Microsatellite Instability Identifies Risk for HNPCC

PHILADELPHIA—A simple new test can detect which individuals may be at risk for hereditary nonpolyposis colon cancer (HNPCC), or Lynch’s syndrome, and therefore should undergo genetic screening for HNPCC mutations.

The test, which analyzes a type of genetic instability known as microsatellite instability, offers greater accuracy than current clinical parameters, Tao Liu, MD, of the Karolinska Institute, Stockholm, Sweden, said at the annual meeting of the American Association for Cancer Research (AACR).

Dr. Liu said that up to 5% of the general population is estimated to have an HNPCC mutation. The current clinical definition of HNPCC, he continued, is the occurrence of colon cancer in at least three individuals from one family over at least two generations and with at least one individual diagnosed under age 50. “Most cases,” he said, “are due to alterations in one of the genes responsible for repairing mistakes in newly copied DNA.”

Tumors from HNPCC patients are characterized by a genetic instability in segments known as microsatellites. The study evaluated affected members from 83 unrelated colorectal cancer families. A mutation was found in 71% of the families whose tumors showed microsatellite instability, but in only 1 of 35 families (2.9%) with stable tumors.

“The finding of microsatellite instability in colorectal tumors from patients with a family history of colorectal cancer or an early onset of disease is the best predictive indicator of a germ-line mutation,” Dr. Liu said.

Must Have a Family History

The test cannot preselect gene carriers among sporadic cases. “However,” he said, “in patients with a family history of colorectal cancer, a test for microsatellite instability can predict a gene carrier, and very few germ-line mutations will remain undetected.”

Identification of gene carriers, he concluded, allows genetic testing in their families. “Gene carriers can be offered surveillance, and the noncarriers can be informed that they are at no increased risk,” Dr. Liu said.