Family history suggests a strong genetic component to TGCT susceptibility, but studies have found only one rare, weakly associated Y-linked locus. The 129 family of inbred mouse strains is an established animal model of TGCTs. Linkage studies in mice have been largely unsuccessful, and no genes controlling susceptibility have been found.
The goal of my research was to identify chromosomes and chromosomal regions containing TGCT QTLs (quantitative trait loci) using chromosome substitution strains (CSSs). My analysis showed that three CSSs have TGCT QTLs. To map the QTLs on chromosome 18, I made a panel of eight congenic strains from 129-Chr 18MOLF. I surveyed congenic males for TGCTs and found evidence for three previously unknown TGCT QTLs on chromosome 18.
Because studies have shown conflicting evidence for a Y-linked factor(s) promoting TGCTs in humans, I tested the role of this chromosome on TGCT development in mice. Sry, the master sex-determining gene in mammals, is on the Y chromosome and is normally required for testis formation and male development. In the absence of the Y chromosome, mice develop as fertile females. To bypass the requirement for Sry in sexual development, I took advantage of the Odd Sex mutation that causes XX animals to develop as males without the Y chromosome. Sex-reversed XX males develop testes with PGCs, which enabled tests of whether the Y chromosome was required for TGCT tumorigenesis. Although normal males developed TGCTs at an appreciable rate, no TGCTs were found in sex-reversed males. I concluded that at least one factor on the Y chromosome was required for TGCT initiation.
The results of my research support the theory that TGCTs are a highly complex trait, and that CSSs are an effective tool for mapping QTLs with weak effects. A more thorough understanding of the heritable component of TGCTs in mice will improve our understanding of the genetic control of susceptibility to complex diseases.