Lynch Syndrome Studies Highlight Screening, Surveillance Opportunities

Counseling for families meeting criteria for Lynch syndrome should be focused on colorectal and endometrial cancer risk even in second- and third-degree relatives, and those with certain genetic mutations could be offered cancer surveillance at a later age, according to the results of two studies published in JAMA Oncology.

The first study, by N. Jewel Samadder, MD, MSc, of the University of Utah in Salt Lake City and the Mayo Clinic in Scottsdale, Arizona, and colleagues examined 202 families who met Amsterdam I and II criteria for Lynch syndrome.

Amsterdam I criteria requires three relatives with colorectal cancer, one of which is a first-degree relative of the other two; colorectal cancer affecting more than one generation; and at least one colorectal cancer diagnosed before age 50. Amsterdam II criteria requires three relatives with Lynch syndrome–related cancers, one of which is a first-degree relative of the other two; Lynch syndrome–related cancer affecting more than one generation; and at least one Lynch syndrome–related cancer diagnosed before age 50.

Samadder and colleagues calculated standardized morbidity ratios (SMRs) by comparing observed rates of cancer in relatives with population-expected rates estimated using the Utah Population Database.

Of the 17,087 people in Utah with colorectal cancer, the 202 families with Lynch syndrome accounted for 2.6% of colorectal cancer cases.

First-degree relatives of Amsterdam criteria pedigrees had significant excess risk for colorectal cancer (SMR, 10.10) and endometrial cancer (SMR, 5.89). Excess risk was also found for stomach (SMR, 2.90), small intestine (SMR, 7.72), prostate (SMR, 1.94), kidney (SMR, 3.22), urinary bladder (SMR, 1.62), and thyroid cancers (SMR, 2.26), as well as non-Hodgkin lymphoma (SMR, 2.10).

Looking further out, second-degree and third-degree relatives also had excess risk for colorectal (SMR, 4.31 and 1.85) and endometrial cancers (SMR, 2.70 and 1.50).

“Although clinicians likely counsel first-degree relatives of members of families that fulfill the Amsterdam criteria to initiate earlier and more frequent colorectal cancer screening, they likely do not provide a similar recommendation to more distant relatives of cancer cases in these families,” Samadder and colleagues wrote. “Our results suggest that second-degree relatives of patients with cancer in families meeting the Amsterdam criteria are at a markedly increased risk (4.3-fold) of colorectal cancer and should be counseled for more intensive screening, similar to what is offered for those with an isolated family history of colorectal cancer.”

The second study was a retrospective analysis of people with Lynch syndrome–associated colorectal, endometrial, and/or ovarian cancer taken from a clinical database of a large referral center for genomic medicine in England.

Mutations in mismatch repair genes-MLH1, MSH2, MSH6, or PMS2-are associated with increased cancer risk. Neil A. J. Ryan, MBChB, of the University of Manchester and St. Mary’s Hospital, and colleagues sought to determine if mutation type was associated with age at onset of Lynch syndrome–associated cancers.

They performed gene sequencing on 1,063 people with Lynch syndrome, ranging in age from 10 to 93 years; 546 men and women with colorectal cancer, 162 women with endometrial cancer, and 49 women with ovarian cancer were included. The mean follow-up was 68.2 months.

Among patients identified with MLH1 mutations, the mutations were associated with colorectal cancer in 61% of men and women, 27% of women with endometrial cancer, and 8% of women with ovarian cancer.

The most commonly identified mutation was MSH2, which was commonly linked with female-specific cancers. These mutations were found in 30% of women with endometrial cancer, 10% of women with ovarian cancer, and 50% of men and women with colorectal cancer.

Compared with mutations in MLH1 or MSH2, mutations in MSH6 were less common and carriers presented with colorectal and endometrial cancer later in life.

The researchers stratified the data by mutation type and found that women with truncating MLH1 mutations had onset of endometrial cancer about 6 years later than those with nontruncating mutations (median difference of 6.6 years). Truncating MLH1 mutation carriers also presented with colorectal cancer at later ages than those with other mutations, but the difference was not significant between the groups.

“The data in the present study originate from a defined geographical area in the northwest of England, and potential local population factors may limit the generalizability of the conclusions,” the researchers wrote. “Rare genetic conditions like Lynch syndrome benefit from collaborative multicenter investigation. The cumulative incidence reported should not be interpreted as the risk for mutation carriers because those diagnosed with cancer are more likely to be tested.”