A prospective study has confirmed that Lynch syndrome, an inherited disorder that predisposes to many types of cancer, significantly raises the risk of both breast cancer and pancreatic cancer.
The trial is the first to "find a strong association between breast cancer and Lynch syndrome," said senior author and genetic epidemiologist Mark A. Jenkins, Ph.D., of the centre for molecular, environmental, genetic, and analytic epidemiology at the University of Melbourne.
Risk of breast cancer was fourfold higher for the Lynch syndrome patients, compared with the general population. The syndrome is known to increase the risk for a wide variety of other cancers, including colon cancer. Patients are typically advised to begin colonoscopies at an earlier age and repeat them more often than does the general population.
The new findings suggest that women with the syndrome might also benefit from enhanced breast cancer screening, but "further clarification of the risk of breast cancer for women at various ages is needed to determine the recommended age for mammography ... and to determine whether additional tests such as MRI are warranted," Dr. Jenkins said.
The researchers also found an 11-fold increase in pancreatic cancers among the Lynch syndrome patients. Although elevated risk of this cancer has long been suspected, the evidence from previous studies has been inconsistent. The results were published online Feb. 13 in the Journal of Clinical Oncology.
The autosomal dominant disorder, detected with a blood test, is caused by a mutation in one of four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. The estimated carrier frequency in the population ranges from 1 in 360 to 1 in 3,010 individuals, depending on whether all four specific mutations, or fewer than four, are included in the calculations.
Family members without the mutation, however, do not have a greater risk for cancer, and do not need more intensive screening than does the general population – something that has been unclear until now.
The investigators followed 446 mutation carriers and 1,029 noncarrier relatives recruited from the Colon Cancer Family Registry in 1997-2010. Almost all study subjects (96%) were white, and slightly more than half were female. At recruitment, mean age ranged from 40 to 50 years for the different subgroups. The registry includes subjects from the United States, Canada, Australia, and New Zealand.
After a median follow-up of 5 years, mutation carriers had a 20-fold greater risk of colorectal cancer, a 31-fold greater risk of endometrial cancer, a 19-fold higher risk of ovarian cancer, an 11-fold greater risk of renal cancer, and a 10-fold greater risk of stomach and bladder cancers, compared with the general population. The increase in risk for breast and pancreatic cancer was 4-fold and 11-fold, respectively.
For each cancer type, the increased rate in mutation carriers was highly significant, with P values ranging from .009 to less than .001. In addition, the Lynch syndrome patients’ cancer diagnoses typically came at an earlier age than it did in the general population. (J. Clin. Oncol. 2012 Feb. 13 [doi:10.1200/JCO.2011.39.5590]).
"Estimates of site-specific cancer risks for MMR gene mutation carriers inform optimal clinical management," the researchers noted. "Screening colonoscopy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy have the potential to decrease the risk of colorectal cancer, endometrial cancer, and ovarian cancer, respectively."
"Eventually, we expect that the management of cancer risk, including the choice and timing of screening, will be able to be tailored to the specific underlying gene mutation in a person with Lynch syndrome." However, there are no data demonstrating that screening for cancers other than colorectal "is beneficial, in part due to the absence of effective screening tests," Dr. Jenkins and colleagues wrote.
The authors said that they have no relevant conflicts of interest. The study was funded by the National Cancer Institute.
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