A new online assessment tool developed at Dana-Farber can help rapidly identify people who should undergo genetic testing for Lynch syndrome, an inherited disorder that greatly increases the lifetime risk of colorectal, endometrial, ovarian, stomach, and other cancers.
An estimated 1 in 279 individuals – nearly a million people in the United States – carry a mutation in one of five different genes that can cause Lynch syndrome. Mutations in these so-called “mismatch repair” genes impair cells’ ability to heal breaks in their DNA, making genetically damaged cells prone to abnormal growth and the development of cancer. The five genes are MLH1, MSH2, MSH6, PMS2, and EPCAM.
The new online model, developed by Dana-Farber researchers and doctors and reported in the Journal of Clinical Oncology, is called PREMM5. It enables people to quickly assess their likelihood of carrying one of these genes associated with Lynch syndrome.
The report’s senior author is Sapna Syngal, MD, MPH, director of Research at the Center for Cancer Genetics and Prevention at Dana-Farber. “Most Lynch syndrome mutation carriers aren’t aware of it because genetic testing rates and knowledge about the condition are much lower than for other cancer-predisposing genes like BRCA1 and BRCA2, which are associated with breast and ovarian cancer,” she explains.
PREMM5 lists 10 questions about the individual’s sex, age, personal history of cancer, and history of certain cancers among relatives. From the answers to these questions, which take less than 2 minutes to complete, the model calculates the probability that the person carries a mutation in any of the five Lynch syndrome genes in their germline – the reproductive cells inherited from parents. Researchers recommend that an individual whose risk is identified by PREMM5 as 2.5 percent or greater be referred for genetic counseling and testing to determine if he or she has a Lynch syndrome mutation.
Someone with Lynch syndrome may have as much as an 80 percent lifetime risk of colorectal cancer and women have a 40 to 60 percent lifetime risk of developing endometrial (uterine) cancer. Lynch syndrome is also associated with elevated risk of cancers of the pancreas, small intestine, bile ducts, urinary tract, brain, and oil glands in the skin.
Because the PREMM5 tool is free and simple to use, it could help expand the reach of Lynch syndrome testing, Syngal says.
“The real power of genetic testing is when it leads to intercepting the development of cancer,” she explains. “We want to extend the use of the model into the primary care setting and the healthy population where Lynch syndrome is more common than previously thought so people can be proactive about their preventive cancer care.”
For individuals diagnosed with Lynch syndrome, earlier and more frequent screening, surveillance, and preventive surgery can dramatically reduce the likelihood of developing cancer. Colonoscopy and removal of precancerous lesions can prevent more than 60 percent of deaths from colorectal cancer. Prophylactic hysterectomy with removal of the ovaries and fallopian tubes is an effective strategy for preventing endometrial and ovarian cancer in women with Lynch syndrome.
PREMM5 was developed by analyzing data from 18,734 patients who underwent germline genetic testing for the Lynch mutations, including numerous healthy patients who did not have cancer but had relatives with cancers. The test order forms provided information on the individuals’ age at genetic testing, sex, personal and family cancer histories – including age at diagnosis – and Syngal’s team concurrently analyzed the germline testing results. By correlating these two sets of data, the researchers produced an algorithm to predict the likelihood a person had inherited a mutation in one of the five genes. The model was then validated in a cohort of 1,058 patients with colorectal cancer who were recruited to an institutional sample registry at Dana-Farber. PREMM5 demonstrated it could effectively discriminate between carriers and non-carriers of the Lynch syndrome genes.