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Lynch Syndrome Analysis Suggests Patients Can Be Stratified for Surveillance Based on Mutation Type

NEW YORK (GenomeWeb) – Individuals with certain Lynch syndrome mutations may be able to begin cancer surveillance at a later age, according to a new study.

People with Lynch syndrome — which is caused by germline mutations in mismatch repair genes — are predisposed to developing colorectal, endometrial, ovarian, and other cancers. However, a University of Manchester-led team of researchers noted that when surveillance should begin to catch these cancers isn't clear.

The researchers conducted a retrospective cohort study of Lynch syndrome patients and, as they reported in JAMA Oncology today, they found that which syndrome-causing mutation the patients have appears to influence when they develop disease. For example, as individuals with MSH6 mutations and truncating MLH1 mutations tend to develop tumors later, they could begin cancer surveillance at an older age, the researchers said.

"Individuals with known Lynch syndrome could be risk stratified by mutated gene and mutation type in tailored surveillance programs," Manchester's Emma Crosbie and her colleagues wrote in their paper.

The researchers gathered genomic and medical record data on 1,063 people with Lynch syndrome. The cohort included 495 men and 568 women, with a mean age of 52 years. The individuals in the cohort had undergone either Sanger sequencing or next-generation sequencing with multiple ligation-dependent probe analysis to confirm they were heterozygous for Lynch syndrome mutations.

The most common Lynch syndrome mutation was in MSH2, but individuals in the cohort also had MLH1, MSH6, and PMS2 mutations.

Overall, 546 people in the cohort developed colorectal cancer, while 162 women developed endometrial cancer and 49 women developed ovarian cancer.

But the timing of disease onset varied by mutation. Individuals with MSH6 mutations developed colorectal cancer later in life than individuals with other mutations — eight years later than individuals with MSH2 mutations and six years after those with PMS2 mutations.

Individuals with truncating MLH1 mutations also appeared to develop colorectal cancer at a later age than those with non-truncating mutations, but the finding wasn't statistically significant, the researchers noted.

Of the women who developed endometrial cancer, those with MSH6 mutations also presented with disease nearly four years later than women with other Lynch syndrome mutations did, the researchers reported. Additionally, women with truncating MLH1 mutations developed endometrial cancer about six-and-a-half years later than those without truncating mutations.

Additionally, among the women who developed ovarian cancer, women with truncating mutations were older at the time of diagnosis than women with non-truncating mutations.

This suggested to the researchers that Lynch syndrome patients could be stratified for disease surveillance based on the mutation they harbored. Assuming that a rate threshold of 0.5 percent cancers per screen was acceptable, the researchers estimated that people with MLH1 and MSH2 mutations could begin colonoscopy screening at age 25, while those with MSH6 and PMS2 mutations could start at age 30.

Likewise, they estimated that women with MSH2 mutations could begin gynecological screenings at age 30, while those with non-truncating MLH1 mutations could being at 35, and those with MSH6 or truncating MLH1 mutations could begin at 40 years of age.

"To our knowledge, this is the first study that promotes an extra tier of risk stratification according to mutation type, and not just mutated gene," the researchers wrote.