GERMLINE MUTATIONS OF HMLH1 AND HMSH2 GENES IN PATIENTS WITH SUSPECTED HEREDITARY NONPOLYPOSIS COLORECTAL-CANCER AND SPORADIC EARLY-ONSET COLORECTAL-CANCER

PURPOSE: The present study was designed to determine the frequency of germline mutations in the hMLH1 and hMSH2 genes in 31 families suspect ed of having hereditary nonpolyposis colorectal cancer who do not fulf ill the criteria of the International Collaborative Group on Hereditar y Nonpolyposis Colorectal Cancer but in whom a genetic basis for colon cancer is strongly suspected and 45 patients with sporadic early-onse t colorectal cancer who developed colorectal cancer before the age of 40 years without any family history of colorectal cancer. METHODS: Gen omic DNAs were prepared from peripheral blood samples of patients who were tested. AU coding exons and exon-intron borders of these two gene s were screened, first with the polymerase chain reaction-single-stran d conformation polymorphism method, followed by sequencing of the DNA fragments displaying an abnormal single-strand conformation polymorphi sm pattern. RESULTS: In 31 families with suspected hereditary nonpolyp osis colorectal cancer, we found six different germline mutations in s even unrelated families, including one missense mutation and three fra me-shift mutations in the hMLH1 gene and one missense mutation and one frame-shift mutation in the hMSH2 gene. Totally, frequency of mutatio n was 23 percent, 16 percent and 7 percent in the hMLH1 and hMSH2, res pectively. Only one missense mutation of the hMSH2 gene was identified in 45 patients (2 percent) with sporadic early-onset colorectal cance r. The mutation detection rate in families with suspected hereditary n onpolyposis colorectal cancer was significantly higher than that of pa tients with sporadic early-onset colorectal cancer (P < 0.05). CONCLUS ION: Our definition of suspected hereditary nonpolyposis colorectal ca ncer is useful in the diagnosis of hereditary nonpolyposis colorectal cancer and for identifying those families who need genetic presymptoma tic diagnosis. Our results indicate that it may be important to perfor m DNA testing in families suspected of having hereditary nonpolyposis colorectal cancer. On the other hand, we only detected a low mutation rate (2 percent) in 45 patients with sporadic early-onset colorectal c ancer.