Familial/bilateral and sporadic testicular germ cell tumors show frequent genetic changes at loci with suggestive linkage evidence

Testicular germ cell tumor (TGCT) is the most common tumor type among adole scent and young adult males. Familial clustering and bilateral disease are suggestive of a genetic predisposition among a subgroup of these patients, but susceptibility genes for testicular cancer have not yet been identified . However, suggestive linkage between disease and genetic markers has been reported at loci on chromosome arms 3q, 5q, 12q, 18q, and Xq. We have analy zed primary familial/bilateral (n=20) and sporadic (n=27) TGCTs, including 28 seminomas and 19 nonseminomas, for allelic imbalance (Al) within the aut osomal regions. DNA from all tumors were analyzed by fluorescent polymerase chain reaction of 22 polymorphic loci at 3q27-ter, 5q13-35.1, 12q21-ter, a nd 18q12-ter. All tumor genotypes were evaluated against their correspondin g constitutional genotypes. The percentages of TGCTs with genetic changes a t 3q, 5q, 12q, and 18q, were 79%, 36%, 53% and 43%, respectively. The frequ encies at 3q and 12q in nonseminomas were significantly higher than in semi nomas (P=.003 and P=.004). In order to evaluate changes at hemizygous Xq lo ci, five loci were analyzed by co-amplification with an autosomal reference marker known to reveal retained heterozygosity in the tumor DNA. Gain of X q sequences was seen in more than 50% of the tumors. The degree of amplific ation varied among the loci in each of five tumors, and based on these brea kpoints, a common region of overlapping gains was found at Xq28. No signifi cant differences were found between the frequencies of genetic changes in f amilial/bilateral versus sporadic tumors, an observation speaking in disfav or of the existence of a single susceptibility gene for TGCT in any of the analyzed regions. Our data suggest that gain of genetic material at distal Xq and losses at 5q and 18q contribute to establishment of seminomas, where as imbalances at 3q as well as gain at distal part of 12q are associated wi th further progression into nonseminomas.