HIGH-FREQUENCY OF APC LOSS IN SPORADIC COLORECTAL-CARCINOMA DUE TO BREAKS CLUSTERED IN 5Q21-22

Abstract

Familial adenomatous polyposis is transmitted by a gene (APC) located within 5q21-22. Hemizygous loss of at least a part of 5q has been reported in 19-36% of sporadic colorectal carcinomas. This suggests that an anti-oncogene is located on that chromosome arm, but the probes used previously gave little information on the status of APC in the tumours. Using DNA probes homologous to polymorphic sequences flanking and close to the APC locus we show that more than half of a large series of carcinomas had lost at least one flanking allele. Mapping of allele losses provides data that imply clustering of breakpoints in a 10-15 megabase region around APC. The commonest chromosome defect responsible for APC loss was interstitial deletion. Mitotic recombination or partial arm loss were less frequent mechanisms. Whole chromosome loss was rare. This pattern contrasts with that reported in acquired homozygosity at other anti-oncogene loci in sporadic tumours and implies that APC loss is an early event in colorectal carcinogenesis. This view is also supported by the observations that 5q21-22 loss occurs with similar frequency in DNA diploid and DNA aneuploid tumours, and also in tumours at all clinical stages of progression.