Study confirms higher risk of pancreatic cancer in Lynch syndrome families

Abstract

 

A new study has documented a nine-fold higher risk of pancreatic cancer in individuals with Lynch syndrome, a rare genetic cancer predisposition syndrome, report scientists from the Dana-Farber Cancer Institute and the University of Michigan Comprehensive Cancer Center.

The study, published in the Oct. 28 issue of theJournal of the American Medical Association, is the first using rigorous statistical methods to confirm the elevated risk, the authors say. Previous studies yielded conflicting results.

"In light of these findings, we believe that if you have Lynch syndrome and there is pancreatic cancer in your family, you should be aggressively screened," said Sapna Syngal, M.D., M.P.H., of Dana-Farber and Brigham and Women's Hospital.

Carriers of the Lynch syndrome gene mutations have an 80 percent risk of colorectal cancer beginning at a young age, as well as an array of other cancers of the digestive system, brain and skin, and endometrium and ovaries in women.

Syngal, director of gastroenterology at Dana-Farber/Brigham and Women's Cancer Center, is the report's senior author along with Stephen B. Gruber, M.D., Ph.D., M.P.H., associate director forcancer prevention and control at the University of Michigan Comprehensive Cancer Center.

Fay Kastrinos, M.D., M.P.H., first author of the publication, noted, "Patients with Lynch syndrome are living longer because we're doing a great job with screening and genetic testing as a strategy for preventing colon cancer." In light of the new findings, she said, "Lynch syndrome should be included in ongoing studies to test the effectiveness of screening modalities for pancreatic cancer."

Kastrinos's research was carried out while at Brigham and Women's Hospital; she is currently at the Irving Comprehensive Cancer Center at New York's Columbia University Medical Center.

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, according to theAmerican Cancer Society, which projects 42,470 cases diagnosed in 2009, and 35,240 deaths.

While colorectal cancer is increasingly being detected early and prevented thorough colonoscopies and removal of precancerous polyps, there is currently no effective means of early diagnosis for pancreatic cancer.

Scientists are testing imaging techniques such as endoscopic ultrasound, CT and MRI scanning in an effort to detect small, treatable tumors, but to date there is no evidence of a survival benefit. Investigators are also searching for biomarkers that might signal the early stages of the disease.

Statistical strategy

Mutations in several "mismatch repair" genes that fix copying errors in DNA underlie Lynch syndrome. The researchers designed the study to estimate the risk of pancreatic cancer in families with these inherited mutations. A total of 147 families were drawn from colorectal cancer registries at Dana-Farber and the University of Michigan Comprehensive Cancer Center.

"Because pancreatic cancer is a relatively rare cancer, pooling together the databases at the University of Michigan and Dana-Farber was critical to this analysis," commented co-first author Bhramar Mukherjee, Ph.D., a biostatistician at the University of Michigan School of Public Health.

"Genetic counseling clinics tend to see more patients from families with multiple cancers, which means risk estimates obtained by a naïve statistical method are often highly inflated," said Mukherjee. "We used appropriate methods to adjust for this bias to provide families with more realistic risk estimates of pancreatic cancer."

The analysis revealed a nine-fold increase in risk of the disease compared with the general population, and the cancer tended to appear earlier. The absolute risk of pancreatic cancer in the Lynch families was 1.31 percent at age 50 and 3.68 percent at 70 years. In the general population, there is only a 0.04 percent risk at 50 years and a 0.52 percent risk at age 70.

Syngal, who is also an associate professor of medicine at Harvard Medical School, noted that pancreatic cancers appear to "cluster" in some Lynch syndrome families, while others don't have an increased incidence of the disease. For that reason, she said, screening is recommended only for patients carrying the Lynch mutations who also have a family history of pancreatic cancer.

The research was funded by the National Cancer Institute and private supporters.

The study's other authors are Nabihah Tayob, M.S., Victoria M. Raymond, M.S., and Fei Wang, M.S., University of Michigan School of Public Health, Ann Arbor; and Jennifer Sparr, M.D., Prathap Bandipalliam, M.D., Elena M. Stoffel, M.D., M.P.H., Dana-Farber.