GENETICS OF COLONIC-CANCER

Research in hereditary forms of colorectal cancer (CRC) has increased almost logarithmically thanks in a major way to momentous discoveries in molecular genetics during the past decade. Between 10 and 20% of th e total CRC burden is due to Mendelian-inherited CRC syndromes. The pa radigm for hereditary CRC is familial adenomatous polyposis (FAP), whe rein the APC germ-line mutation has been identified. This has contribu ted to the elucidation of genomic and clinical heterogeneity within th e syndrome, wherein an attenuated form of FAP has been identified as a result of intragenic mutations within this large APC gene. The most c ommon form of hereditary CRC is hereditary nonpolyposis colorectal can cer (HNPCC). Several mutator genes, namely hMSH2, hMLH1, hPMS1, hPMS2 and, more recently, hMSH6/GTBP, have been identified. These molecular genetic discoveries are providing new insights into the pathogenesis o f CRC. Individuals within these kindreds who are harbingers of these g erm-line mutations will benefit from screening and, one day, chemoprev ention.