Risk of Pancreatic Cancer in Families With Lynch Syndrome

JAMA. 2009 Oct 28;302(16):1790-5. doi: 10.1001/jama.2009.1529.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Colorectal Neoplasms, Hereditary Nonpolyposis / epidemiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Mismatch Repair / genetics*
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Female
  • Genotype
  • Germ-Line Mutation
  • Humans
  • Male
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / genetics*
  • Nuclear Proteins / genetics*
  • Pancreatic Neoplasms / epidemiology
  • Pancreatic Neoplasms / genetics*
  • Pedigree
  • Phenotype
  • Proportional Hazards Models
  • Registries
  • Risk
  • SEER Program
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • Nuclear Proteins
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein