INTERDISCIPLINARY PROGRAM AREA

SUMMARY OF ACTIVITIES

Our focus has been on the differences between the two countries in the frequency of certain cancers, and on exploring these differences for new opportunities for research Exchange scientists have been selected to expand the ideas and knowledge that originates at these workshops.
From April 1986 to March 31, 1987, two workshops, one of which was called a symposium were held, and three exchange scientists were dispatched from Japan to the United States in the Program Area.

WORKSHOPS
(1) Hepatitis B Virus and Primary Hepatocellular Carcinoma
A workshop on “Hepatitis B Virus (HBV) and Primary Hepatocellular Carcinoma” (PHC) was held in Honolulu, Hawaii, on January 29-30, 1987. The workshop was organized by Dr. Tomoyuki Kitagawa from the Cancer Institute, Japanese foundation for Cancer Research, Tokyo, and Dr. W Thomas London from the Fox Chase Cancer Center in Philadelphia. The workshop was intended as a forum for a small group of scientists (13 altogether) from the two countries to exchange information and to develop new research projects. Sessions started from relatively comprehensive epidemiological and pathological topics, and then proceeded to problems at the cellular and molecular level.
Worldwide, there are 200 million HBV carriers, and about 80% of PHC cases are thought to be etiologically associated with chronic HBV infection. Little is known, however, about the real mechanism of HBV-related hepatocarcinogenesis.
After an epidemiological review, a hypothesis that iron nutrition and metabolism may affect viral replication and the pathogenesis of PHC was presented. This hypothesis was based on the analysis of serum ferritin levels of patients in Korea and Taiwan, and provoked active discussion.
Next, information from chemical carcinogenesis was introduced, with emphasis on the multifactorial and multistep aspect of hepatocarcinogenesis. In response to this subject the role of chemical carcinogens, especially aflatoxins, alcohol, schistosomiasis and thorotrast in HBV-associated carcinogenesis became the topics of discussion.
The results of the analysis on the frequency and mode of HBV integration in PHC and liver tissue with chronic HBV infection were reported by several participants. Evidence has been accumulated that viral integration provokes host chromosomal rearrangements and deletions. In a particular case, an insulin-like growth factor on chromosome llp was shown to be activated, presumably by viral integration. However, the conclusion was that promoter insertion is not a common mechanism of HBV-related hepatocarcinogenesis. The significance of viral integration, if any, might be different from case to case.
An exciting topic was the discovery of a new PHC-related oncogene lca. Lca was shown to be located on chromosome 2 and activated in PHC. The activation of lca was, however, not related to HBV integration.
The function of HBV X gene product has recently been the focus of interest. Sera from 86% of 21 PHC patients reacted with anti-X gene products. The real meaning of these data was, however, obscure.
Woodchucks, ducks and ground squirrels are important animals for studies of HBV-related carcinogenesis since these animals are infected with a hepatitis virus similar to HBV. The critical issue of whether all hepadna viruses cause liver cancer in their respective species was addressed by two reports of participants confirming the development of PHC in carrier ducks and ground squirrels after more than three years of observations.
The replication process and gene function of hepadna viruses have been clarified considerably in duck and woodchuck systems. It was reported that duck hepatitis B virus replicates via a complex process involving reverse transcription of an RNA progenome.
Research on HBV and liver cancer has been slowed by the lack of proper liver cell lines. Establishment of a woodchuck liver cell line was introduced in this meeting by two investigators, and a possible core sequence of WHV enhancer was detected.
The participants stated that the new systems and techniques described at this workshop would lead to rapid progress in understanding the components of hepatocarcinogenesis in humans.
A report of this meeting has been published in the Japanese Journal of Cancer Research (GANN), 78: 869-874, 1987.

(2) Genetics of Human Cancer
The workshop was held in Los Angeles on March 23-25, 1987. The purpose was to learn about the frequency, chromosomal and molecular mechanism in carcinogenesis of certain cancers with significant genetic backgrounds.
The meeting was co-organized by Dr. Frederick P. Li, National Cancer Institute and Dr. Hiraku Takebe, Kyoto University. Eight scientists from the United States attended, one from Canada and ten from Japan with interests in cancer genetics, epidemiology, pathology, radiation, biology, biochemistry, cell biology, surgery, and dermatology.
The topics included:

1. Retinoblastoma
-- The incidence of Rb shows some variations worldwide, and appears to be higher in Japan than in the United States. Rb occurs in a hereditary form (up to 40% of cases) and a non-hereditary (sporadic) form. Occurrence of these 2 forms can be explained by the 2-mutation model of Knudson.
-- Cytogenetics studies revealed primarily deletions of 13q14 and other minor alterations. The Rb gene was localized to 13q14. Dr. William F. Benedict (Children’s Hospital of Los Angeles) succeeded in the cloning and sequencing of the Rb gene. When retinoblastoma was examined with the new probe, internal deletions were demonstrated in the majority of tumors. Furthermore, osteosarcoma, fibrosarcoma and other tumors also show internal deletions of the Rb gene.

2. Renal tumors
-- The annual incidence rate of Wilms’ tumor in Japan was 3.8 per million children, which was low compared to that of other countries.
-- Dr. Alfred G. Knudson (FOX Chase Cancer Center) emphasized that the genes for retinoblastoma and Wilms’ tumor are examples of anti-oncogenes, the loss of which is associated with tumor development.

3. Colorectal cancer
-- The hereditary component of colorectal cancer not associated with polyposis coli and heterogeneity of polyposis syndromes were widely reviewed.
-- Studies on FPC at the molecular level revealed: 1) no association between FPC and HLA on the basis of linkage analysis; 2) reaction with monoclonal antibodies in some adenomas and adenocarcinomas; 3) increased c-myc gene expression in adenocarcinoma; 4) rare c-myc amplification in adenocarcinoma; 5) absence of transforming activity with DNA from FPC transfected into NIH3T3.

4. Mechanisms of carcinogenesis
-- Epidemiology, clinical features, and biology of xeroderma pigmentosum (XP) were extensively discussed. It fails to confirm similarity in the processes of carcinogenesis and mutagenesis in cancer-prone hereditary diseases such as XP, ataxia telangiectasia Bloom’s syndrome and Fanconi’s anemia.
-- A new assay system using plasmids was introduced as a tool to measure DNA repair and mutagenesis in XP cells.

5. Cancer syndromes
-- Multiple endocrine neoplasia type 2 (MEN-2) in Japan was reviewed. Cytogenetic studies and linkage analyses fail to place the MEN-2 gene locus at 20pl2.2. Also, no loss of heterozygosity has been found by polymorphic DNA markers.
-- Biochemical and biological characteristics of medullary thyroid carcinoma and thyroid C cell malignancy were examined. Calcitonin is a good marker for C cells, and the calcitonin gene was cloned and localized to the short arm of chromosome 11.
-- Dr. Li widely reviewed families with sarcomas and other neoplasms, called the Li-Fraumeni syndrome, as a new model for examining inherited cancers.

6. Epidemiology and laboratory methods
-- Characteristics of cancer in Japan were reviewed, and various cancers and conditions in the United States and Japan were compared.
-- Studies of biochemical mutations in the children of atomic bomb survivors and results showed similar mutation rates in children of cases and controls.
-- The importance of various new methods, such as gene mapping, in situ hybridization genetic linkage analysis and fragile sites in the understanding of mechanism in carcinogenesis were discussed.

In conclusion, the frequency, the comparison between the two countries, the biology and clinical features of various genetic cancers were presented in this workshop. Among them the highlight was a demonstration of the evidence of the deletion of the Rb gene in retinoblastoma and osteosarcoma and an introduction of a new concept of “anti-oncogene” or “recessive oncogene” by Dr. Knudson. Introduction of various new molecular methods, such as gene mapping, in situ hybridization, plasmid, marker genes such as the CT gene will give a rapid progression in elucidation of the carcinogenic mechanism of genetic cancers.

EXCHANGE SCIENTISTS
1. Dr. Isamu Kino, Hamamatsu Medical School, visited Dr. L. H. Sobin, Armed Forces Institute of Pathology, for studying the development of stomach cancer for one month.
2. Dr. Okio Hino Cancer Institute, visited Dr, C. E. Rogler, Albert Einstein College of Medicine, for studying hepatitis B virus and hepatocarcinoma for one month.
3. Dr. Mitsuru Mori, Sapporo Medical College, visited Dr. B.E. Henderson, University of Southern California, studying the epidemiology of hormone-related cancers for one month.