A novel type of genetic instability characterized by length alterations within simple repeated sequences, termed microsatellite instability (MSI), occurs in the majority of HNPCC and in a subset of sporadic cancers. Recent studies have revealed that there are two types of MSI: high-frequency MSI (MSI-H) and low-frequency MSI (MSI-L). Cancers with MSI-H and those without MSI-H have been shown to exhibit fundamental differences in clinical, pathological, and molecular characteristics. For instance, colorectal cancers with MSI-H exhibit low frequencies of somatic mutations in the p53, K-ras, and APC genes. Inactivation of the DCC gene and overexpression of COX-2 are also less frequent in colorectal cancers with MSI-H. On the other hand, gastrointestinal cancers with MSI-H have a high rate of slippage-induced frameshift mutations in target genes such as TGFβRII and BAX and high frequencies of aberrant DNA hypermethylation of tumor suppressor genes, including hMLH1 gene. Pancreatic cancer with MSI-H has been shown to exhibit characteristic features such as a wild-type K-ras gene and a medullary phenotype. A frequent loss of imprinting of the IGFII gene has been reported in colorectal cancer tissues as well as in the matched normal colonic mucosa of patients with MSI-H or MSI-L cancer. From biological and clinical points of view, it is important to characterize the MSI status of given tumors.

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In usual medical situations, it is not our practice to take accurate family history in detail. This paper described some practical methods to take accurate and useful family history in case of familial cancer syndromes.

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Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant familial cancer syndrome characterized by tumors in parathyroids, enteropancreatic endocrine tissues, and anterior pituitary. In 1997, the MEN 1 gene was identified and cloned. It is on chromosome 11q13 and has 10 exons. It encodes a 610 amino acid protein called MENIN. However, many different germline mutations in MEN 1 families have been reported, there were no hotspot of mutation. The correlation between MEN 1 mutation and clinical datas has not been established yet. Recently, the possible function of MENIN protein has been reported. MEN 2 is also autosomal dominant trait, characterized by medullary thyroid carcinoma (MTC), and it can be divided into two type, MEN 2A and 2B. In 1993, RET gene was identified and it,s mutations has shown to be associated with MEN 2. In recent years, the correlation between RET mutation and clinical features have been revealed. The identification of MEN 1 and RET mutation by employing DNA test, will facilitate early diagnosis and treatment.

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The purpose of this study was to develop procedures to recruit participants and consent forms to enhance informed decision making for prospective participants in a research involving genetic testing for susceptibility to breast cancer. The consent process should be taken place in multi-stages. We made the consent forms for the proband and families and also the documents to inform the test results. The consent forms consist in the directions to medical professionals and information to the participants. The pretest consent form described facts about genes, genetic testing for hereditary breast cancer, and the other legal requirements to obtain informed consent. The consent for disclosure of the test results to family members at risk and the consent for the provision of blood sample for the future research have to be obtained respectively. To evaluate effectiveness of these written materials, five patients with family history of breast and/or ovarian cancer were interviewed with questionnaires before and after providing the consent forms. Patients receiving the consent forms showed increased comprehension and stated that the information were helpful. Findings suggest that the written materials are useful methods to improve participants, understanding of the genetic testing.

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Thyroid cancer is often found in tumor spectra of familial breast cancer and occur frequently in primary multiple canceres including breast cancer. We herein report five breast-thyroid cancer prone families. Genetic testing was performed in only one family, then genetic relation to thyroid cancer was obscure. According to our clinical observation, there are two types of breast-thyroid cancer prone families: 1) thyroid cancer occurring in BRCA linked hereditary breast cancer families, and 2) thyroid and breast cancer were clustered in families. Taking a family history in clinical practice is important to reveal cancer prone families.

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We report a case which fulfilled with Amsterdam criteria for HNPCC and in which five metachronous primary cancers in colon, lung and duodenum had been resected so far. The patient had undergone operations for ascending colon cancer at age of 32, right lung cancer (adenocarcinoma) at age of 53, early cancer of descending colon at age of 57, advanced cancer of descending colon at age of 58, duodenal cancer at age of 59. His mother, elder brother and younger brother also had histories of colon cancers, therefore, his family history shows that 4 colon cancer cases had accumulated in successive generations. We extracted DNA from formalin-fixed, paraffin embedded tissues which were resected in operations and analyzed microsatellite instability (MSI) using 5 fluorescencelabeled microsatellite markers. Some of the specimens were judged as MSI High and immunohistochemical study showed the lack of protein product of hMLH1, suggesting the defect of hMLH1 gene. Then, we assumed that there might be a mutation in hMLH1 gene, however, germline mutation was detected neither in hMLH1 nor hMSH2 by direct sequencing. It is necessary for us to recognize the existence of such case which is compatible with HNPCC criteria but could not be shown to harbour any germline mutation of hMLH1 and/or hMSH2 gene. A new, highly-efficient method for detection of disorder of mismatch repair gene(s) is needed and also useful surveillance protocol could be established in near future.

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[in Japanese]

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