CANCER RISK ASSOCIATED WITH GERMLINE DNA MISMATCH REPAIR GENE-MUTATIONS

The autosomal dominant syndrome of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is due to germline DNA mismatch repair gene mutations i n most cases, However, the penetrance of such mutations outwith classi cal HNPCC kindreds is unknown because families studied to date have be en specifically selected for research purposes, Using a population-bas ed strategy, we have calculated the lifetime cancer risk associated wi th germline DNA mismatch repair gene mutations, irrespective of their family history, We identified 67 gene carriers whose risk to age 70 fo r all cancers was 91% for males and 69% for females. The risk of devel oping colorectal cancer was significantly greater for males than for f emales (74% versus 30%, P = 0.006). The risk of uterine cancer (42%) e xceeded that for colorectal cancer in females, emphasising the need fo r uterine screening, Our findings give further insight into the biolog ical effect of defective DNA mismatch repair. We have demonstrated a s ystematic approach to identifying individuals at high risk of cancer b ut who may not be part of classical HNPCC families, The risk estimates derived from these analyses provide a rational basis on which to guid e genetic counselling and to tailor clinical surveillance.