Clinical and biologic heterogeneity of hereditary nonpolyposis colorectal cancer

MMR gene mutations and MSI are not found in all clinically diagnosed HNPCC families. We evaluated whether MMR genotyping and tumor MSI analysis could identify distinct clinical subgroups among HNPCC families. Twenty-nine clin ical HNPCC families were divided into 3 groups: A, families with hMLH1 or h MSH2 gene mutations; B, MMR gene mutations not present but MSI present in a t least 50% of tumors tested; C, mutational and MSI analyses negative. We e valuated tumor spectrum, age at onset, risk of cancer in the follow-up and survival for CRC in the 3 groups. Tumors of the target organs in HNPCC (col on and rectum, endometrium, ovary, small bowel, stomach, renal pelvis and u reter) were more frequent in the first 2 groups than in the latter. Colon c ancer was more frequently located in the proximal colon and showed an earli er age at onset in families with MMR gene mutation or with MSI than in fami lies with stable tumors. Comparing the occurrence of tumors in the follow-u p, in the first 2 groups patients younger than 50 years had a higher RR, wh ich was particularly marked for CRC (RR = 18.6 for group A vs. group C, RR = 16.7 for group B vs. group C). CRC patients in the first 2 groups had a b etter clinical prognosis. The results of molecular analysis could distingui sh, within clinically defined HNPCC families, different subgroups to which specific programs of surveillance could be addressed. (C) 2001 Wiley-Liss, Inc.