Cancer risk associated with germline DNA mismatch repair gene mutations

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.

Efficacy of an educational intervention on family physicians’ risk assessment and management of colorectal cancer

“…This risk is even higher if more than one relative is affected or if a relative was diagnosed under age 50 (Cremin et al 2009;Leddin et al 2004). Those with Lynch syndrome have a lifetime risk of CRC ranging between 30 and 74 % (Dunlop et al 1997;Hampel et al 2005;Jenkins et al 2006) with average age at diagnosis between 44 and 61 years (Cremin et al 2009;Hampel et al 2005).…”

Genetic testing for maturity onset diabetes of the young: uptake, attitudes and comparison with hereditary non-polyposis colorectal cancer

“…Predictive testing for some forms of cancer, including hereditary nonpolyposis colorectal cancer (HNPCC), has been available since 1995 [10,11]. HNPCC mutation carriers are estimated to have an 80% lifetime risk of colorectal cancer and an additional risk of extra-colonic malignancies, especially endometrial cancer [12][13][14]. In a large Finnish study, the uptake for a predictive test for HNPCC was remarkably high: 75% of all individuals at risk and 96% of those who attended counselling wanted the test [15].…”

Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters

“…Colorectal and endometrial cancers are the cancer types most frequently reported; mutation carriers are at an estimated lifetime risk of up to 70 and 27-71%, respectively [1,12,23,33,34]. In addition, cancers of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain are part of the HNPCC tumour spectrum [35,38].…”