Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer.
Dr de la Chapelle and colleagues from Columbus assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome.
Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study.
|117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations|
|New England Journal of Medicine|
The researchers used genotyping of the tumor for microsatellite instability as the primary screening method.
The research team searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes among patients whose screening results were positive for microsatellite instability.
The team searched for mutations with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies.
The investigators counselled family members of carriers of the mutations, and those found to be at risk were offered mutation testing.
The researchers reported that of 1066 patients enrolled in the study, 208 had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome.
Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age.
The team also reported that 5 patients did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer.
The researchers included the use of age and family history to identify patients at high risk for the Lynch syndrome.
The researchers noted that genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands.
In addition, the research team observed that of the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not.
Dr de la Chapelle concludes, “Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected.”
“These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.”