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A number of compounds known as heterocyclic aromatic amines (HAAs) are formed during the normal process of cooking meat, fish and fowl at high temperatures, especially by frying, broiling, or barbecuing. They are formed by the reaction of creatinine with an amino acid(s) at high temperatures. Thus far, 19 HAAs have been identified and generally they are very potent mutagens in a bacterial assay system known as the Ames test. In addition, 10 of the 19 HAAs have been tested and shown to be carcinogenic when administered to rodents and one of the HAAs referred to as PhIP induces only two types of tumors at a high percentage in rats, i.e. breast and colon. The mutagenic and carcinogenic effects of the HAAs is due to their metabolism to reactive forms which can react with DNA to form complexes known as adducts. In addition to rodents, DNA-adducts have also been found in nonhuman primates being administered selected HAAs and one of the HAAs known as IQ is also a potent carcinogen in nonhuman primates inducing liver tumors in a high percentage of the animals in about one-seventh of their lifetime. Studies underway may allow an estimation of the risk of the HAAs to human cancer etiology and methods to mitigate this risk.
Molecular Studies with the p53 Tumor Suppressor Gene
The most common cancer-related genetic change known at the molecular level is mutation in the p53 tumor suppressor gene, which is implicated in lung, breast, colon, liver and many other cancers. These p53 mutations can lead to losing normal tumor suppressor functions of p53 and to gaining functions as an oncogene. Different carcinogens cause characteristic mutations in the p53 gene. Exposure to one common carcinogen, ultraviolet light, is correlated with transition mutations at dipyrimidine sites in skin cancer; dietary aflatoxin B1, exposure is correlated with G:C to T:A transversions that lead to a serine substitution at residue 249 of p53 in hepatocellular carcinoma; and exposure to cigarette smoke is correlated with G:C to T:A transversions in lung and head and neck carcinomas. These observations provide strong evidence for a molecular mechanism for chemical carcinogenesis and raises the exciting prospect that mutational analysis may uncover the molecular "fingerprints" left by other environmental carcinogens. Accumulating evidence indicates that the p53 mutational spectrum differs among various cancers, and analysis of these mutations is providing clues to the etiology of diverse tumors and to the function of specific regions of p53.
Studies on the Li-Fraumeni Syndrome
Only about 100 families around the world are known to have the rare genetic disorder known as the Li- Fraumeni syndrome (LFS), but they serve to highlight the point that cancer is in some cases an inherited disease. Members of these families are highly susceptible to several tumors, especially breast cancer, often developing the malignancies before they are 30 years old. NCI scientists and their collaborators at Massachusetts General Hospital in Boston reported that the gene defect underlying the LFS is a mutation in the p53 gene, and that the gene defect is present in the germ cells, which means it can be passed from one generation to another. This was an important breakthrough because it will make it possible to identify precisely which members of LFS families carry the gene defect and are thus at high risk of getting cancer. These individuals could then be the subject of individual monitoring in order to detect cancer early on, when they are most curable. To date, at least 7 component cancers of the syndrome have been identified on the basis of their excess occurrence in Li-Fraumeni families; breast cancer, soft-tissue sarcoma, osteosarcoma, acute leukemia, brain tumors, adrenocortical carcinoma, and gonadal germ-cell tumors. Recent studies have detected germ line p53 mutations in a few patients with multiple cancer at an early age but no family history, suggesting new mutations. On the other hand, germ line p53 mutations have not been detectable in some families with classical Li-Fraumeni syndrome, raising the possibility of genetic heterogeneity and providing an impetus for further molecular study of LFS with apparently normal p53. The clinical, psychosocial, legal and ethical issues posed by p53 testing have led to published recommendations that can be applied to other cancer susceptibility genes that are discovered.
Human Papillomaviruses and Cancer Risk
The papillomaviruses are small DNA-containing viruses which are associated with benign warts and papillomas in a variety of higher vertebrates, including man. There are now 70 human papillomaviruses (HPVs) which have been identified. Approximately 20 of these have been associated with lesions of the human genital tract; several of these have been associated with genital warts which rarely progress to carcinoma. Others have been associated with cervical dysplasia and other pre-neoplastic lesions which may progress to malignancy. HPVs have also been linked to human cervical carcinoma and other anogenital carcinomas including cancer of the penis, vulvar carcinoma, and perianal carcinoma. Recently many major advances have been made in understanding the molecular biology of the HPVs. The viral genes which are expressed in cervical cancer tissues have been identified and shown to be at least in part responsible for the malignant characteristics of the cells. Two viral genes, designated E6 and E7, are now recognized to be transforming genes of the HPVs. The E7 protein has been shown to form stable complexes with a cellular protein, the product of the retinoblastoma (RB) gene. The RB gene is missing or inactivated in a variety of human cancer, leading researchers to believe that the RB protein normally acts to regulate cell growth. By binding to the RB protein, E7 may alter the activity of RB, thereby allowing cells to grow in an uncontrolled fashion. Evidence now exists that the E6 gene product also complexes with the p53 cellular protein, that, as described above, is also involved in regulating cell growth. The identification of the viral genes which contribute directly to the deregulated growth of the cancer cell and the identification of the cellular protein with which they interact should provide insight for the screening and development of antiviral agents.
Studies of Cancer in Women
NCI epidemiologists are pursuing a wide variety of analytical studies designed to elucidate the relationship of exposures and host factors to cancer outcomes specific to women. The approaches utilized in these studies have been both retrospective and prospective in nature, with many of the studies utilizing laboratory probes to better define exposures. Cancers unique to women are the focus of these studies, and include malignancies of the breast, ovary, cervix, endometrium, and vagina/vulva. Of particular interest with respect to breast cancer etiology are the effects of exogenous hormone use (oral contraceptives and menopausal hormones) and of different dietary patterns, including recent as well as adolescent diet. These factors are currently being analyzed in a recently completed large case-control study. This study also will be able to address reasons for differing incidence rates in black versus white women and will examine possible biologic mechanisms for identified risk factors through a variety of serologic measurements. Other NCI studies are evaluating radiotherapy for breast cancer as a primary risk factor for second primary breast cancer occurring in the contralateral breast. If such a risk exists, the dependence of the risk on dose and age at exposure will be evaluated. Individual dosimetry determinations are being made; the record abstraction is underway. NCI epidemiologists are also assessing the role of pesticides and other agricultural exposures, as well as cooking practices, in determining a woman's risk for breast cancer.
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