Cancer Risks forMLH1andMSH2Mutation Carriers

Abstract

We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC) and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks to age 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (p<0.001), with cumulative risks to age 70 years estimated to follow U-shaped distributions. For example 17% of male MSH2 mutation carriers have estimated lifetime risks of 0-10% while 18% have risks of 90-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.

Risk of Prostate Cancer in Lynch Syndrome: A Systematic Review and Meta-analysis

“…Of the 12 studies that did quantify the risk, six of these reported a statistically significant increase in prostate cancer for Lynch syndrome (19,27,32,33,35,36). The remaining six studies found no evidence for an increased risk of prostate cancer (14,15,(22)(23)(24)34). Three studies estimated prostate cancer risk using retrospective cohort of family members including relatives of confirmed carriers who were not tested themselves for a germline mutation (24,27,35).…”

“…Three studies estimated prostate cancer risk using retrospective cohort of family members including relatives of confirmed carriers who were not tested themselves for a germline mutation (24,27,35). Eight retrospective cohort studies estimated prostate cancer risk only for mutation carriers using population-based resources (22) or clinic-based resources (19,24,32,(34)(35)(36) or both population-and clinic-based resources (15). Only one study estimated risk using a prospective cohort design; estimating prostate cancer risk for carriers without a prior diagnosis of any cancer (14).…”

“…Tumors are more likely to develop from cells lacking any of the four MMR proteins, as a consequence of germline mutation and/or somatic loss of the MMR gene function. Excess of early-onset colorectal cancer and endometrial cancer are the most commonly observed phenotypes in Lynch syndrome, along with increased risks, albeit to a lesser degree, of extracolonic cancers--ovary, stomach, small bowel, ureter, and renal pelvis (13)(14)(15).…”

“…Attempts have been made to directly estimate the risk of prostate cancer in Lynch syndrome using studies of cancer history of men from Lynch syndrome families (14,15,19,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). These studies have generally been limited in terms of size and analytic methods used, so as a consequence, estimates are imprecise and inconsistent.…”

Reply to Win and Jenkins

“…3,4 There is published evidence suggesting that performing a WCR analysis would not change the results significantly. A major argument for not performing a WCR was given in a recent publication by the Jenkins research group, 5 where they report that evidence of CRC and endometrial cancer (EC) risk being dependent on setting (clinic vs. population) was weak or absent due to the fact that there was no difference observed between clinic-and population-based families for either CRC or EC risk. This is supported by the unweighted and weighted analysis reported by Pande et al, 6 where there is no or very little difference in the observed hazard ratio (HR) between the unweighted and WCR when testing ascertainment source-clinic.…”