August 03, 2017
2 min read

Mutation type can tailor cancer surveillance in Lynch syndrome

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Mutated gene and mutation type can dictate at which age patients with Lynch syndrome should begin cancer surveillance, according to results of a retrospective cohort study.

Specifically, researchers found individuals with MSH6 mutations can begin surveillance at a later age, and those with truncating MLH1 mutations can also begin endometrial cancer surveillance later than those with nontruncating mutations.

Lynch syndrome — caused by inherited germline mutations — predisposes individuals to colorectal, endometrial, ovarian and other cancers, outcomes of which can be improved with surveillance programs.

However, the age at which such surveillance programs should commence has been disputed.

Emma J. Crosbie, PhD, consultant gynecologic cancer surgeon and clinical senior lecturer at The University of Manchester in England, and colleagues used a clinical database of a large quaternary referral center for genomic medicine in Northwest England to evaluate data from 1,063 individuals (female, n = 568; mean age, 52 years; range, 10-93) with Lynch syndrome. Researchers aimed to determine whether mutated gene and type of mutation influenced age at onset of Lynch syndrome-associated cancers.

Mean follow-up was 68.2 months.

Overall, colorectal cancer occurred in 305 men and 241 women, endometrial cancer occurred in 162 women and ovarian cancer occurred in 49 women.

Colorectal cancer occurred in 249 of 409 individuals (61%) with MLH1 mutations, 239 of 479 (50%) with MSH2 mutations, 43 of 129 (33%) with MSH6 mutations, and 15 of 46 (32%) with PMS2 mutations. Women had an older age at diagnosis than men (median difference, 3.3 years; P = .002).

Older age at colorectal cancer diagnosis also appeared associated with MSH6 mutations compared with MLH1 mutations (median difference, 9 years), MSH2 mutations (median difference, 8 years) and PMS2 mutations (median difference, 6 years; P < .001). Researchers observed a trend for older age at diagnosis with truncating MLH1 mutations.

Endometrial cancer occurred in 26 of 68 women (38%) with MSH6 mutations, 83 of 279 women (30%) with MSH2 mutations and 53 of 196 women (27%) with MLH1 mutations.

Women with MSH6 mutations presented with endometrial cancer at older ages (median age at onset, 53 years) than women with MLH1 mutations (mean age at onset, 49 years; median difference, 3.9 years) and MSH2 mutations (mean age at onset, 47 years; median difference, 5.7 years; P = .002 for variance).

When stratified by mutation type, those with truncating MLH1 mutations presented with endometrial cancer at an older age than those with nontruncating mutations (median difference, 6.6 years; P = .002).


Ovarian cancer occurred in 10% of the women with MSH2 mutations, 8% of those with MLH1 mutations and 7% of those with MSH6 mutations. Median age at ovarian cancer diagnosis was 47 years. However, diagnosis occurred later in those with truncating mutations (median difference, 6.3 years; P = .04).

Researchers then used a threshold of 0.5% cancers per screen to determine at what age surveillance should begin.

Results showed colonoscopies should begin at age 25 years for those with MLH1 and MSH2 mutations and at age 30 years from those with MSH6 and PMS2 mutations. Gynecologic surveillance appeared appropriate starting at age 30 years for those with MSH2 mutations, 35 years for those with nontruncating MLH1 mutations, and age 40 years for those with MSH6 and truncating MLH1 mutations.

Researchers noted the cumulative incidence of cancers reported by mutation type should not be interpreted as risk because those diagnosed with cancers are more likely to undergo genetic testing. – by Alexandra Todak

Disclosures: The researchers report no relevant financial disclosures.