Gene mutations linked to levels of cancer risk in Lynch syndrome

French researchers have pinpointed genetic mutations associated with decreased cancer risk in patients with Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer syndrome) and also mutations linked to elevated risk of ovarian and endometrial cancer. Patients with the syndrome have a high risk of colon cancer and an above-normal risk of other cancers.

To estimate cancer risks associated with mutations in the genes MLH1, MSH2, and MSH6, the researchers analyzed 537 families with Lynch syndrome-248 with MLH1-, 256 with MSH2-, and 33 with MSH6-mutated genes-enrolled between January 2006 and December 2009 at 40 French cancer genetics clinics.

Estimated cumulative cancer risk varied significantly among the 3 genes. For colorectal cancer, risks by 70 years of age were 41% for patients with MLH1 mutations, 48% for MSH2, and 12% for MSH6; for endometrial cancer, risks by 70 years were 54% for MLH1, 21% for MSH2, and 16% for MSH6; and for ovarian cancer, risks by 70 years were 20% for MLH1, 24% for MSH2, and 1% for MSH6.

For other cancers linked to Lynch syndrome, the estimated risks by 70 years didn’t exceed 3% overall and were consistently lower in families with MSH6 mutations compared with the other gene mutations.

“Clinical guidelines state that prophylactic gynecological surgery should be considered in women with Lynch syndrome,” the authors write. “Our findings should help in identifying more precisely the target population for surgery and address the issue of optimum age.”

The estimated cumulative risks of colorectal cancer in carriers of the gene mutations didn’t begin to increase until they reached 30 years of age, regardless of mutation. For endometrial cancer, the estimated cumulative risk didn’t exceed 2% by 40 years of age, regardless of gene mutation. Further, the estimated cumulative risk of ovarian cancer didn’t exceed 1% by age 40 years, irrespective of gene mutation.

Results were published in the Journal of the American Medical Association (2011:305[22]:2304-2310).