Allelic losses in carcinoma in situ and testicular germ cell tumours of adolescents and adults: evidence suggestive of the linear progression model

Testicular germ cell tumours (TGCTs) may arise through a process of multi-s tep carcinogenesis, and loss of heterozygosity (LOH) at specific loci is li kely to be an important early event, although this has not been studied in detail. In order to explore the pathogenetic relationships among TGCTs, we investigated the genetic changes in testicular tumours that exhibit a disea se continuum through the precursor carcinoma in situ (CIS) to either semino ma (SE) and/or non-seminomatous germ cell tumour (NSGCT). Universal amplifi cation has been performed on 87 TGCT specimens and 36 samples of CIS cells microdissected from single paraffin-embedded tumour sections from 40 patien ts, including multiple specimens of CIS and TGCT cells of varied histology microdissected from 24 individual patients. Seventy-seven microsatellite ma rkers were used to assay these samples for LOH at candidate regions selecte d from the literature, mapping to 3q, 5q, 9p, 11p, 11q, 120, 17p and 18q, C onstruction of deletion maps for each of these regions identified common si tes of deletion at 3q27-q28, 5q31, 5q34-q35, 9p22-p21 and 12q22, which corr elate with allelic losses we have also observed in the precursor CIS cells. Evidence for allelic loss at 3q27-q28 was observed in all of the embryonal carcinoma samples analysed. We conclude that inactivation of gene(s) withi n these regions are likely to be early events in the development and progre ssion of TGCTs. These results also provide molecular evidence in support of the hypothesis that SE is an intermediate stage of development within a si ngle neoplastic pathway of progression from CIS precursor cells to NSGCT. ( CT) 2000 Cancer Research Campaign.