CHROMOSOME 3P14 HOMOZYGOUS DELETIONS AND SEQUENCE-ANALYSIS OF FRA3B

Loss of heterozygosity (LOH) involving 3p occurs in many carcinomas bu t is complicated by the identification of four distinct homozygous del etion regions, One putative target, 3p14.2, contains the common fragil e site, FRA3B, a hereditary renal carcinoma-associated 3;8 translocati on and the candidate tumor suppressor gene, FHIT: Using a similar to 3 00 kb cosmid/lambda contig, we identified homozygous deletions in cerv ix, breast, lung and colorectal carcinoma cell lines, The smallest del etion (CC19) was shown not to involve FHIT coding exons and no DNA seq uence alterations were present in the transcript, We also detected dis continuous deletions as well as deletions in non-tumor DNAs, suggestin g that FHIT is not a selective target, Further, we demonstrate that so me reported FHIT aberrations represent normal splicing variation, DNA sequence analysis of 110 kb demonstrated that the region is high in A- T content, LINEs and MER repeats,whereas Alu elements are reduced, We note an intriguing similarity in repeat sequence composition between F RA3B and a 152 kb segment from the Fragile-X region, We also identifie d similarity between a FRA3B segment and a small polydispersed circula r DNA. In contrast to the selective loss of a tumor suppressor gene, w e propose an alternative hypothesis, that some putative targets includ ing FRA3B may undergo loss as a consequence of genomic instability, Th is instability is not due to DNA mismatch repair deficiency, but may c orrelate in part with p53 inactivation.