Prospective assessment of allelic losses at 4p14-16 in colorectal cancer: Two mutational patterns and a locus associated with poorer survival

Previous studies have shown that allelic losses in a locus mapping to the c hromosomal region 4p14-16 are indicative of poor prognosis in colorectal ca ncer. To further characterize the region involved and to confirm earlier ob servations, we have analyzed losses of heterozygosity (LOH) in nine microsa tellite markers spanning this region in a prospective series of 181 colorec tal carcinomas, The extent and the nature of the allelic imbalance were als o ascertained by comparative genomic hybridization analysis of selected cas es. The minimum common deleted region was confined to marker D4S2397 (LOH i n 35% of the informative cases). Surrounding markers displayed LOH in 13-25 % of informative cases and (other than the D4S2397 marker itself) showed a higher rate of allelic imbalances in association with mutations in the p53 tumor suppressor gene. Tumors with lymph node invasion also displayed incre ased rates of LOH in most markers, Regarding patient outcome, LOH solely at the D4S2397 locus was indicative of a shorter disease-free survival (P = 0 .027), In consequence, two patterns of allelic loss are defined within the 4p14-16 region: (a) gross losses associated with tumor progression and prob ably attributable to the genomic instability related to the inactivation of the p53 tumor suppressor gene; and (b) specific losses limited to the D4S2 397 locus (within an estimated fragment of 2 Mb) and associated with increa sed tumor aggressiveness, The presence of one or more putative tumor suppre ssor genes in this region is postulated.