Lynch Syndrome Mutation Study Suggests Changes to Clinical Management

NEW YORK – Based on a prospective observation of more than 6,000 individuals with the gene mutations associated with Lynch syndrome, investigators have suggested that management guidelines for the condition may need to be revised based on evidence of different gene and gender-specific risks and a relatively good prognosis for the most commonly associated cancers.

Considering the observed gender and gene-based differences in cancer risk, Lynch syndrome as a whole might better be considered an umbrella term for three or four clinically distinct syndromes, with different implications for counseling, surveillance, and treatment, the authors wrote.

Published yesterday in Genetics in Medicine, the study describes an analysis of data from the Prospective Lynch Syndrome Database (PLSD). Although researchers have made significant strides in understanding the genetic backbone of this cancer predisposition disorder — the most common hereditary cancer syndrome — precise knowledge has been lacking as to how associated variants affecting the genes MLH1, MSH2, MSH6, and PMS2 affect cancer risk and outcome.

According to the authors of the new report, unexpected findings from prior studies have included evidence that MLH1 and MSH2 mutation carriers maintain a significant lifetime colorectal cancer risk despite surveillance colonoscopy. Shorter intervals between colonoscopies do not seem to reduce this incidence either, suggesting that the current practice of surveillance and removal of precancerous lesions doesn't necessarily do anything for these individuals.

Previous studies of the PLSD itself have also shown that individuals with mutations in PMS2 have no increase in cancer risk before 40 years of age.

In their analysis published this week, a multinational group led by researchers from Oslo University Hospital, Cardiff University School of Medicine, and the University of Helsinki set out to prospectively calculate cancer risks gene by gene in a combined set of 6,350 database subjects in order to assess the cohort's post-cancer survival rates more thoroughly than prior retrospective efforts.

Among the 6,350 Lynch syndrome carriers (a combination of previously studied and new subjects, all with mismatch repair variants confirmed as class 4 or 5 in the International Society for Gastrointestinal Hereditary Tumors database) there were 1,808 prospectively observed cancers. 

Mirroring earlier findings, the lifetime risk of colorectal cancer for MLH1 and MSH2 pathogenic mutation carriers in the cohort was 50 percent, despite patients being followed with colonoscopy and having suspicious polyps removed. Both men and women with these mutations saw higher risks of urinary tract and upper gastrointestinal cancers at older ages, with men with MSH2 mutations in particular showing an increased risk for prostate cancer.

"Future research should seek to address the reasons for continuing occurrence of CRC in LS despite supposedly preventive colonoscopy and the prevention and treatment of those LS cancers that continue to have a poor prognosis," the authors wrote.

Breast cancer risk was similar across all four LS genes, representing a relatively insignificantly increase compared with reported general population risks.

The combined analysis did find, though, that female carriers of MLH1, MSH2, and MSH6 mutations have a rapidly rising risk of gynecological cancers starting at 40 years of age. Importantly MSH6 did not correspond to a similarly high risk of colorectal cancer in males, just 18 percent. This suggests a sex-limited trait with relatively low penetrance in males that could lead to families escaping detection by family history.

"As only a minority of males with [pathogenic MSH6] variants will develop LS-associated cancers, 'skipped generations' will be common … and such families are not identified efficiently by current clinical criteria for LS that assume high penetrance in both genders," the authors wrote.

"Testing of incident endometrial cancers for MMR deficiency, as has been adopted widely for CRC, may provide a more effective strategy to identify [these] families," they added.

Particularly notable in the findings was that the risk of cancer for PMS2 pathogenic mutation carriers only started to increase after 50 years of age, and even then relatively marginally. 

"We conclude that although [pathogenic PMS2] variants have been shown robustly to cause a rare recessively inherited cancer syndrome of childhood and adolescence … the cancer risk in heterozygotes is not increased in young to middle-aged adults and remains uncertain in older individuals," the authors wrote. "The relative lack of follow-up years for … carriers is a weakness of the current study and further expansion of this group in PLSD would be particularly helpful."

Taken together, the results suggest that there is room for improvement in how clinicians assess and follow Lynch syndrome individuals. "Available clinical approaches for identifying LS and criteria for the classification of pathogenicity of MMR gene variants were developed assuming that all pathogenic variants have high penetrance. This is neither the case for [pathogenic MSH6] variants in males nor for [pathogenic PMS2] carriers of either gender," the authors wrote.

Looking to the future, the investigators proposed a redefinition of the term Lynch syndrome to encompass four clinically distinct inherited cancer risk syndromes. More specifically, they argue, PMS2 mutation carriers should not be grouped together with carriers of MLH1 and MSH2 pathogenic variants, considering that both genetic counseling and clinical management would differ for the two groups. MSH6 mutations may also justify specific surveillance strategies tailored to this genotype. 

In the meantime, the authors reported that the PLSD website now includes a cancer risk algorithm based on the results reported this week, allowing calculation of remaining lifetime risk for cancer in any LS patient by inputting their age, gender, and gene variant.