Cancer is a heritable disorder of somatic cells. Environment and hereditary both operate in the origin of human cancer. Hereditary cancer is rare, but it has served as a useful model in the understanding of carcinogenesis. A number of cancer genes have been identified by the study of hereditary cancers and implicated in sporadic forms of the same tumors. In this article, I reviewed Knudson's famous "two-hit" hypothesis of tumor suppression.

Along with the marked development of molecular biology, familial cancer study has made a giant breakthrough in understanding carcino-genesis and provided an evolutional opportunity for genetic testing which has opened an encouraging scope in development of cancer prevention strategy Progress of molecular biology will be accelerated to overcome the cost effectiveness barrier in near future. However, there are no way to reduce a lag time required for the longitudinal observational study on these tested individuals not only in physical but also in psychosocial aspects, and on result of preventive intervention on their course, those which are essential indeed in achieving the aim of the research. In this regards, we urgently need to create the essential infrastructure involving construction of the permanent and nation wide cancer genetic information system, our own fundamental agreement on ELSI and decisiveness to acknowledge the need for educating and recruiting cancer genetic counselor. In this occasion, UICC symposium is the most timely event that will elicit an realistic impact in the new era of cancer research, in Japan.

We examined 20 cases (21 specimens) of ocular adnexal lymphoid proliferations, using the histological, immunohistochemical and molecular genetic methods. The latter two protocols were performed to detect the light chains restriction of immunoglobulin with peroxidase-antiperoxidase (PAP) methods, and the clonality of immunoglobulin heavy chain gene with the hemi-nested polymerase chain reaction (PCR) method, respectively. Although in 8 cases it could not be morphologically determined whether they were neoplastic or not, clonality was revealed in 1 case with immunohistochemistry and in 4 cases with PCR. Two cases showed discordant results between immunohistochemistry and PCR probably due to somatic mutation of the framework region of the immunoglobulin heavy chain gene. Therefore, we, concluded that examination with these methods contribute to a better understanding of the nature of the ocular adnexal lymphoid proliferations. Furthermore, the immunoglobulin gene PCR method is very useful in practical examination, as it can be used with formalin-fixed paraffin-embedded specimens.

Androgens are required for the development of normal prostate and prostate cancer, through their action via the androgen receptor (AR). Although prostate cancer is potentially curable in the early stages by radical prostatectomy, androgen ablation is standard treatment for metastatic prostate cancer. Metastatic prostate cancer is incurable despite temporary remission commonly achieved by androgen ablation therapy. To investigate the mechanism for the development of human prostate cancer, examination was made of AR gene mutations.

Eighty percent of prostate cancer with metastasis respond to androgen ablasion, showing initial androgen-sensitive growth. However, more than half of responders gradually loses dependency up to 5 years. Animal experiments reveal that loss of androgen sensitivity is attributable to complex reasons; adaptation, paracrine control by other androgen-independent tissues, genetic changes and mutation of androgen receptor. Most important event is explained from alteration of expression on oncogenes and suppressor genes. Counterplan of the progression was discussed.

The demonstration tha RNA can be cleavaged by cis-ribozyme(catalytic RNAs, RNA enzyme) has potentially important therapeutic implications. Ribozymes are effective for modulation of gene expression because of their simple structure, site-specific cleavage activity and catalytic potential. The targets of ribozyme-mediated gene modulation have ranged from cancer cells to foreign genes that cause infectious diseases. Additional target sites for ribozymes are in initial phases of development and design. Ribozymes have been targeted against myriad genes, including oncogenes (ras, BCR-ABL) and drug resistance genes(MDR-1, c-fos, DHFR). These ribozymes have cleaved the target RNAs in culture system(in vitro) and developed in vivo system. We reported that anti-fos ribozyme has altered the expression of c-fos and DNA repair genes in cisplatin-resistance cancer cells, and reversed the sensitivity to ciaplatin. Furthermore, we have developed high efficiency by the transfer system using an electroporation in vivo.

The recent highlighted points in prognostic factors after breast cancer operation include: 1) the emergence of many genetic and biochemical markers, including c-erbB-2, int-2, EGFR, p53, nm23, LOH, E cadherin, s-phase fraction. The prognostic value of these factors is related to their role in cell cycle regulation, invasion/metastasis mechanisms, etc. The agents related to therapeutic effectiveness, namely p-glycoprotein, pS2, and bcl-2 may become important stratification factors when conducting clinical trials. Pathologic factors, like nodal status, however, are the most useful prognostic factors at the moment. Many newly developed prognostic factors should be examined by multivariate analysis and validated prospectively before clinical use.

In yeast functional assay (YF assay), a newly developed screening system for p53 mutation, wild-type p53 gives white yeast colonies and transcriptionally inactive mutant p53 gives red colonies. In the present study, the author applied YF assay to the detection of p53 mutations in human oral squamous cell carcinoma (SCC). Total RNA was extracted from samples and YF assay was performed. Four SCC cell lines (SAS, HSC-2, HSC-3 and Ca9-22) known to have p53 mutations all gave 100% red colonies, whereas nine oral non-tumor tissues gave 2.9-10% (average 5.2 +/- 2.7%) red colonies. Furthermore, a rat hepatoma cell line, WHp53, which had been transfected with human wild-type p53 expression vector, presented 7.8% red colonies. Thus the functional assays of tissues or cells containing only wild-type p53 give 3-10% red colonies as a background. To assess the detectability of p53 mutations, YF assay was performed on mixtures of wild-type and mutant p53 PCR products at serial ratios. The result showed that the mutation was detectable if 6% population of transcriptionally inactive mutant p53 mRNA were present in the total p53 mRNA. Twenty-two clinical samples of human oral SCC were then tested by YF assay. Fourteen out of 22 cases gave more than 20% red colonies. In these 14 cases, clonal p53 mutations with deletion, nonsense mutation or missense mutation were identified. In a case which gave 17% red colonies, identical p53 mutation was found in 2 out of 6 independent red colonies. However, no identical mutations were found in the cases giving 13, 9 and 8% red colonies. Based on these results, the author proposes that 20% of red colonies is the minimal value for the diagnosis of p53 mutation in YF assay under PCR conditions using Pfu polymerase and hot start method.

Two renal cell carcinoma (RCC) cell lines, JMSU2 and JMSU3, derived from the primary sites of mixed cell type and spindle cell type RCC, respectively, have been established and maintained for 31 and 22 months. Karyotypic analysis revealed human karyotypes with modal numbers of 84 and 55, respectively. Consistent chromosomal abnormalities were 1p+, 3p-, 6q- or 8p- in the JMSU2 cells and 1p-, inv (5p + q-) or loss of sex chromosome in the JMSU3 cells. Electron microscopy revealed abundant glycogen granules, lipid droplets and microvilli. The JMSU3 cells transplanted to nude mice produced tumors with a spindle cell pattern similar to that of the original tumor. High concentrations of cytokines, such as interleukin-6 (145,000 pg/ml), interleukin-8 (35,300 pg/ml) and granulocyte-colony stimulating factor (6,340 pg/ml), were detected in the culture supernatant of the JMSU3 cells. Interleukin-1 beta (IL-1 beta) dose-dependently inhibited the proliferation of the JMSU2 and JMSU3 cells in culture. Tumor cytotoxic factor/hepatocyte growth factor (TCF/HGF) dose-dependently enhanced JMSU3 cell proliferation, but suppressed JMSU2 cell proliferation. These findings suggest that IL-1 beta and TCF/HGF have regulatory roles in the proliferation of RCC.

Gene expression of HGF and c-met proto-oncogene was examined during rat brain development and in cultured PC-12 cells, using reverse-transcriptase (RT)-polymerase chain reaction (PCR) technique. The both mRNAs of HGF and c-met proto-oncogene were remained at low levels in the middle and late stages of gestation (E-13 and E-18). After birth, and the level of both mRNA expression suddenly increased. During P-1 and P-12, their high level of expression continued and then decreased in P-20 and adult brain. Both HGF mRNA and c-met photo-oncogene mRNA were transiently expressed between day 2 and day 5, and disappeared in cultured PC-12 cells treated with NGF. The neurites of PC-12 cells that were treated with anti-sense oligonucleotides of HGF and c-met proto-oncogene, were shorter and fewer in number than untreated control cells. We conclude that neurite extension of PC-12 cells treated with NGF may ensue by way of c-MET protein activation and signal transduction pathways. Thus, c-MET protein activation and up-regulation of the two mRNAs may also play an important role in neuronal maturation in the developing rat brain.