Genes and Cancer J

GENES AND CANCER J. Michael Bishop, Me1 Greaves and Janet D. Rowley, Organizers February 1 1 - February 17, 1984 Plenary Sessions February 12: The Genetics of Cancer. ................................. 27-28 DNA Damage and Tumorigenesis ........................... 28-30 February 13: The Genetics of the Cancer Cell ............................ 3 1-32 Viral Models for Oncogenes ............................... 32-33 February 14: Oncogenes in Human Tumors. ............................. 33-34 Cellular Oncogenes: Structure, Function and Pathogenicity .......... 34-36 February 15: Chromosomal Anomalies and Cellular Oncogenes . 37-38 February 16: Pathobiology of the Tumor Cell ............................. 38 Poster Sessions February 1 2: Poster Session No. 1 Poster Abstracts 0079 - 0121 39-53 February 13: Poster Session No. 2 Poster Abstracts 0122 - 0160 ............................ 53-66 February 14: Poster Session No. 3 Poster Abstracts 0161 - 0195 ............................ 66-77 February 15: Poster Session No. 4 Poster Abstracts 0196 - 0238 ....... 78-92 25 Genes and Cancer The Genetics of Cancer 0052 CLINICAL ECOGENETICS OF CANCER, John J. Mulvihill , Clinical Epidemiology Branch. National Cancer Institute, Bethesda MD 20205. Ecogenetics. the study of heritable variations in response to environmental agents, may be a useful concept in understanding carcinogenesis, to avoid considering exogenous factors to the exclusion of genetic determinants and vice versa. A paradox in the cancer problem arises because, at the level of the cell, cancer is a genetic disease, whereas, in populations, cancer has minor familial aggregation and is largely attributed to environmental influences. Ecogenetics implies the need for joint studies by epidemiologists (to deal with population characteristics), clinicians (to provide information and specimens on patients), and laboratory scientists (to dissect mechanisms within tissues, cells, and genes). Clinical geneticists recognize 200 single gene traits that have neoplasia as feature or complication; 13 of these, as well as at least one inborn cytogenetic disorder, clearly represent inborn susceptibility to environmental carcinogens. Examples include radiation sensitivity in xeroderma pigmentosum, ataxia-telangiectasia, and four other traits; viruses in the X-linked hyperproliferative syndrome; and diet in the polyposes coli , hemochromatosis, and tyrosinemia. The mapping of single gene traits in man is merging with the chromosomal abnormlities in cancers of both environmental and inherited origins. Among the leads for further studies the c-onc genes draw current attention. Other loci deserve exploration, such as nucleoside phosphorylase on chromosome 14q, neurofibromatosis possibly of 4p, and the Y chromosome in gonadal dysgenesis and the Klinefel ter syndrome. Specimens from well characterized patients and families, stored at the National Cancer Institute and elsewhere, could be a source of DNA and cell lines for further studies of cancer genes. 0053 GENE MAPPING IN CANCER STUDIES, Robert S. Sparkes, Department of Medi- cine, University of California, Los Angeles, CA 90024 A number of recent developments have contributed to our understanding of the role of genetic factors in cancer. Among these has been the expansion of capabilities to map genes. This will be illustrated through the use of gene mapping studies in human retinoblastoma, which is a developmental eye tumor and occurs with a frequency of 1/20,000 in the first few years of life. In slightly less than half the cases, there is a positive family history following an autosomal pattern of inheritance. The remaining cases are sporadic, but among these, there is a small group which has a partial deletion of the long arm of a chromosome 13. A gene for the enzyme esterase D had been mapped previously to chromosome 13 by using interspecific somatic cell hy- brids. This enzyme was evaluated in the patients with the small chromosome deletion of 13 and was found to be half normal: based upon a gene dose rela- tionship, this indicated that the genetic locus for esterase D is located in the deleted segment. Through the study of several patients, it was found that the comon region of deletion was band 13q14 and that patients having this deletion had half normal enzyme activity. These studies suggested a genetic factor located in this band related to retinoblastoma. It was possible in one patient to identify a small chromosome’deletion which was too small to be seen by cytogenetic techniques, but was inferred by the patient having half normal esterase D activity. The patient’s tumor tissue was examined and was found to have no esterase D activity: chromosome studies on this tumor demonstrated only a single chromosome 13, which although on cytogenetic evaluation appeared to be normal, was interpreted to be the chromosome 13 containing the submicro- scopic deletion. These studies suggested that at the cellular level, the manifestation of the retinoblastoma follows a recessive mechanism. These studies are being followed up by recombinant DNA analysis to isolate probes Close to the retinoblastoma gene with the ultimate objective being to isolate the retinoblastoma gene and identify its normal function. Another question ad- dressed was whether the gene for the hereditary form of retinoblastoma is located in the same chromosomal region. Because esterase D shows a genetic polymorphism on electrophoresis, it was possible to carry out these enzyme studies in families with the hereditary form of retinoblastoma and ,to demon- strate close genetic linkage between the gene for the hereditary retinoblastoma and esterase D. 27 Genes and Cancer THE GENETICS OF SUSCEPTIBILITY TO THYMIC LYMPHOMA IN MICE. Frank Lilly and Maria L. 0054 Duran-Reynals, Albert Einstein College of Medicine, Bronx, NY 10461. During the last twenty years, a number of mouse genes that influence the occurrence of thymic lymphoma (resistance genes) have been identified. The mechanism of each of these genes appears to be different from that of any other gene of the set. Thymic lymphoma in mice can either be MuLV-associated (i.e., induced by administration of exogenous MuLV or associated with endogenous MuLV sequences, as in spontaneous AKR lymphoma) or it can result from treat- ment of mice with physical or chemical agents (e.q., x-rays or methylcholanthrene). These two types of thymic lymphoma are difficult or impossible to distinguish from each other clinically and phenotypically. Nevertheless, it appears that the resistance genes that can interfere with the emergence of one of the two types of the disease have little or no effect on the occurrence of the other type. These genes will be briefly described and their mechanisms summarized. It is suggested that, if endogenous MuLV sequences are involved in the second category of lymphoma (i.e., induced by x-rays or methylcholanthrene), as has seemed possible on certain experimental grounds, then the molecular mechanisms of their involvement are likely to fundamentally different from those in classical MuLV-induced thymic lymphoma. DNA Damage and Tumorigenesis THE IE0L.E OF THE CELLULAR GmW IN THE STAGES OF CARCINOGENESIS, Henry C. 0055 Pitot, McArdle Laboratory, The Medical School, University of Wisconsin, Madison, Wisconsin 53706 The process of carcinogenesis in most instances can be dissected into three distinct stages, initiation, promotion and progression. Initiation is an irreversible, hereditary process which appears to involve single hit kinetics but no readily measurable threshold in response to known physical, chemical and biologic carcinogenic agents (1). On the basis of such findings initiation is presumably the result of an alteration in the DNA of the cellular genome. Tumor promotion, which follows the process of initiation is readily modulated by environmental factors such as nutrition, hormonal status and age, and does exhibit a threshold or no-effect level as well as a maximal effect following a single dose of an initiating agent (2). Some promoting agents exhibit tissue specificity through their interaction with tissue-specific receptors. The direct action of promoting agents appears to result from their ability to alter gene expression. Indirect actions of sane promoting agents include toxic effects on the cell resulting from the formation of reactive radicals of oxygen (3). This latter process may effect the transition from the stage of promotion to that of progression. Although promoting agents cannot initiate cells, they do promote cells fortuitously initiated by ambient environmental factors. Progression results from alterations in the genome which are characterized by translocation, addition, deletion and/or amplification of genes and/or controlling elements in the DNA of the genome of the cell (4). Cells in the stage of progression are capable of incorporating exogenous DNA into their genome such that progeny of such transfections exhibit the phenotypic characteristics of the new genetic information. Thus a thorough understanding of the characteristics and mechanisms of the stages of carcinogenesis can serve to clarify the role of apparently divergent observations such as "epigenetic" carcinogenesis, transfection of oncogenes and the extreme chemical diversity of pranoting agents in the development of cancer. 1. Scribner, J.D. and Suss, R. Tumor Initiation and Promotion. Int. Rev. Exp. Path. 18: 137-198 (1978). 2. Boutwell, R.K. Function and Mechanism of Promoters of Carcinogenesis. CRC Crit. Rev. Toxicol. 2:

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