Risk of pancreatic cancer in families with Lynch syndrome

Abstract

Context: Lynch syndrome is an inherited cause of colorectal cancer caused by mutations of DNA mismatch repair (MMR) genes. A number of extracolonic tumors have been associated with the disorder, including pancreatic cancer; however, the risk of pancreatic cancer in Lynch syndrome is uncertain and not quantified.

Objective: To estimate pancreatic cancer risk in families with germline MMR gene mutations.

Design, setting, and patients: Cancer histories of probands and their relatives were evaluated in MMR gene mutation carriers in the familial cancer registries of the Dana-Farber Cancer Institute (n = 80), Boston, Massachusetts, and University of Michigan Comprehensive Cancer Center (n = 67), Ann Arbor, Michigan. Families enrolled before the study start date (June 2008) were eligible. Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk were calculated and compared with the general population using modified segregation analysis, with correction for ascertainment.

Main outcome measures: Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk.

Results: Data on 6342 individuals from 147 families with MMR gene mutations were analyzed. Thirty-one families (21.1%) reported at least 1 case of pancreatic cancer. Forty-seven pancreatic cancers were reported (21 men and 26 women), with no sex-related difference in age of diagnosis (51.5 vs 56.5 years for men and women, respectively). The cumulative risk of pancreatic cancer in these families with gene mutations was 1.31% (95% confidence interval [CI], 0.31%-2.32%) up to age 50 years and 3.68% (95% CI, 1.45%-5.88%) up to age 70 years, which represents an 8.6-fold increase (95% CI, 4.7-15.7) compared with the general population.

Conclusions: Among 147 families with germline MMR gene mutations, the risk of pancreatic cancer was increased compared with the US population. Individuals with MMR gene mutations and a family history of pancreatic cancer are appropriate to include in studies to further define the risk of premalignant and malignant pancreatic neoplasms and potential benefits and limitations of surveillance.

Figure 1. Age-specific cumulative risk of pancreatic cancer in families with pathogenic mutations in MLH1, MSH2 or MSH6 genes

MMR Carriers=families with mismatch repair gene carriers (MLH1, MSH2 or MSH6) The penetrance curves in Figure 1 were generated by plotting the age-specific cumulative risks of pancreatic cancer (as presented in Table 3) for a set of discrete ages from 20 to 70 years at five-year intervals and then applying a smoothing spline function. The 95% Confidence Intervals corresponding to the age-specific cumulative risk of pancreatic cancer for MMR carrier families were also plotted for ages 50 to 70 years. Population estimates of age-specific cumulative risks of pancreatic cancer are given by pancreatic cancer incidence rates reported in Surveillance Epidemiology and End Results (SEER) 13, from 1992–2005 (http://seer.cancer.gov).