Identifying and surveying those individuals at risk for familial cancer are extremely important for the prevention and early detection in order to avoid early death from cancer. In this article, the background, domain, components, and goal of cancer genetic counseling for familial cancer as a part of the process of cancer risk counseling are described, drawing upon US and UK literatures and our own clinical experience. The differences between this type of counseling and that of genetic counseling for reproductive issues are also discussed. A decision tree for the process of cancer risk counseling was developed that recognizes the interaction of hereditary and environmental factors. In the tree, DNA testing was included as an optional strategy for confirming susceptibility to the development of cancer. For each point of decision in the tree, references are provided where necessary and intervention strategies are included. The strategies described in the tree reveal the characteristics of cancer risk counseling : educational intervention is essential for the prevention of cancer. Counseling activities and training programs of genetic counselor for cancer risk counseling in US and UK are introduced, and the necessity for training of counselor in Japan is emphasized.

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HNPCC is a hereditary disease of autosomal mode of inheritance. Patient develops colorectal cancer in younger age, with right-side predominance. Responsible genes have been cloned since 1993. Those are human homologue of mut genes, namely hMSH-2, hMLH-1, hPMS-1, hPMS-2, hMSH-6. When one of these genes was mutated, more than 90% of tumors show microsatellite instability, which can be a good indicator of prediction of second primary cancer. Penetrance rate was calcurated approximately as 90% at the age of 80. But real penetrance rate is still unknown, because it is suspected that there are unidentified responsible genes. International guide lines for evaluation of microsatellite instability in colorectal cancer was made by NCI-HNPCC (National Cancer Institute-HNPCC) meeting. Limitation of genetic diagnosis and clinical implication of microsatellite instability were discussed.

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Deficiency of mismatch repair system has been shown to cause hereditary non-polyposis colorectal cancer as well as approximately 20% of the sporadic colorectal cancer. In advancement of molecular oncology, several molecular mechanisms of the resistance against antineoplastic agents have been elucidated. Besides its function of mismatch repair, the MMR system also recognizes certain DNA adducts or distortion caused by chemotherapeutic agents, which ultimately leads to cell cycle arrest or cell death. MMR deficient cells acquire resistance to some alkylating agents, such as platinum, and 5FU because the defected MMR system can not recognize the DNA damage caused by such agents. The knowledge of the resistance to some chemotherapeutic agents caused by MMR deficienty should be considered in a clinical setting near future.

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A 24-year old woman was referred to our hospital because of vomiting.At the age of 20 years, she was treated for thyroid cancer associated with familial adenomatous polyposis (FAP). Upper gastrointestinal endoscopy revealed a Type 4 (diffuse type)gastric cancer. At proximal gastrectomy, the cancer had exposed over the serosa(T3) with adjacent lymph node metastases(N1) and scattered peritoneal involvement(P1). Lavage cytology of the pelvic cavity showed cancer cells. The tumor was mixture of signet-ring cell carcinoma and poorly differentiated adenocarcinoma with apparent serosal invasion. The colon had no cancer, and it was not treated. Diffuse type gastric cancer in a very young person with FAP has not been reported in our knowledge. We speculated that this gastric carcinoma arose not from adenoma but de novo.

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We carried out for the first time immunohistochemical analysis to search for mutations in hMSH2 in primary endometrial adenocarcinomas belonging to Hereditary Nonpolyposis Colorectal Cancer (HNPCC) and its related disease (Clinical Criteria for HNPCC was divided into four groups, including patients satisfying criteria of Amsterdam (n＝2), modified Amsterdam (n＝3), young age at onset (n＝12), and HNPCC-variant (n＝4). In addition, patients with sporadic endometrial cancer (n＝32) were registered in this study as a control. Immunohistochemistry was used to screen and localize the expression of hMSH2 gene products precisely to specific cells in these patients. Thirteen of the 21 patients (61.9％) failed to stain hMSH2 gene product. In contrast, 2 (6.5％) of 32 control patients showed no staining for hMSH2. Observations resulting from this study revealed that the hMSH2 expression was frequently abolished in familial endometrial cancer. Our results support the hypothesis that hMSH2 is mutated in the endometrial cancer characterized by HNPCC and its related disease. This preliminary result indicates that immunohistochemistry is an ideal technique to search for the expression of hMSH2 gene product in the familial endometrial cancers.

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A case of hereditary nonpolyposis colorectal cancer (HNPCC) without a family history of colorectal cancer was reported. We analyzed germline mutation of mismatch repair genes because of the presence of multiple primary malignancy inclusive of metachronous multiple colon cancers, uterine cancer and gastric cancer indicated the possibility of HNPCC. Germline mutation in hMSH2 gene was identified. Genetic testing of hMSH2 gene was performed to her siblings and children, but nobody had the mutation.

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