Hereditary nonpolyposis colorectal cancer（HNPCC） is a familial cancer of the autosomal dominant inheritance form. Since complications of endometrial cancers develop at a high frequency in HNPCC patients, it has become known that part of endometrial cancers are HNPCC-related familial cancers. It has also been suggested that ovarian cancers and breast cancers, in addition to endometrial cancers, are related to HNPCC. HNPCC-associated endometrial cancers appear to have unique characteristics biologically and clinico- pathologically, but the exact nature is unknown. There is an urgent need for gynecologists to undertake a nationwide analysis with correct knowledge and detailed research about family history.
Hereditary nonpolyposis colorectal cancer（HNPCC） is a syndrome in which several cancers are involved in the colon, rectum, endometrium, small bowel, and ureter and renal pelvis. Although new genetic technologies are attempting to grasp HNPCC with regard to genes, HNPCC still has unclear features from genetico- and clinico-epidemiological points of view. In order to investigate the unclear points of HNPCC, the HNPCC registry and genetic testing project has been implemented from September 2002, by the Japanese Society for Cancer of the Colon and Rectum （JSCCR）. This project is the largest one since the ethical guidelines for human genomic research were established by governmental ministries in 2000. In this paper, we present an introduction to the project, which includes detection of HNPCC, registration, genetic testing and follow-up. In the future, the project would benefit by collaborating with associations and study groups related to HNPCC care in order to make a consortium dealing with all matters related with HNPCC, from medical issues to social issues. Such comprehensive approaches would lead to better medical services for HNPCC patients and their families.
To find fresh mutations in HNPCC cases, synchronous multiple colorectal cancers were examined. We selected thirty-one lesions in 19 cases of synchronous multiple colorectal cancers. Findings of MSI-High were detected in 6 of the 19 cases （31.6％）and 11 of the 31 lesions（35.5％）. The MSI-positive findings（MSI-H or MSI-L） were detected in 16 of the 19 cases（84.2％） and 26 of the 31 lesions（83.9％）. Fifteen of the 31 lesions（48.4％）showed negative stainings for MLH1 and/or MSH2 antigen, using immunhistochemical methods. Nine of the 11 lesions（81.8％）indeed showed negative immunostaining for MLH1 and/or MSH2 antigen. The results of the MSI status and expression of MLH1 and MSH2 agreed between different plural tumors in the same case. Moreover, the correlation between MSI-High and inactivation of MLH1 and MSH2 was recognized. These results suggest that MSI and immunohistochemical studies with antibodies of MLH1 and MSH2 are useful methods to find new HNPCC-patients who are not consistent with the criteria for HNPCC.
Human homologues of the bacterial DNA mismatch repair genes, hMLH1 and hMSH2, assigned on chromosome 3p21-23 and 2p21-22 are involved in hereditary nonpolyposis colorectal cancer （HNPCC）. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair gene hMLH1 or hMSH2. Loss of the wild-type allele results in a mutator phenotype and accelerating tumorigenesis, which especially cause carcinomas in the gastrointestional and genitourinary tracts. We examined germline mutations of mismatch repair genes, hMLH1 and hMSH2., in a patient with multiple primary neoplasms （multiple stomach cancer, colon cancer and brain tumor）. In screening by long RT-PCR from the RNA, we found skipping of exon 2 in hMLH1. The analysis of the genomic DNA showed a GT delation in the splice-donor site of exon 2, which is compatible with the splicing variant detected by long RT-PCR analysis. This is a novel germline mutation that has not been reported previously. We attempted to define the syndrome as a part of HNPCC.