According to researchers, the risk of colorectal cancer in individuals with Lynch Syndrome can vary substantially depending on both gender and the specific underlying pathogenic germline MMRgene alterations. The findings from this study were published in Genetics in Medicine.

Lynch Syndrome, the most common hereditary cancer disorder, is an autosomal dominant genetic condition associated with germline pathogenic alterations in DNA mismatch repair (MMR) genes (ie, MLH1; MSH2; MSH6; PMS2), the function of which is to maintain DNA genetic stability.

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Previous research has shown increased risks of specific cancers, including colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, and cancers of the small bowel, bile duct, pancreas, and upper urinary tract, depending on which MMR gene is mutated. Nevertheless, limitations of these studies, including retrospective design, variability in how MMR gene alterations were classified, and the absence of independent validation of study findings have weakened conclusions related to specific cancer risks associated with the different pathogenic MMR gene alterations.

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This study prospectively followed carriers of pathogenic MMR gene alterations included in the Prospective Lynch Syndrome Database (PLSD). Individuals in the study were followed according to clinical guidelines, at the point that the first prospectively planned colonoscopy was completed.

The length of time to first cancer for each organ type was determined only for those without a previous diagnosis of cancer, and there was no control group. Data on gender, pathogenic MMR gene mutation, age at study inclusion, age at diagnosis of any cancer, age at last update, and age at death, as well as specific cancer diagnosed, were collected.

In addition, an independent cohort of individuals with Lynch Syndrome was recruited from mostly different centers than those from which the PLSD cohort was recruited to determine whether study findings for the PLSD test group could be validated.

The PLSD cohort included 2823 carriers of pathogenic MMR alterations, whereas 3527 individuals with pathogenic germline alterations in MMR genes were included in the validation cohort.

Following a finding of similar cumulative risks for any cancer and colorectal cancer for each MMR gene in both the test and validation cohorts, the 2 cohorts were merged. The mean age of patients in the combined cohort was 46.8 years, and the percentages of carriers with each type of pathogenic MMR mutation were as follows: MLH1 (41.1%), MSH2 (39.3%), MSH6 (13.2%), and PMS2 (6.4%).

Of the 1808 cancers diagnosed during the prospective observation period, 32.1%, 11.9%, 9.6%, and 7.0% were cancers of the colon, skin, endometrium, and rectum, respectively.

Mutations in MLH1 and MSH2 were associated with the highest risks of cancer.

Interestingly, for MSH6 mutation carriers, the cumulative incidence of a first cancer was significantly lower for men compared with women. While female MSH6 carriers were observed to have a high risk of endometrial cancer, colorectal cancer risk was relatively low for both men and women. Other observed gender differences included higher risks of colon, stomach, small bowel, bile duct, gallbladder, and pancreatic cancer in male MLH1 carriers compared with women with this germline alteration.

With respect to age, a high risk of colorectal cancer was observed in younger MSH2 carriers, whereas the risk of cancers of the upper urinary tract, prostate, brain, and gastrointestinal system was high in older individuals with a MSH2 alteration.

Notably, no elevation in cancer risk was observed for carriers of PMS2 alterations before the age of 50 years, and the increase in this risk for those 50 years and older was not significant.

Rates of 10-year crude survival for pathogenic MLH1, MSH2, and MSH6 carriers were relatively high following diagnosis of the following cancers in patients younger than 65 years: colon (88%), rectal (70%), endometrial (89%), prostate (70%), breast (82%), upper urinary tract (67%), and urinary bladder (68%).

In summarizing the results of this study, the authors stated that “based on the differences in cancer risks associated with the 4 pathogenic MMR genes, we propose that Lynch Syndrome should now be considered as a generic term for four clinically distinct inherited cancer risk syndromes. Our findings suggest that carriers of pathogenic PMS2 variants should not be grouped together with carriers of pathogenic MLH1 and pathogenic MSH2 for genetic counseling or clinical management, and the lower risk and later onset of colorectal cancer in pathogenic MSH6 carriers may also

justify specific guidelines for surveillance that are tailored to this genotype.”

They further noted that “the cancer risk algorithm at the PLSD website ( is based upon the results presented in this report and enables interactive calculation of remaining lifetime risks for cancer in any Lynch Syndrome patient by giving their age, gender, and gene variant, thereby facilitating personalized medicine for pathogenic MMR carriers.”


Dominguez-Valentin MSampson JRSeppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database [published online July 24, 2019]. Genet Med. doi: 10.1038/s41436-019-0596-9