TUMORIGENESIS IN COLORECTAL TUMORS FROM PATIENTS WITH HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER

Tumorigenesis of colorectal cancer in patients with hereditary non-pol yposis colorectal cancer (HNPCC) has been postulated to follow a diffe rent pathway from that of sporadic colorectal tumors. A characteristic of HN-PCC-asssociated tumors is the replication error phenotype. We s tudied tumorigenesis in 8 fresh-frozen and 67 paraffin-embedded colore ctal tumors derived from 29 families with HNPCC or a familial aggregat ion of colorectal cancer. By using intragenic markers, inactivation of the wildtype allele of hMLH1 was shown to occur through loss of heter ozygosity and not through a somatic point mutation, Microsatellite ins tability is very common and occurs early in almost all colorectal tumo rs from HNPCC patients. Transforming growth factor beta type II recept or (T beta RII) mutations occur in these tumors at a high frequency. O f colorectal cancers from families with HNPCC, 63% have frameshift mut ations in T beta RII, compared with 10% of sporadic colorectal cancers . APC and K-RAS mutations appear to be as frequent in the HNPCC tumors as in the sporadic counterpart.