Calculation of Risk of Colorectal and Endometrial Cancer Among Patients With Lynch Syndrome
Received 8 May 2009; accepted 8 July 2009. published online 21 July 2009.
Background & Aims
Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome. Some previous estimates of lifetime risk for CRC and endometrial cancer (EC) did not control for ascertainment and were susceptible to bias toward overestimated risk.
Methods
We studied 147 families with mismatch repair gene mutations (55 MLH1, 81 MSH2, and 11 MSH6) identified at 2 US cancer genetics clinics. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general population using modified segregation analysis. The likelihood for each pedigree was conditioned on the proband and first-degree relatives affected with CRC to reduce ascertainment bias and overestimation of penetrance.
Results
We analyzed 628 cases of CRC, diagnosed at the median ages of 42 and 47 years for men and women, respectively. The cumulative risk of CRC was 66.08% (95% confidence interval [CI], 59.47%–76.17%) for men and 42.71% (95% CI, 36.57%–52.83%) for women, with overall HRs of 148.4 and 51.1, respectively. CRC risk was highest for males with mutations in MLH1. There were 155 cases of EC, diagnosed at a median age of 47.5 years. The cumulative risk of EC was 39.39% (95% CI, 30.78%–46.94%) with an overall HR of 39.0 (95% CI, 30.4–50.2). For women, the cumulative risk of CRC or EC was 73.42% (95% CI, 63.76%–80.54%).
Conclusions
Lifetime risks of CRC and EC in mismatch repair gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer surveillance is necessary.
⁎Brigham and Women's Hospital, Boston, Massachusetts
‡Dana-Farber Cancer Institute, Boston, Massachusetts
§Department of Biostatistics, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan
¶Department of Epidemiology and Human Genetics, University of Michigan Medical School and School of Public Health, Ann Arbor, Michigan
∥Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
Reprint requests Address requests for reprints to: Stephen B. Gruber, MD, MPH, PhD, Division of Epidemiology and Human Genetics, University of Michigan School of Public Health, 1524 BSRB, Ann Arbor, Michigan 48105. fax: (734) 647-7950
E.S. and B.M. contributed equally to this work.
Conflict of interest The authors disclose the following: Dr Syngal and Dr Gruber have been external advisors to Myriad Genetic Laboratories. The remaining authors disclose no conflicts.
Funding This work was supported in part by the National Cancer Institute (RO1 CA81488 to S.B.G., K07 CA 120448-01-A2 to E.S., and K24 CA 113433 to S.S., R03 CA130045 to B.M.), the University of Michigan's Cancer Center Support Grant (5 P30 CA46592).
ABSTRACT