Cancer risk associated with germline DNA mismatch repair gene mutations

TLDR

Hereditary Nonpolyposis Colorectal Cancer is caused by germline mismatch repair gene mutations, but the penetrance of these mutations outside classic families is unknown. The study aimed to calculate lifetime cancer risk for carriers of germline mismatch repair mutations using a population‑based approach. A population‑based cohort was used to estimate lifetime cancer risk irrespective of family history. Carriers had a 91 % (males) and 69 % (females) lifetime cancer risk by age 70, with colorectal cancer risk higher in males (74 % vs 30 %) and uterine cancer risk (42 %) exceeding colorectal risk in females, underscoring the need for uterine screening and providing a basis for tailored genetic counseling and surveillance.

Abstract

The autosomal dominant syndrome of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is due to germline DNA mismatch repair gene mutations in most cases. However, the penetrance of such mutations outwith classical HNPCC kindreds is unknown because families studied to date have been specifically selected for research purposes. Using a population-based strategy, we have calculated the lifetime cancer risk associated with germline DNA mismatch repair gene mutations, irrespective of their family history. We identified 67 gene carriers whose risk to age 70 for all cancers was 91% for males and 69% for females. The risk of developing colorectal cancer was significantly greater for males than for females (74% versus 30%, P= 0.006). The risk of uterine cancer (42%) exceeded that for colorectal cancer in females, emphasising the need for uterine screening. Our findings give further insight into the biological effect of defective DNA mismatch repair. We have demonstrated a systematic approach to identifying individuals at high risk of cancer but who may not be part of classical HNPCC families. The risk estimates derived from these analyses provide a rational basis on which to guide genetic counselling and to tailor clinical surveillance.