Lynch syndrome is an autosomal dominantly inherited disorder due to germline mutations in DNA mismatch repair genes. Mismatch repair mutation carriers are at increased risk of several cancers, with endometrial cancer being one of the most commonly diagnosed cancers in women with Lynch syndrome.
In a recent study published in Journal of the National Cancer Institute, Aung Ko Win, MBBS, MPH, University of Melbourne, and colleagues found that women with Lynch syndrome and a diagnosis of endometrial cancer were at significantly increased risk of colorectal cancer, cancer of the kidney/renal pelvis/ureter, urinary bladder cancer, and breast cancer compared with all women in the general population as well as women in the general population with a diagnosis of endometrial cancer.1
The investigators used data from the Colon Cancer Family Registry to identify a cohort of 127 women with a diagnosis of endometrial cancer preceding any diagnosis of other cancers who had a mutation in 1 of 4 mismatch repair genes: 30 had mutations in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2. Women had a mean age of 46 years at diagnosis of endometrial cancer.
Among the 127 women, 70 (55%) developed at least one primary cancer after diagnosis of endometrial cancer, with 19 (15%) developing more than one. These cancers included colorectal cancer in 31% of women, followed by cancer of the breast in 9%, skin in 7%, urinary bladder in 6%, kidney/renal pelvis in 4%, ureter in 3%, small intestine and pancreas in 2% each, and stomach, thyroid, gall bladder, biliary tract, vulva, and head and neck in 1% each.
The cumulative risks for primary cancers at 10 and 20 years after endometrial cancer were 20% and 48% for colorectal cancer, 2% and 11% for kidney/renal pelvis/ureter cancer, 1% and 9% for urinary bladder cancer, and 5% and 11% for breast cancer. In general, the types of cancers observed in these women were not unexpected, given previously reported risks among women who are mismatch repair mutation carriers; however, the risk for breast cancer was higher than expected.
Increased Risk of Colorectal and Other Cancers
After endometrial cancer, the women were at significantly increased risk of several cancers compared with the general population; risks were increased 40-fold for colorectal cancer (standardized incidence ratio [SIR] = 39.9, 95% confidence interval [CI] = 27.2–58.3), 28-fold for kidney/renal pelvis/ureter cancer (SIR = 28.3, 95% CI = 11.9–48.6), 24-fold for urinary bladder cancer (SIR = 24.3, 95% CI = 8.56–42.9), and 2.5-fold for breast cancer (SIR = 2.51, 95% CI = 1.17–4.14).
The risks for other cancers in mismatch repair mutation carriers were also significantly greater than risks for other primary cancers in women in the general population with endometrial cancer; risks were increased 36-fold for colorectal cancer (SIR = 36.3, 95% CI = 25.8–49.6), 29-fold for kidney/renal pelvis/ureter cancer (SIR = 29.3, 95% CI = 13.2–56.9), 17-fold for urinary bladder cancer (SIR = 16.95, 95% CI = 6.8–35.2), 2.4-fold for breast cancer (SIR = 2.4, 95% CI = 1.2–4.2), 38-fold for cancer of the small intestine (SIR = 38.3, 95% CI = 7.65–119.0), and 9-fold for pancreas cancer (SIR = 8.9, 95% CI = 1.8–26.3).
Although analysis was limited by the relatively small numbers of women with individual mismatch repair mutations, no significant differences were observed for 10- or 20-year cumulative risks for each cancer according to type of mismatch repair mutation present. There were no significant differences in SIRs for cancers according to mismatch repair mutation except for colorectal cancer. For colorectal cancer, SIRs were 38.7 for women with the MLH1 mutation and 58.5 for those with the MHS2 mutation, compared with 4.5 for women with the MSH6 mutation.
As noted by the investigators, limitations of the study included the absence of information on treatment history for endometrial cancer, which may have affected risk for subsequent cancers, and insufficient statistical power to fully distinguish risks associated with specific mismatch repair gene mutations. The findings also may not apply to women with poorer-prognosis endometrial cancer; such patients were less likely to have been included in the current analysis, since they were less likely to be able to provide a blood sample for genetic testing or to complete study questionnaires.
In addition, it is not known whether women in the study were informed of their mismatch repair mutation status prior to the mutation testing performed for the current study. Since mismatch repair mutation is known to carry increased risk of colorectal cancer, knowledge of mismatch repair status on the part of the women or their physicians might have affected the frequency of surveillance for colorectal polyps and cancer. Overall, 55% of women reported having at least one surveillance colonoscopy or sigmoidoscopy after diagnosis of endometrial cancer, with the average interval between evaluations being 2.1 years.
The investigators concluded, “[W]omen carrying [mismatch repair] gene mutations with a previous diagnosis of endometrial cancer have increased risks of a range of cancers, including breast cancer. This study provides the most accurate representation of their ongoing cancer risks, providing a basis for effective long-term surveillance and risk reduction strategies. Further larger studies are recommended for refining risk estimates separately for specific [mismatch repair] gene mutations to optimally inform practice and policy for clinical risk management.” ■
Disclosure: The study was supported by the National Cancer Institute and through cooperative agreements with members of the Colon Cancer Family Registry and principal investigators. The authors had no conflicts of interest to report with regard to this article.
1. Win AK, Lindor NM, Winship I, et al: Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst 105:274-279, 2013.
The current uncertainty regarding the relative frequencies of cancers of various anatomic sites in Lynch syndrome poses a difficulty in commenting on the syndrome’s overall cancer spectrum. It is even more vexing to address the order in which these cancers are prone to occur. What we do know is...