Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry

Abstract

The spectrum of cancers seen in a hospital based Lynch syndrome registry of mismatch repair gene mutation carriers was examined to determine the distribution of cancers and examine excess cancer risk. Overall there were 504 cancers recorded in 368 mutation carriers from 176 families. These included 236 (46.8 %) colorectal and 268 (53.2 %) extracolonic cancers. MLH1 mutation carriers had a higher frequency of colorectal cancers whereas MSH2, MSH6 and PMS2 mutation carriers had more extracolonic cancers although these differences were not statistically significant. Men had fewer extracolonic cancers than colorectal (45.3 vs. 54.7 %), whereas women had more extracolonic than colorectal cancers (59.0 vs. 41.0 %). The mean age at diagnosis overall for extracolonic cancers was older than for colorectal, 49.1 versus 44.8 years (P ≤ 0.001). As expected, the index cancer was colorectal in 58.1 % of patients and among the extracolonic index cancers, endometrial was the most common (13.8 %). A significant number of non-Lynch syndrome index cancers were recorded including breast (n = 5) prostate (n = 3), thyroid (n = 3), cervix (n = 3), melanoma (n = 3), and 1 case each of thymoma, sinus cavity, and adenocarcinoma of the lung. However, standardized incidence ratios calculated to assess excess cancer risk showed that only those cancers known to be associated with Lynch syndrome were significant in our sample. We found that Lynch syndrome patients can often present with cancers that are not considered part of Lynch syndrome. This has clinical relevance both for diagnosis of Lynch syndrome and surveillance for cancers of different sites during follow-up of these patients.

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).…”

“…The mean or median age at diagnosis of prostate cancer for men with Lynch syndrome was reported to be approximately 59 to 60 years in the four studies (14,19,26,32), 64 to 65 years in the four studies (31,33,34,36) and 67 to 69 years in the two studies (15,35), compared with the median age of 69 years for the U.S. general population (44).…”

“…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.…”

Prostate cancer incidence in males with Lynch syndrome.

“…Some studies have revealed an increased incidence of prostate cancer, especially in patients carrying an MSH2 mutation, [5][6][7][8] whereas others have not shown an increased incidence. 2,9,10 Two studies have shown a lack of MMR protein expression in prostate cancer tumors in patients with LS. 6,11 Other studies have focused on patients with hereditary prostate cancer and have looked for signs of MSI or lack of MMR proteins on IHC.…”