Renal Cell Carcinoma (RCC) is classified into six cell pathological types by the Thoenes classification (5). Deletion of DNA (loss of heterozeigosity: LOH) is seen with a high frequency in human RCC of all 6 types at chromosome 3p 14-25. The presence of at least three tumor suppressor genes at this domain has been pointed out. The VHL gene, one of the tumor suppressor genes (TSG), was identified in 1993 at chromosome 3p25-26 as the gene responsible for VHL disease. As a consequence, it was demonstrated that inactivation of the von Hippel-Lindau (VHL) gene is responsible for sporadic clear cell RCC. Activating mutations of c-Met receptor type tyrosine kinase has been demonstrated in papillary renal cell carcinoma families. Possible involvement of the FHIT tumor suppressor gene, located at the fragile site (FRA3B) of chromosome 3p14, has been detected in sporadic RCC. Recently, methylation of RASSF1A at chromosome 3p21.3 was pointed out in sporadic RCC. Thus, it has become apparent that chromosome 3p14-25 3 has possible TSGs for RCC. Furthermore, it was pointed out in April that germline mutation of fumarate hydratase, a Krebs cycle enzyme (FH), is present in multiple cutaneous and uterine leiomyomatosis families that develop papillary RCC. The functional significance in these genes for the development of RCC is still not apparent, except for the VHL gene. Thus, there is still a long way to go before we find all responsible TSGs in all pathological subtypes in sporadic RCC.

p53 protein, a tumor suppressor protein, is accumulated and activated by ionizing radiation. It activates various downstream genes whose functions are involved in cell cycle arrest, apoptosis, and DNA repair. Although it was thought generally that G1 arrest by p53 activation after ionizing radiation was a transient phenomenon to facilitate DNA repair, we found that it is irreversible and permanent in both normal human cells and tumor cells. Because cells arrested irreversibly express various phenotypes, such as cell enlargement and expression of senescence associated-beta-gal, this is related to cellular senescence, but not to apoptosis. Therefore, we termed this phenomenon senescence-like growth arrest (SLGA). These results indicate that SLGA is the main form of cell death caused by ionizing radiation. SLGA can be utilized as an index of cancer therapy, because it is induced not only by radiation but also by anticancer drugs and is easy to examine by vital staining, thereby making the induction of SA-beta-gal an index.

We investigated the death pattern of cancer cells by using different kinds of linear energy transfer (LET) radiation. We used two human squamous cell carcinoma cell lines with an identical genotype except for the p53 gene. SAS/mp53 cells were established by transfection with the mp53 gene to SAS cells having functional p53 (wtp53). As the control, a neovector was transfected to the SAS cells (SAS/neo cells). Both types of cells were exposed to X-rays (1.5 KeV/micron) or accelerated C-beams (30-100 KeV/micron). The frequency of cell death (apoptosis and necrosis) was measured by acridine orange/ethidium bromide(AO/EB) double staining for fluorescence microscopy. We found that (1) low-LET radiation induced apoptosis only in SAS/neo cells; (2) high-LET radiation at an iso-survival dose induced apoptosis not but necrosis in SAS/neo cells at a higher frequency; (3) high-LET radiation induced p53-independent apoptosis even in SAS/mp53 cells. Our findings suggest that high-LET radiotherapy is expected to (1) have validity in its application to patients carrying mutated p53 cancer cells and (2) reduce injury to adjacent normal tissue for high-frequency-induced apoptosis without inflammatory response. We propose that elucidation of p53-independent apoptosis-related genes might provide new insights into radiotherapy for cancer.

Genetic testing for hereditary cancers and other common diseases are still considered as the research testing, not for the clinical testing in Japan. One of the major reason of this situation is related to the guidelines regarding the human genetic testing issued successively in the spring of 2001, one by joint work of the eight learned societies and the other by the Japan clinical laboratories association. Both of these guidelines warn the condition of the clinical application of genetic testing after research stage must have the evidence data for clinical utility. We describe the situation of the genetic testing in the U.S. focusing the social background of increasing breast cancer cases and the contribution of Myriad Genetic Laboratories, Inc. for the genetic testing industry. We also describe the Japanese situation of the genetic testing and problems to be solved before spreading widely.

Gastrointestinal stromal tumor (GIST) is a quite common gastrointestinal mesenchymal tumor entity that has been recently established by pathologists. The prediction of the biologic behavior of GISTs is relatively difficult. Recently, classifications of the biologic behavior of GISTs according to metastatic potential (low risk, intermediate, high risk) have been proposed. The gain-of function mutation of c-kit proto-oncogene has been detected in GISTs and its role in molecular pathogenesis of GIST has been established. Imatinib mesylate (formerly STI 571, Glivec, Novartis Pharmaceuticals Corp, Switzerland) inhibits the tyrosin-kinase activity of KIT receptor, and clinical trials for GIST are in progress. In the past, no effective drug was known for the treatment of GISTs. Recently, the effectiveness of Imatinib mesylate in patients bearing metastatic GISTs has been reported. The treatment and prognosis of GIST will change significantly in the coming few years, as the clinical application of Imatinib mesylate becomes more common. In the near future, the value of Imatinib mesylate as a post-operative adjuvant chemotherapy for patients with GISTs without metastasis should be studied, and the way to classify GISTs according to biologic behavior will become quite important.

A 46-year-old woman was diagnosed as having acute myeloid leukemia (M 1) with translocation t(16;21) (p11;q22). The leukemic cells were positive for CD 13, CD 33, CD 34, CD 41, CD 56 and HLA-DR. After induction chemotherapy, the patient achieved complete remission (CR). However, 8 months later she relapsed with various additional chromosomal abnormalities. Although the patient achieved a 2nd CR after re-induction chemotherapy, the patient had extramedullary tumors in the right breast twice and relapse occurred frequently. The tumor cells were characterized by the same immunophenotypes and t(16;21) with additional 1 q trisomy. Although there was no evidence of hematological relapse, another type of 1 q trisomy was observed. Furthermore, an increase of abnormalities with 1 q trisomy was noted concomitant with re-increase in the number of blasts. The patient underwent allogeneic bone marrow transplantation (BMT), but she died from BMT complications. The case could have been a karyotype of t(16;21) with additional chromosomal abnormalities through consecutive approaches. Because of the high occurrence rate of relapse, we consider various additional chromosomal abnormalities and the expression of CD 56 as prognostic factors of this condition.

H. pylori infection is associated with major gastroduodenal diseases, i.e. peptic ulcer, cancer and MALT lymphoma in the stomach. The pathogenesis of H. pylori in these diseases has been elucidated. Non-atrophic diffuse antral gastritis is correlated with duodenal ulcer and multifocal atrophic gastritis is correlated with both gastric ulcer and cancer. It is well known that Japanese tend to have multifocal atrophic gastritis. H. pylori eradication therapy dramatically reduces the recurrence rates of gastroduodenal ulcers in humans and bacterial eradication for peptic ulcer patients has been recommended in many countries. Mongolian gerbils have provided an excellent model of gastric carcinogenesis and H. pylori enhanced (promoted) chemical carcinogen-induced carcinogenesis in the stomach using this model. H. pylori eradication reduced the incidence of gastric cancer in the Mongolian gerbil model. It was a recently discovered that a transforming clone carrying the translocation t (11;18) (q21;q21) forms a MALT lymphoma, the growth of which is independent of H. pylori and will not respond to bacterial eradication. In the early stage, the tumor can be successfully treated by eradication, but at a later stage additional genetic abnormality in the lymphoma may show no response to H. pylori eradication therapy.

Follicular lymphoma, derived from ocular adnexa as defined by World Health Organization Classification of neoplastic diseases of the hematopoietic and lymphoid tissues, is quite rare in Japan.

Cancers can be classified as hereditary or sporadic based on the difference in the involvement of genetic factors. Hereditary cancers, which account for approximately 2% of all cancers, are caused by germline mutations of defined genes inherited in an autosomal dominant or recessive manner. Dozens of tumor suppressor genes, oncogenes and DNA repair genes have been identified as being responsible for hereditary cancers. Common cancers (sporadic cancers) make up the remaining 98% of all cancers. It is considered that susceptibility to sporadic cancers in each individual is determined by the combination of multiple genetic polymorphisms. Case-control studies, mainly focusing on the genes involved in drug metabolisms and DNA repair, have shown that dozens of genes are associated with cancer risks.

Mutations in signal transduction molecules, which regulate cell differentiation and proliferation, are involved in the development of leukemia. Aberrations of receptor type tyrosine kinases are known to arise from FLT3 mutations in acute myeloid leukemia (AML) and myelodysplastic syndrome, and c-Kit mutations in mast cell tumors. BCR/ABL found in chronic myelogenous leukemia (CML) is a hallmark of the constitutively active forms of cytoplasmic tyrosine kinases. Downstream of the tyrosine kinase is the RAS GTP-binding protein, and genetic mutations related to this protein have been found in a wide variety of malignant tumors including hematopoietic tumors. In the nucleus, transcription factor-encoding genes are frequently detected as the targets of chromosomal translocations found in specific types of leukemias. For instance, the AML1 gene generates AML1/MTG8 chimera by t (8;21) translocation in AML (M2), AML1/EVI-1 chimera by t (3;21) translocation in blastic crisis of CML, and TEL/AML1 chimera in t (12;21) translocation (pre-B cell type acute lymphoblastic leukemia). Another example of abnormal transcription factors is PML/RAR alpha generated by t (15;17) translocation found in acute promyelocytic leukemia. Mutations or deletions of tumor suppressor genes are frequently found in cell cycle regulators such as p53, RB and p16 genes. Therefore, mutations of any molecules involved in the signal transduction pathways from growth factor receptors to inside the nucleus are thought to contribute to neoplastic transformation of hematopoietic cells.

The p300 and closely related CBP acetyltransferases function as global transcriptional coactivators and play important roles in a broad spectrum of biological processes, including cell proliferation and differentiation. The p300 protein is targeted by viral oncoproteins, and mutations of the p300 gene associated with second allele inactivation have been identified in certain types of human cancers and carcinomas. This study shows that 300 mutants identified in human carcinoma cells retain the capacity to bind p300/CBP interacting proteins, E1A, PCAF, and Smads. However, carcinoma cell lines expressing only mutant p300 severely impaired transcriptional responses to some signaling, including that of TGF beta, which responses have been shown to be mediated by p300 and CBP. Furthermore, tumor-derived p300 mutants did not affect the proliferation of p300-deficient cells in the presence or absence of TGF beta. These results suggest that p300 plays an important role in epithelial carcinogenesis by mediating transcription that negatively regulates cell proliferation.

In March 2000, a 30-year-old Chinese male was initially diagnosed as having non-Hodgkin's lymphoma because of right cervical lymphadenopathy. He had received 8 cycles of chemotherapy including doxorubicin in China. As of February 2001, he was treated in our hospital with the CEPP regimen including etoposide, and was admitted in June 2001 because of leukopenia and thrombocytopenia. Peripheral blood showed hemoglobin 12.7 g/dl, platelets 4.1 x 10(4)/microliter and white blood cells 2300/microliter with 15% blasts. Bone marrow was hypocellular with 48% blasts, which were positive for myeloperoxidase, CD13 and CD33. Chromosome analysis showed 46,XY, t(9;11) (p21;q23) in all 20 metaphase spreads. He was diagnosed as having therapy-related acute myeloblastic leukemia (AML). Because of hypoplastic bone marrow, induction therapy with the CAG regimen including cytarabine, aclarubicin and granulocyte-colony stimulating factor (G-CSF) was started, but no apparent effect was observed. The patient was then treated with the AVG regimen comprising 250 micrograms of G-CSF and continuous infusion with 20 mg of cytarabine and 50 mg of etoposide for 14 days. Complete hematological and cytogenetic remission was achieved after two courses of the AVG regimen. Although it has been shown that the CAG regimen is effective for refractory and/or secondary AML, our results indicate that the AVG regimen should be tried for cases of AML resistant to the CAG regimen.