A COMPARISON OF THE GENETIC PATHWAYS INVOLVED IN THE PATHOGENESIS OF 3 TYPES OF COLORECTAL-CANCER

Patterns of allele loss (loss of heterozygosity, LOH) have been studie d in order to investigate the genetic pathways involved in the pathoge nesis of three types of colorectal cancer (CRC): sporadic CRC without replication errors (RER-) (32 cases); sporadic RER+ CRC (23 cases); an d ulcerative colitis-associated CRC (UCACRC) (16 cases). Each tumour w as assessed for allele loss at ten microsatellite markers which map cl ose to known or putative tumour-suppressor genes: APC (5q21-q22); DCC (18q21.1); 1p35-p36; p16 (9p21); 22q; 8p; E-cadherin (16q22.1); beta-c atenin (3p22-p21.3); RB1 (13q14.1-q14.2); and HLA. Overall, high frequ encies of allele loss (>30 per cent) were found near DCC (42 per cent) , p16 (38 per cent), 22q (37 per cent), 1p35-p36 (34 per cent) and APC (31 per cent), and low frequencies (<20 per cent) near RB1 (16 per ce nt) and E-cadherin (13 per cent), LOH near beta-catenin, HLA, and on 8 p occurred at frequencies between 20 and 30 per cent. The overall freq uency of allele loss did not differ among the three tumour groups, but some variation was seen at individual loci. There was a significantly higher frequency of LOH at 1p35-36 in RER+ tumours compared to RER- t umours. Allele loss at this site was also associated with a more advan ced Dukes' stage at presentation, In addition, RER- rumours showed a h igher frequency of allele loss at p16 than RER+ tumours. No significan t difference existed at any locus between the frequency of LOH in spor adic CRC and in UCACRC. Pairwise analysis showed a negative associatio n between LOH at APC and DCC, and between LOH at chromosome 22p and p5 3 overexpression. Thus, there mag be specific differences between the mutation spectra of RER+ and RER- CRCs, but there are large degrees of overlap among the underlying genetic pathways of these cancers and UC ACRCs. (C) 1998 John Wiley & Sons, Ltd.