The Japanese Society for Cancer of the Colon and Rectum started the HNPCC registry and genetic testing project in September 2002. This project enrolled patients who met the modified Amsterdam II criteria including gastric cancer as an HNPCC-related tumor. The HNPCC patients registered in this project corresponded to approximately 2.1% of all colorectal cancer patients in the collaborating hospitals. We further carried out gene testing in 85 patients who gave informed consent to the analysis. Among the colorectal tumors arising in the HNPCC patients, those located in the right colon comprised 47.9%, and mucinous carcinoma comprised 8.4%, which were both significantly higher incidences than those in sporadic colorectal tumors. We searched for mutations of MSH2, MLH1, and MSH6 genes, and identified pathogenic mutations in approximately 54% of the probands. These data should contribute to a better understanding of the characteristics of Japanese HNPCC, and useful for Japanese HNPCC patients and their family members by facilitating a correct diagnosis and providing information about the disease.

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Mismatch repair（MMR）proteins contribute to genome integrity by correcting replication errors. We performed functional assay of many MLH1 mutants to clarify the pathogenicity of hereditary nonpolyposis colorectal cancer. The mutants were categorized by our two-type of functional assay. In higher eukaryotes, MMR proteins also regulate the cellular response to specific DNA damage caused by oxidization, alkylation or crosslinking. Previous studies have shown that MMR proteins were involved in the activation of apoptosis through p53- dependent and p53-independent mechanisms. MMRdeficient cells are known to be resistant to several DNA-damaging agents and exhibit various defects in the induction of p53 and its related p73 proteins, which are activators of apoptosis.

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[in Japanese]

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Some cases of endometrial carcinoma are thought to be associated with a familial tumor, hereditary non-polyposis colorectal cancer （HNPCC）, and their development may be due to mutation of the MMR gene in germ cell. In this study, we examined 36 cases of endometrial carcinoma associated with familial predisposition to cancer or double cancer, and analyzed germ cell mutations in 3 MMR genes （hMLH1, hMSH2 and hMSH6） to elucidate the pathogenesis. MMR gene mutations in germ cells were detected in 6 of 36 patients （16.6%）. The most frequent mutation was a frame shift in the hMSH6 gene, which was identified in 3 patients. None of the 6 patients with mutations met the current clinical diagnostic criteria for HNPCC. MMR gene mutations in germ cells were detected at high frequency by taking into account familial predisposition to cancer in patients with endometrial carcinoma. Furthermore, mutations in the hMSH6 gene may be particularly important for carcinogenesis of this tumor.

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[in Japanese]

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Counseling for family members of cancer families is not common at hospitals, even in cancer centers, in Japan. At Shikoku Cancer Center, we have started a counseling service for family members of cancer families in 2000. Although we sometimes had counseling of patients with breast or colorectal cancer who requested to receive counseling, we hesitated to recommend all the patients who are possible members of families of familial cancer to receive a gene test and tell other family members that they may be very likely to have the same cancer in the near future because we may have had some troubles with them by doing so. However, we saw a very young female patient with locally advanced breast cancer recently, and she was an elder sister of the patient who died of breast cancer at 21 years at our hospital. When we saw the latter patient, we suspected that she was a member of cancer family but her family did not fulfill the criteria of breast cancer family. Therefore, we did not tell anything about the possibility of inheritance of the disease to the other family members. If we had told it to the elder sister, her cancer could have been found at an early stage. After we experienced this patient, we have decided to change our policy from a passive stance to an active one.

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Familial adenomatous polyposis（FAP）is frequently complicated by gastric lesions, which is common in many FAP pedigrees. Gastric lesions complicated by FAP include histologically different lesion types such as fundic gland polyps, gastric adenomas and gastric cancers. Fundic gland polyps are pathologically classified as hamartoma and is a distinct gastric lesion accompanying FAP with high incidence. There have recently been a few reports of FAP case in which a portion of this fundic gland polyp appeared to develop gastric carcinogenesis by dysplasia during long-term observation. Onset of adenoma is characterized by localization in the pyloric antrum, occurrence in younger people, and a high tendency toward multifocality. However, macroscopic and microscopic findings of gastric adenoma complicated by FAP are not different from those of normal gastric adenoma. This phenomenon of carcinogenesis of gastric adenomas is not considered specific to gastric adenoma in FAP. It has been reported that the complication rate of FAP by gastric cancer is approximately 5％. Most cases develop gastric cancer in the gastric antrum and whose clinical features are not uniform in histological type or depth of tumor invasion. However, the mechanism of gastric carcinogenesis in FAP is still unclear. We report here a 51-year-old female with FAP who developed advanced gastric cancer with multiple hepatic metastase after longterm observation. Gastric cancer arose from the upper gastric body. There was nodetectable adenoma in the vicinity of cancer or dysplasia of fundic gland polyp. However, some areas with atypical cells were found near the cancer. Focusing on these areas, p53 and cytokeratin 7 expressions were observed immunohistochemically and double staining consistently demonstrated two concurrent protein expressions. In this case, p53 and cytokeratin 7 expressions may be associated as the mechanisms of gastric carcinogenesis.

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Gastrointestinal stromal tumors（GISTs）are the most common mesenchymal tumors in the human gastrointestinal tract. In the past, basically all of the gastrointestinal mesenchymal tumors had been assumed to be of smooth muscle cell origin. However recent advances in understanding the biology of the tumors demonstrated that most gastrointestinal mesenchymal tumors show differentiation towards gastrointestinal pace maker cells, called interstitial cells of Cajal（ICCs）. We first found that most GISTs expressed KIT, a receptor tyrosine kinase encoded by the protooncogene c-kit, and that approximately 90 ％ of the sporadic GISTs had somatic gain-of-function mutations of the ckit gene. Because both GISTs and ICCs were doublepositive for KIT and CD34, GISTs were considered to originate from ICCs. We also found that about half of the sporadic GISTs without c-kit gene mutations had gain-of-function mutations of platelet-derived growth factor receptor alpha（PDGFRA）gene that encodes another receptor tyrosine kinase. Furthermore, we showed that germline gain-of-function mutations of the c-kit gene resulted in familial and multiple GISTs with diffuse hyperplasia of ICCs as the preexisting lesion. Some knock-in mouse models of familial and multiple GISTs have been genetically created, and may be useful for further investigation of GIST biology. A selective tyrosine kinase inhibitor, imatinib, inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for metastatic or unresectable GISTs as a molecular target drug. Mutational analyses of c-kit and PDGFRA genes are considered meaningful for prediction of imatinib effect in patients with advanced GISTs.

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In recent years, pharmacogenomics have focused increasing attention on the growing interest in personalized medicine. It is empirically clear that there are inter-individual differences that affect the appearance or absence of adverse effects of anti-cancer drugs. Recent research has demonstrated that the appearance of adverse effects of cancer chemotherapeutics depends on the polymorphisms of a recipient,s genome. As demonstrated in certain chemotherapeutics, deleterious mutations on genes related to drug metabolism increase the risk of adverse effects. These relationships include poly-morphisms in the DPYD gene and adverse effects of 5-FU, MTHFR gene and methotrexate, UGT1A1 gene and irinotecan, TPMT gene and 6-MP. In particular, information on deleterious polymorphisms of the UGT1A1 gene appears in the package information insert of irinotecan in the USA. This means clinical application of pharmacogenomics will be available in the near future. This review begins with a overview of recent pharmacogenomic findings and then describes future trends in pharmacogenomics to realize personalized medicine.

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Because hereditary cancer is characterized by familial aggregation, frequent occurrence, an onset in youth, and so forth, it is considered to impose an extremely heavy burden of medical expenses on such affected families. Under universal health insurance coverage, patients need to pay for part of the total medical cost in Japan. There are several public medical cost assistance systems to reduce the patients, payment, which cover the total or partial costs of certain named diseases, especially if the disorder tends to require considerable expense. However, these systems to seem to function imperfectly for hereditary cancer. Accordingly, we have investigated the current situation of the public medical cost assistance system for hereditary cancer and clarified the actualities thereof. The results of our investigation show that the medical costs of all malignant cancers are covered by the public medical cost assistance system for those under 18 years of age, regardless of whether or not the cancers are hereditary, however, for those who have reached adulthood, only the medical costs of Neurofibromatosis type I/type II, Fanconi anemia, Ataxia telangiectasia, and X-linked lymphoproliferative syndrome are covered by the public medical cost assistance system. In conclusion, the public medical cost assistance system for hereditary cancer detected after reaching adulthood remains insufficient at present. It is necessary to consider how to establish an effective system for such patients and their families as soon as possible.

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