Published online Oct 15, 1998. doi: 10.3748/wjg.v4.iSuppl2.51
Revised: July 18, 1998
Accepted: August 4, 1998
Published online: October 15, 1998
AIM: To determine the frequency of the germline mutations of the mismatch repair (MMR) genes in hereditary nonpolyposis colorectal cancer (HNPCC) and the suspected-HNPCC families.
METHODS: We screened germline mutations of the mismatch repair genes (hMLH1, hMSH2, hMSH3, and hMSH6) in 35 Korean HNPCC families and 44 suspected HNPCC families by using polymerase chain reaction-single strand conformation polymorphism analysis followed by sequencing. For the definition of suspected HNPCC, two criteria (criteria I and II) were devised. Criteria I consisted of at least two first degree relatives affected with colorectal cancer with at least one of the following: development of multiple colorectal tumors including adenomatous polyp; at least one colorectal cancer case diagnosed before the age of 50; and occurrence of a HNPCC extracolonic cancer (endometrium, urinary tract, small intestine, stomach, hepatobiliary system, and ovary) in family members. Criteria II consisted of noe colorectal cancer patient with at least one of the following: early age of onset ( < 40 years); endometrial, urinary tract, or small intestine cancer in the index patient or a sibling ( < 50 years); and two siblings with other integral HNPCC extracolonic cancers (one < 50 years). A question aire was mailed to members of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer to determine the mutation detection rate in mismatch repair genes from the families fulfilling these criteria.
RESULTS: In 35 korean HNPCC families, we found 11 germline mutat ions (31%), all in the hMLH1 gene. In 44 korean suspected HNPCC families, we fou nd 11 (25%) germline mutations, 7 in hMLH1 gene, 2 in hMSH2 gene, and 2 in the polycytosine repeat sequence of the hMSH6 gene. Through the international collaborative study on the genetic diagnosis of suspected HNPCC, we were able to obtain data on 123 suspected HNPCC families from 8 different institutions. The mutation detection rate for families fulfilling the criteria I was 28% (19/67), while the mutation detection rate for families fulfilling criteria II was 9% (5/56).
CONCLUSION: Genetic testing should be an integral part of the ma nagement of HNPCC and suspected HNPCC families. The criteria I for the diagnosis of suspected hereditary nonpolyposis colorectal cancer have the advantages that they can be applied to nuclear families and include extracolonic cancers. Our results suggest that families fulfilling the criteria I should be offered genetic testing. The relatively low mutation detection rate in those families fulfilling criteria II suggests that using current techniques, genetic testing in these families is not a practical proposition. An international collaborative study under the revised criteria II is in progress. Also, our data indicates that genetic testing for hMSH6 gene can be considered in suspected HNPCC families without mutations in the hMLH1 and hMSH2 genes.