NORMAL COLONIC MUCOSA IN HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER SHOWS NO GENERALIZED INCREASE IN SOMATIC MUTATION

Hereditary non-polyposis colorectal cancer (HNPCC) has recently been l inked to germline defects of DNA repair genes. Colorectal rumours in H NPCC frequently show DNA microsatellite instability, but it is not cer tain whether this mutator phenotype occurs throughout the morphologica lly normal colonic mucosa. We have previously used the mPAS histochemi cal technique in human colorectal mucosa to identify a polymorphism fo r O-acetyltransferase activity that shows monogenic inheritance and to show that crypt-restricted loss of O-acetyltransferase activity in he terozygotes is due to somatic mutation. We have now used this histoche mical technique to measure the somatic mutation frequency in the uninv olved colon of 12 heterozygous patients with HNPCC, 15 with ileocaecal Crohn's disease and 16 with sporadic colorectal cancer (CRC). HNPCC p atients showed a significant increase in mutation frequency with age ( Mann-Whitney U, P=0.02). In HNPCC patients aged <49 years the mean ste m cell mutation frequency was significantly lower than in the slightly younger group of patients with Crohn's disease (0.8 +/- 0.9 x 10(-4) vs 3.5 +/- 3.3 x 10(-4) P<0.01), probably reflecting an increased muta tion rate relating to chronic mucosal damage in Crohn's disease. Altho ugh not statistically significant, the stem cell mutation frequency wa s slightly less in HNPCC patients >50 years than in sporadic CRC cases (4.9 +/- 3.4 x 10(-4) vs 5.9 +/- 3.6 x 10(-4), P>0.5). We conclude th at germline defects in HNPCC do not result in a generalised increase i n liability to mutation in normal colonic mucosa but that a second, so matic, event is required. We postulate that this second event occurs i n crypt stem cells at low frequency, giving rise to scattered individu al crypts composed of mutation-prone cells. The cells in these crypts are then at high risk of acquiring the mutations that lead to adenomas , and to rapid progression to carcinoma.