Early-onset colorectal cancer with stable microsatellite DNA and near-diploid chromosomes

Colorectal cancer has been described in terms of genetic instability select ively affecting either microsatellite sequences (MIN) or chromosome number and structure (CIN). A subgroup with apparently stable, near-diploid chromo somes and stable microsatellites (MACS) also exists. These distinctions are important, partly because of their value in highlighting different pathway s of carcinogenesis, and partly because of their direct relevance to progno sis. Study of early-onset cancer has often proved a fruitful resource for t he identification of the nature and function of cancer susceptibility genes . In a study of colorectal cancer with stable microsatellite DNA, we descri be 22 early-onset tumours (mean age = 33), compared with 16 late-onset tumo urs (mean age = 68). Both groups contained carcinomas with the MACS phenoty pe, characterized by near diploid DNA content, as defined by flow cytometry , and minimal chromosome arm deletion or amplification (six or less events per genome), determined by comparative genomic hybridization (CGH). Minimal chromosome imbalance correlated strongly with diploid DNA content (P<0.001 ). The proportion of MACS cancers was significantly greater in early-onset as compared to late-onset tumours (64 vs 13%, P=0.005). Of the chromosome a rm imbalances commonly observed in late-onset tumours, only 18q- was observ ed more than twice amongst the 14 early-onset MACS tumours. Seventy-nine pe r cent of these MACS tumours were located in the distal colon, and 69% were at advanced clinico-pathological stages (with lymph node or distant metast asis). A positive family history of colorectal or other cancers was elicite d in seven patients in the MACS early-onset group, and one additional patie nt in this group had a metachronous ovarian cancer. The results suggest tha t MACS cancer may have a genetic basis different from either MIN or CIN, an d further studies of these cancers may lead to discovery of new mechanisms of colorectal carcinogenesis and cancer susceptibility.