Lynch syndrome is an inherited condition that increases an individual’s risk for certain types of cancer. It’s caused by a mutation in any of five specific genes: MLH1, MSH2, MSH6, PMS2, and EPCAM.
People born with a mutation in one or more of these genes have a significantly increased risk of developing colorectal or uterine cancer and a somewhat elevated risk of:
- ovarian cancer
- urinary tract (bladder, kidney, ureter) cancer
- stomach cancer
- small intestinal cancer
- pancreatic cancer
- biliary tract cancers
- uncommon skin tumors known as sebaceous adenomas and carcinomas
Lynch syndrome is the most common hereditary cancer syndrome and exists in approximately one in every 280 people in the United States. It accounts for about 2-4% of all cases of colorectal cancer.
At Dana-Farber, researchers are working to better understand the links between Lynch syndrome and certain cancers as well as to detect such cancers early and, ultimately, prevent them.
Lynch syndrome registry and biobank
Dana-Farber has established a registry of people with Lynch syndrome — both those who have developed cancer and those who have not. Participants fill out questionnaires about their health, family medical history, diet, lifestyle, exercise habits, and other health-related issues.
Researchers will use this information for insights into the variability of Lynch syndrome – why some people with the syndrome are more likely than others to develop certain forms of cancer.
Researchers have also established a bank of biological materials from people in the registry. This “biobank” holds blood and stool specimens and will soon be expanded to include urine samples and tissue samples removed for biopsy — examination by a pathologist. Together with the registry, the biobank will give researchers a wide-ranging picture of people’s health profile, which can be searched for clues to the development of cancer.
By including cancer survivors as well as “previvors” — people who are at genetic risk for cancer but haven’t developed the disease — the registry and biobank enable researchers to compare the two groups.
“We can look for differences – in whether they smoked, for example, or had different dietary patterns, or a different bacterial profile in the colon – between those who go on to develop cancer and those who don’t,” says Matthew Yurgelun, MD, director of Dana-Farber’s Lynch Syndrome Center, who is helping lead the effort. The registry, which is open to people with Lynch syndrome regardless of whether or not they’re a Dana-Farber patient, currently has data on more than 350 individuals.
Early detection of pancreatic cancer
Dana-Farber researchers are part of a consortium studying whether screening for pancreatic cancer in people with an inherited predisposition to the disease — either from Lynch syndrome or other genetic risk — can detect the disease at an early stage, when it is most treatable.
Early data from the CAPS5 study, for example, show that when magnetic resonance imaging (MRI) or endoscopic ultrasound detect pancreatic cancer in these individuals, the cancer is most often at stage I. The long-term survival rate of those whose pancreatic cancer was detected by MRI or endoscopic ultrasound was 73% — exceptionally high for this difficult-to-treat disease.
“The results have given us a great deal of enthusiasm that early detection is possible in pancreatic cancer and that early detection increases survival,” Yurgelun says.
Dana-Farber and other researchers have recently launched a companion study for individuals participating in CAPS5. The new study is examining whether testing participants’ blood every six months for a marker called CA19 and certain markers of diabetes can further improve pancreatic cancer detection.
A preventive vaccine
Researchers are working on vaccines that harness the immune system to prevent cancers in people with Lynch syndrome. The promise of this approach is grounded in an array of scientific evidence: Immunotherapies often work exceptionally well in people with Lynch syndrome who develop cancer; and there’s even evidence of an immune response in people with Lynch syndrome who have precancerous conditions.
Dana-Farber has joined a trial of a vaccine designed to spur an immune system attack on cancerous and precancerous cells, lowering the chance of developing colorectal and other cancers.
CORAL study
This study is evaluating a new version of Cologuard®, an at-home colorectal cancer screening test the looks for blood and cancer cell DNA in a stool sample, in people with Lynch syndrome. The original Cologuard, designed for adults 45 and over at average risk of colon cancer, detects 92% of colon cancers, but was not recommended for people with Lynch syndrome.
PREMM5
An online tool developed by Dana-Farber investigators, PREMM5 helps people determine whether they should be tested for Lynch syndrome based on their responses to questions about their sex, age, personal and family history of cancer. From the questionnaire, 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 – reproductive cells inherited from parents.
Researchers recommend that individuals whose risk is 2.5 percent or greater as identified by PREMM5 model be referred for genetic counseling and testing to determine if they have a Lynch syndrome mutation.