Patients with familial malignant melanoma(FMM) are susceptible for melanoma and multiple dysplastic nevi(atypical mole). FMM is also called as dysplastic nevus syndrome or familial atypical mole and melanoma syndrome. The number of Japanese patients with FMM is very low. In 1994, p16(MTS1, INK4A, CDK4I, CDKN2) gene was cloned as the gene for FMM. p16 gene locus also codes for p14ARF and acts as tumor suppressor through activation of Rb by p16 and p53 by p14ARF. Approximately 20% of FMM patients were shown to carry the germline mutations of p16, indicating the presence of another gene or other genes for FMM, which also may be involved in the development of sporadic malignant melanoma.

The nevoid basal cell carcinoma syndrome is an autosomal dominant disorder characterized by multiple cutaneous basal cell carcinomas, jaw keratocysts and a variety of other tumours, and developmental abnormalities. Recently, this syndrome was shown to result from germ line mutations in human patched(PTC) gene, which encodes a membrane receptor and functions as an important developmental regulator and a tumour suppressor. Haploinsufficiency for the PTC locus is likely to give rise to developmental abnormalities characterized by symmetrical defects and malformed spine and ribs. Postnatal loss of the normal PTC allele leads to multiple basal cell carcinomas and other cancers. PTC mutations and loss of the remaining wild-type allele have also been identified in sporadic basal cell carcinomas and meduloblastomas.

The last decade has seen many great successes in isolating genes involved in inherited disease, a process that is now scaled up by Human Genome Project. The identification of genes responsible for hereditary tumors has made it possible to do the genetic diagnosis of hereditary tumors. However, the benefits and limits of genetic testing for cancer susceptibility are different in each hereditary tumor. It is important to continue the analysis of significance(frequency and penetrance) of mutations of cancer predisposition genes and to make clear the genotype-phenotype and other correlation. Hereditary breast cancer and hereditary non-polyposis colorectal cancer are reviewed and the significance of genetic epidemiology of hereditary tumor is discussed.

To compare clinical and histopathological findings to tumor DNA copy number changes, comparative genomic hybridization (CGH) was performed on 18 primary oral squamous cell carcinomas. Copy number increases were most frequently observed on 8q, 3q, 13q, 11p, and 11q, while copy number decreases most frequently on 10q, 1p, 18q, 9p, and 19q. Copy number changes in relationship to WHO grading were examined with the result that DNA copy number increase on chromosome 6p23-25 was characteristically observed in the groups of Grade II and Grade III, and DNA copy number decreases on chromosomes 9p21 and 11p11-13 were observed in the same groups. Furthermore, comparison of DNA copy number changes to TNM classification indicated that the decreases on chromosomes 1p36 and 10q25-26 might be related to tumor progression. Moreover, the relationship of DNA amplification or deletion to metastasis was investigated. It was found that the majority of the metastasis-positive tumors showed increases on 3q26 and 17q12-21 and showed decreases on chromosome 18q21. The data suggested that these DNA copy number changes on each chromosome in the three categories might be associated with tumor cell differentiation, tumor size, and lymph node metastasis.

DNA diagnosis is useful and significant for clinical oncology, but its use is limited due to a difficulty in preparing tumor-derived DNA materials. To overcome this problem, we investigated the characterization of plasma DNA and it application to successfully detecting K-ras mutation at codon 12 in normal persons, hematopoietic neoplasms, and solid tumors. The range of plasma DNA in each group was 15.8 +/- 5.2 ng/ml, 43.3 +/- 29.8 ng/ml, and 26.8 +/- 17.0 ng/ml, respectively. The ranges in patients with solid tumor were gradually decreased to the normal level of around 15 ng/ml in 3 weeks postoperatively. Plasma DNAs consisted of about 200 bp DNA fragmentation and were convenient for PCR amplification of K-ras gene. The mutation at codon 12 by PCR-RFLP analysis was detected in 13(27%) of 49 patients with solid tumors such as pancreatic cancer, breast cancer, colon cancer, and gastric cancer. The diagnostic specificity was 100%. Serial observations by the PCR-RFLP analysis revealed disappearance of the mutant K-ras about 7 days after successful curative surgery in a patient with gastric cancer.

Genetic diagnosis is necessary to correct mistaken cancer therapy. Today, the human genome project is rapidly progressing, and genetic diagnosis is also growing more diversely. To make genetic diagnosis truly useful in the treatment of cancer patients, we need to establish a new system which gives real benefit to the patient. One way to make such a system is based on the idea of focusing on the proper characteristics of individual cancers. In addition, we should never forget that the surgically resected tissue reflects the spirit and life of the patient.

The PCR-SSCP (single strand conformational polymorphism) method has been widely employed to screen mutations in a variety of genes because of its rapidity and simplicity in the operation. Using this method, we have examined mutations of some tumor-related genes including p53 and Ki-ras. In this study, we have evaluated the PCR-Cold (non radioactive) SSCP method for detection of p53 point mutations in comparison with immunohistological detection of p53 and PCR-direct sequencing. The results indicated that the PCR-Cold SSCP method had the same sensitivity with that of PCR-direct sequencing method, and had higher sensitivity than that of immunohistochemical method (IHC).

Gene therapy for hereditary tumor was discussed in two aspects: preventive and therapeutic approaches. A practical approach to prevention is the transfection of a wild type gene into presymptomatic lesions or normal tissue which may potentially give rise to malignant tumor. Preliminary trials of this approach have already been reported by several investigators. Therapeutic approach is much more difficult since metastasis generally occurs simultaneously at multiple sites and no appropriate delivery system for transgenes to target multiple lesions has been so far developed. We have most recently established a method by which transgenes can be specifically delivered to multiple-metastasized tumors via transferrin receptor and found this method to have successful therapeutic effects. The future direction of gene therapy for hereditary tumor was also addressed.

We, Clinical Genetics Unit, Kyoto University Hospital, have established an internet homepage, Clinical Genetics Network(Idennet)(URL: http:¿www.kuhp.kyoto-u.ac.jp/idennet) to provide various information necessary for genetics clinics. One of the most important contents is the "Online Database of Gene Tests" which provides real time information on gene tests performed at research facilities such as universities and available for outsiders. The point of this database is direct input of information by registered users, making information always updated. 46 gene tests for hereditary tumors have been registered in the "Online Database of Gene Tests". This database will be a useful tool for clinical management of patients and family members with hereditary tumors.

Human genetics, or medical genetics have been rarely taught in most of the medical schools in Japan, as there are only several medical schools with genetics departments among 80 medical schools in Japan. Bioethics has just been becoming an important issue in the medical community in Japan. People hate to be told of hereditary diseases, possibly due to the traditional concept of hereditary diseases as punishment for the evil acts of the ancestors. Recent rapid progress in genetic diagnosis and therapy, however, requires the medical community in Japan to consider the bioethical aspects related to human genetics. We need proper guidelines, and the efforts have been made by the government as well as by the Society for Familial Tumor to propose practical guidelines for human genetics. They may considerably be different from those in the Western countries.

Gene testing elucidates the identification of heterozygous carrier for hereditary cancer and the needs for genetics services are increasing in cancer hospitals. Genetic services include educational explanation for the disease and Mendelian inheritance, risk assessment, orientation for gene testing, post-test counseling for cancer prevention and psychosocial issues, and support services. This review outlines how they are performed in the clinic of cancer hospital.

Chemopreventive effect of tamoxifen on familial breast cancer was studied. As it is impossible to use medicines for prevention of human breast cancer in Japan, a lot of investigations on animals using natural foods like as green tea, seaweed etc has been done. Seaweed wakame was effective on breast cancer proliferation in rat. In this paper 3 reports(Fisher, Powles and Veronesi) were reviewed and the results of some Japanese investigations in chemoprevention on animals were introduced. In Fisher's report tamoxifen was effective on breast cancer prevention, however in other 2 reports no effects were noticed because of the difference of risk. Study of Tamoxifen And Raloxifene(STAR) was started by NSABP in 1999.