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Lynch syndrome, also known as hereditary nonpolyposis colon cancer syndrome (1), is a rare, autosomal, dominantly inherited syndrome caused by germline mutations in DNA mismatch repair genes, which confer substantial risks for cancers of the colorectum and endometrium and increased risks for cancers of the stomach, small intestine, hepatobiliary system, kidney, ureter, ovary, and sebaceous tumors (2,3). Mutations in the mismatch repair genes, MLH1 and MSH2, account for 70%-80% of all Lynch syndrome colorectal cancers (ie, colorectal cancers occurring in people with germline DNA mismatch repair gene mutations) (4-7).Mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers and 0.4% of all colorectal cancers (4-7), with the greater proportion of colorectal cancer diagnosed at a younger age (4,6). The prevalence of MSH6 mutations in women with endometrial cancer who were not selected for family history is less well established with estimates ranging from 1.0% to 3.8% (8-12).Few studies have attempted to estimate the age-specific cumulative cancer risk for carriers of germline mutations in MSH6 (penetrance) (13-18), so information on the consequences of such mutations remains uncertain. Most of these studies (13-16) have analyzed data from families that were ascertained because of a strong family history of cancers related to Lynch syndrome, or preferentially mutation-tested individuals with colorectal cancer over individuals without colorectal cancer, and appear not to have correctly taken into account the ascertainment when deriving their penetrance estimates. Recruiting families from family cancer clinics will result in oversampling of family members who have been diagnosed with colorectal or other cancers, and such recruitment has been shown to result in inflated estimates of cancer risks

Objective Surgical management of colon cancer for patients with Lynch Syndrome who carry a mismatch repair gene mutation is controversial. The decision to remove more or less of the colon involves the consideration of a relatively high risk of metachronous colorectal cancer (CRC) with the impact of more extensive surgery. Our aim was to estimate and compare the risks of metachronous CRC for Lynch Syndrome patients undergoing either segmental or extensive (subtotal or total) resection for first colon cancer. Design Risk of metachronous CRC was estimated for 382 MMR gene mutation carriers (172 MLH1, 167 MSH2, 23 MSH6 and 20 PMS2) from the Colon Cancer Family Registry, who had surgery for their first colon cancer using retrospective cohort analysis. Age-dependent cumulative risks of metachronous CRC were calculated using the Kaplan-Meier method. Risk factors for metachronous CRC were assessed by a Cox proportional hazards regression. Results None of 50 subjects who had extensive colectomy was diagnosed with metachronous CRC (incidence rate 0.0; 95%CI 0.0–7.2 per 1000 person-years). Of 332 subjects who had segmental resections, 74 (22%) were diagnosed with metachronous CRC (incidence rate 23.6; 95%CI 18.8–29.7 per 1000 person-years). For those who had segmental resections, incidence was statistically higher than for those who had extensive surgery (P <0.001). Cumulative risk of metachronous CRC was 16% (95%CI 10–25%) at 10 years, 41% (95%CI 30–52%) at 20 years and 62% (95%CI 50–77%) at 30 years after segmental colectomy. Risk of metachronous CRC reduced by 31% (95%CI 12–46%; P 0.002) for every 10 cm of bowel removed. Conclusions Lynch Syndrome patients with first colon cancer treated with more extensive colonic resection have a lower risk of metachronous CRC compared with those receiving less extensive surgery. This finding will better inform decision-making regarding the extent of primary surgical resection.

Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.