FEINBERG, AP, JOHNSON, LA, LAW, DJ, KUEHN, SE, STEENMAN, M., WILLIAMS, BRG, THOMAS, G., BOLAND, CR, RAINIER, S. and KOI, M. Multiple Tumor Suppressor Genes in Multistep Carcinogenesis. Tohoku J. Exp. Med., 1992, 168 (2), 149-152 One of the most exciting areas of molecular oncology is the convergence of two independent lines of evidence suggesting involvement of multiple tumor suppressor genes in a given type of cancer. First, epidemiology and somatic cell genetics indicate the presence of multiple tumor suppressor genes in each of several malignancies. Second, cancers often lose multiple chromosomal regions during tumor progression. We will use two tumors, colorectal cancer and Wilms tumor, to illustrate the questions that multiple tumor suppressor genes raise. allelic loss of chromosome; DNA methylation; multistep carcinogenesis; tumor suppressor genes; Wilms tumor (WT)

We have found that colorectal cancers lose multiple tumor suppressor genes on chromosomes 5, 17, and 18. While the identity of these genes is now known, a crucial and largely ignored question is, are these losses related to one another or do they occur independently? To address this question, we analyzed the frequency of each genetic change in a two by two comparison with every other genetic change in all tumors informative for at least two non-syntenic loci. When we compared allelic losses on chromosome 17 p and chromosome 18, there was an easily noticeable and highly significant association: 12 of 36 tumors had an allelic loss on 17 p but not on 18, and 53 of 66 had a loss on both chromosomes (p< 0.001). In the other comparisons, 33 of 66 showed a loss on 17 p but not on 5q, and 26 of 32 showed a loss on both (p< 0.02); 36 of 60 had a loss on 18 but not on 5q, and 26 of 32 showed a loss on both (p< 0.05). We concluded that loss of alleles on Address for reprints: 4520 MSRBI, Ann Arbor, Michigan 48109-0650, USA. 149