Family-Based Testing Strategy May Better Detect HNPCC

STOCKHOLM, Sweden—A new way to select for further testing those people who are at risk for Lynch syndrome may increase detection of the disorder, also known as hereditary nonpolyposis colorectal cancer (HNPCC). The syndrome, which predisposes people to developing colorectal cancer at a young age, is caused by germline mutations in DNA mismatch repair (MMR) genes.

Kristina Lagerstedt Robinson, PhD, of the Karolinska University Hospital in Stockholm, Sweden, and her colleagues selected a group of 285 families who had been referred to the Karolinska University Hospital for genetic counseling between 1990 and 2005 because they were at high risk for HNPCC. From those families, 112 people (ideally the youngest person in the family) were screened for MMR gene mutations (MLH1, MSH2, MSH6, and PMS2).

The 112 individuals were selected for MMR screening based on family history, microsatellite instability (MSI), and immunohistochemical (IHC) analysis of MMR protein expression. Patients who were negative for MMR mutations were also screened for BRAF V600E mutations, and people with these mutations were considered as non-HNPCC, since BRAF V600E mutations are almost never found in HNPCC tumors.

The researchers uncovered MMR gene mutations in 69 patients (57 pathogenic). Sixteen of the 69 mutations (23%) were missense mutations. Among patients with MSI-positive tumors, pathogenic MMR mutations were found in 38 of 43 patients (88%) from families who met the stringent Amsterdam criteria of HNPCC based on family history, and in 13 of 22 patients (59%) from families who did not meet the Amsterdam criteria (J Natl Cancer Inst 99:291-299, 2007).

Notably, pathogenic MMR mutations were found in 5 of 17 patients (29%) from families with MSI-negative tumors who met the Amsterdam criteria, and in 1 of 30 patients (3%) from non-Amsterdam families (with one patient younger than age 50). These represent individuals who might not have been screened using current testing standards.

The findings suggest, the authors said, "that missense MMR gene mutations are common in HNPCC and that germline MMR mutations are also found in patients with MSI-negative tumors."

Dr. Lagerstedt Robinson commented: "Although a population-based mutation-screening strategy has the potential to also identify nonfamilial HNPCC patients, more patients will need to be screened. The most important advantage with the family history-based selection process we used is that non-HNPCC families are also identified and can be offered preventive programs."