Carriers of germline mutations in DNA mismatch repair (MMR) genes who have already had colorectal cancer (CRC) are at increased risk for genitourinary, breast, prostate and other cancers later in life, a new study has confirmed.
Using data from the Colon Cancer Family Registry for 764 carriers of a mutation of the MMR gene—including the 316 MLH1, 357 MSH2, 49 MSH6 and/or 42 PMS2 mutations—who had a previous diagnosis of CRC, the authors calculated 10- and 20-year risk rates for the development of cancer in other organs following what has become known as Lynch syndrome cancer or hereditary nonpolyposis colorectal cancer (HNPCC). The results of the study were published in the Sept. 19 issue of the Journal of the National Cancer Institute (2012;104:1363-1372, PMID: 22933731).

The most common primary cancers following Lynch syndrome CRC were located in the urinary tract. Over the 10 years following diagnosis of CRC, the cumulative risks for primary extracolonic cancers were about 2% for cancers of the kidney, renal pelvis or ureter (the 20-year risk rate was about 5%), and the risk was about 2% for bladder cancer (20-year risk rate was 3%). Standardized incidence ratios (SIRs), when compared with the general population, amounted to a 12.54-fold increased risk for cancers of the kidney, renal pelvis or ureter; and a 7.22 SIR for urinary bladder cancer. The cumulative risk was approximately 1% for small-bowel cancer over the 10 years following CRC diagnosis (20-year risk rate was 4%; SIR was 72.68) and 0.7% for gastric cancer (20-year risk rate was 1%; SIR was 5.65).

The most common primary cancer following Lynch syndrome CRC in women was endometrial (SIR of 40.23). Prostate cancer in men with Lynch syndrome amounted to an SIR of 2.05 compared with the general population. The authors observed no statistically significant differences in 10- and 20-year cumulative risk rates among individual MMR gene mutations and, in general, observed no differences in the SIRs based on the site of CRC, the gender of the carriers, or their age at diagnosis.
►  EXPERT INSIGHT
Benjamin Tan, MD
Staff Physician,
Siteman Cancer Center at Barnes-Jewish Hospital and
Washington University School of Medicine in St. Louis, and
Associate Professor of Medicine,
Washington University School of Medicine in St. Louis
Approximately 2% to 4% of all CRC cases are associated with Lynch syndrome. Consensus exists among experts regarding performance of immunohistochemistry or tumor microsatellite instability testing for newly diagnosed CRC to evaluate for possible HNPCC. Patients with pathogenic mutation in one of the MMR genes are also at risk for developing extracolonic cancers. Caregivers, including medical oncologists, geneticists and gastroenterologists, need to discuss with the patient and their families such risks and also outline strategies for surveillance, possible prevention (if any) and treatment in the event that such cancers are detected.  This study represents one of the largest registries and adds to the growing literature detailing risk estimates for specific cancers in this population. The increased risks for breast and prostate cancers are not as widely known (these risks should be added to future versions of the National Comprehensive Cancer Network [NCCN] guidelines) compared with other cancers, such as urinary tract and upper gastrointestinal (GI) cancers. The risk for dermatologic cancers was not even reported in this study.
Despite these risks, there are currently no clear recommendations for surveillance and prevention for any extracolonic malignancies except for endometrial cancer. The NCCN guidelines1 recommended “total abdominal hysterectomy and bilateral oophorectomy should be considered an option to reduce risk for patients who completed childbearing.” Although data are limited, caregivers can offer transvaginal ultrasound and endometrial biopsy to screen for gynecologic cancers, annual urinalysis for urinary tract cancers and upper GI or capsule endoscopies for upper GI cancer screening. More data is needed to recommend earlier mammograms and prostate examinations for patients with Lynch syndrome.

References

  1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Colorectal cancer screening. Version 2.2012. Accessed October 16, 2012 at www.nccn.org.
Dr. Tan reported no relevant financial disclosures.