Cancer and the Environment Gene-Environment Interaction (2002) / Chapter Skim
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Abstracts of Talks
Pages 70-107
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From page 70... ...
Genetic Basis for Colorectal Neoplasia. The genetic basis for the development of colorectal cancer involves the accumulation of specific somatic mutations in proto-oncogenes and tumor suppressor genes with increasing age 2Supported by a Cancer Research Foundation of America grant, Public Health Service grants CA41108 (Colon Cancer Prevention Program Project)
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From page 71... ...
It is evident too that variability in carcinogen-metabolizing genes influences the risk of colorectal neoplasia in humans (Gertig and Hunter, 1998; Hussain and Harris, 1998a; Pereira, 1998~. It is clear that susceptibility to colorectal cancer is related to interindividual variability in biotransformation of endogenous and exogenous substances, as well as in DNA repair and cell cycle control.
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From page 72... ...
Furthermore, CIMP-positive adenomas were found to have lower levels of COX2 expression because of promoter methylation, and their dependence on expression of DNA methyltransferase to maintain tumor suppressor gene silencing via hypermethylation. Folate, MTHFR, and Gene Methylation.
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From page 73... ...
Low MTHFR activity is thought to protect against colorectal cancer since less tetrahydrofolate is converted to 5-methyltetrahydrofolate, allowing more folate to be shunted toward DNA synthesis and repair. In these studies, an inverse association was shown for the presence of the val/val genotype and colorectal cancer among individuals with adequate folate intake, whereas this effect was not seen among those with low folate intake (Chen et al., 1996; Ma et al., 1997~.
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From page 74... ...
, a lower risk of colorectal cancer associated with higher intake of folate was shown among individuals with the val/val genotype as compared to those with the ala/ala genotype who had low folate intake (odds ratio (OR) = 0.6; 95% confidence interval = 0.4-1.0~.
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From page 75... ...
compared to those with the CC genotype and homocysteine levels below the median. The results of these analyses suggest a modest effect of plasma homocysteine levels on adenoma recurrence and a risk-enhancing effect of high homocysteine levels on adenoma recurrence among individuals with the TTMTHFR genotype.
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From page 76... ...
Overall, the data are fairly consistent for an association between frequent consumption of cured meats during gestation and childhood brain tumors. Further research will be needed to determine if the brain tumors are due to the NOCs in cured meats or to a nutrient such as high fat or low folate in the diet.
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From page 77... ...
Current epidemiologic evidence and suggestions for preventing prostate and breast cancer in humans indicate that we should return to the original type of diets under which our ancestors evolved. The recent development of the Western-type diet is associated with breast and prostate cancer throughout the world.
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From page 78... ...
DuBois, M.D., Ph.D. Risk factors for colorectal cancer include a positive family history, meat consumption, smoking, and alcohol consumption.
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From page 79... ...
Although the molecular and statistical tools to examine complex gene-environment interactions are still in development, opportunities now exist for population and family-based studies using biomarkers that integrate the search for susceptibility genes and the exogenous and endogenous exposures that cause cancer. While the methodologic challenges of "molecular epidemiology" are formidable, this interdisciplinary approach to cancer etiology should provide unprecedented opportunities to enlarge our understanding of environmental and genetic risk factors and their biological pathways, and set the stage for new clinical and public health strategies aimed at preventing and controlling cancer.
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From page 80... ...
All of these factors are evident in the largely rural and predominantly white population of Appalachia, particularly in the Central Highlands, including the Appalachian counties of Ohio, West Virginia, Kentucky, Tennessee, and Virginia. Lung cancer is a leading cause of male cancer deaths in central Appalachia, with the highest rate in Appalachian Kentucky, the geographic area where the Behavioral Risk Factor Surveillance Survey data (BRFSS)
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From page 81... ...
Harris, M.D. Environmental, occupational, and recreational exposures to carcinogens contribute to cancer risk in humans.
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From page 82... ...
transversions are the most frequent substitutions observed in cancers of the lung, breast, stomach, and liver, and are more likely to be due to bulky carcinogen-DNA adducts. G:C to T:A transversions also are more common in lung cancers from smokers compared to never smokers (Takeshima et al.,1993; Hussain and Harris, 1998b)
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From page 83... ...
The p53 mutational spectrum in radon-associated lung cancer from uranium miners also differs from lung cancer caused by tobacco smoking alone (Vahakangas et al., 1992; Taylor et al., 1994~. Hepatic angiosarcomas induced by occupational exposure to vinyl chloride have a high frequency of A:T to T:A p53 mutations when compared with sporatic angiosarcoma (Hollstein et al., 1994; unpublished results)
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From page 84... ...
Molecular epidemiology also explores host cancer susceptibilities, such as carcinogen metabolic activation, DNA repair, endogenous mutation rates, and inheritance of mutated tumor suppressor genes. Substantial interindividual variation for each of these biological end points has been shown (Harris, 1991)
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From page 85... ...
The aim of this study was to provide reliable estimates of genetic and environmental effects for the most common cancer sites and to assess the modification of such estimates by age at diagnosis. Data from 90,000 twins were combined to assess the cancer risks at 28 sites for co-twins of twins with cancer.
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From page 86... ...
Thus, the results on heritability summarize the total genetic effects. The recent data identified significant heritable effects for colorectal, breast, and prostate cancer.
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From page 87... ...
Etiologic clues may even be found in childhood environment or in long-lasting family habits, because the shared environment appeared to contribute to some forms of cancer in which common environmental risk factors have not been identified, including those of the gallbladder and corpus uteri. The most challenging result, however, was the large heritability of all cancer and of colorectal, breast, and prostate cancer in particular.
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From page 88... ...
The strong, consistent association between a woman's menstrual history and breast cancer risk implicates lifetime exposure to sex steroid hormones as a major factor in the causation of breast cancer. A recent meta-analysis of epidemiological studies implicated estrogens more directly, by showing that circulating levels of the biologically most potent estrogen, estradiol (E2)
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From page 89... ...
These specific 5'-termini sequences are all spliced onto exon II at the common 3'-splice junction. The association of obesity with postmenopausal blood estrogen levels as well as breast cancer risk may at least in part be mediated by an increased aromatization of androstenedi
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From page 90... ...
may exert a direct effect on breast cancer risk or potentiate the effects of estrogens on breast epithelium (Oh, 1998~. IGFs have been recognized as major regulators of mammary epithelium and breast cancer cell growth (Clarke et al., 1997)
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From page 91... ...
While we have focused our major research effort on estrogen biosynthesis, genetic variation, and breast cancer risk, we have concomitantly evaluated germline missense variants in genes involved in breast cancer progression. We have confirmed a previous observation that a missense variant (Ile 655 Val)
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From page 92... ...
MSF children need to be included in prospective cohort studies to prove scientifically whether or not chronic exposure to pesticides from childhood into adulthood places humans at risk of developing deleterious health outcomes, including cancer during childhood and later in life, (2) the measurement of OCP levels should be included in ongoing and future studies; and also (3)
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From page 93... ...
Clusters also require a community relations specialists who not only speaks their language, but is able to understand their issues. In the future, approaching disease clusters will require collection of disease rates in registries because if we don't know the baseline level of any disease, it is impossible to know if the reported cluster is a statistical aberration or not.
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From page 94... ...
The last decade has witnessed important advances in the understanding of factors that influence cancer risk. Several environmental factors continue to surface as potentially instrumental in explaining the wide global variation in the incidence and biological behavior of tumors.
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From page 95... ...
The past decade has witnessed great strides in understanding the biological basis of cancer. Discoveries that both essential and nonessential dietary nutrients can markedly influence several key biological events including cell cycle regulation, processes involved with replication/or transcription, immunocompetence, and factors involved with apoptosis have strengthened convictions that specific foods and/or components may markedly influence cancer risk.
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From page 96... ...
Collectively these studies reveal that individual dietary components are capable of bringing about a host of intracellular changes that may influence cancer risk. The utilization of genomic technologies to evaluate the effects of nutrients offers hope in determining which cellular change is most important in bringing about a change in the incidence or behavior of a tumor.
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From page 97... ...
We and others have hypothesized that clinically evident lung cancers have accumulated 10-20 different genetic abnormalities in dominant oncogenes and/ or tumor suppressor genes (TSGs) (Sekido et al., 1998; Fong et al., 1999~.
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From page 98... ...
Analysis of all of the data indicated multiple regions of localized 3p allele loss. A panel of six markers in the 600-kb 3p21.3 homozygous deletion region showed loss in 77% of lung cancers (100% SCLC, 100% squamous, 90% adenocarcinomas)
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From page 99... ...
. We conclude that 3p allele loss is nearly universal in lung cancer pathogenesis; involves multiple, discrete, 3p LOH sites that often show a "discontinuous LOH" pattern in individual tumors; occurs in preneoplastic/preinvasive lesions of smokers with and without lung cancer; and frequently involves breakpoints in at least three very small, defined genomic regions.
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From page 100... ...
Our findings indicate that multiple small clonal or subclonal patches containing molecular abnormalities are present in normal or slightly abnormal bronchial epithelium of patients with lung cancer. In detailed studies of bronchial epithelium and bronchial biopsies from current or former smokers without lung cancer, we also find thousands of clonal patches showing allele loss in histologically normal-appearing respiratory epithelium.
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From page 101... ...
With the exception of bronchoalveolar lung cancer, all histologic types have smoking and tobacco carcinogens as the major underlying etiologic factor. Clearly, SCLC etiology is strongly tied to cigarette smoking.
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From page 102... ...
Future studies need to identify the specific genes involved at these multiple sites and determine whether these provide new tools for early molecular detection, for monitoring of chemoprevention efforts, and as specific targets for developing new therapies. We conclude from our global and quantitative studies that clinically evident lung cancers have acquired 20 or more clonal genetic alterations; SCLC and NSCLC have acquired different genetic lesions; alterations in 3p TSGs appear especially early, followed by changes in 9p, 8p, and then multiple other sites; tumor-acquired promoter hypermethylation is a frequent mutational mechanism in lung cancer; changes consistent with oxidative damage leading to mitotic recombination are frequently seen; smoking-damaged histologically normal epithelium, as well as epithelium with preneoplastic/preinvasive changes, has thousands of clonal patches containing genetic alterations; and correcting even single genetic abnormalities can reverse the malignant phenotype.
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From page 103... ...
Detection of HER-2/neu amplification in tumors is therefore an important factor in prognosis and choice of therapies. These examples reveal the clinical value of addressing the genetic basis of cancer and illustrate the importance of understanding genetic mechanisms in developing methods of cancer prevention, early detection, and targeted therapies.
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From page 104... ...
TILs have been identified that can recognize unique cancer antigens on murine and human cancers including melanoma, breast cancer, colon cancer, and lymphoma. The major histocompatibility complex MHC restricted recognition of human cancer antigens was detected by assaying panels of human leukocyte antigen (HLA)
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From page 105... ...
Lung cancer risk is dependent on the dose of tobacco carcinogens, which in turn is modulated by genetic polymorphisms in the enzymes responsible for carcinogen activation (e.g., myeloperoxidase) and detoxification (e.g., glutathione s-transferases)
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From page 106... ...
Genetics, diet, and reproductive factors do not explain all of the differences. Indeed, women with inherited genetic predisposition may never suffer from breast cancer, just as not all smokers get lung cancer.
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From page 107... ...
Additionally, migratory patterns have shifted in the United States as individuals from different countries or regions of a country immigrate distinctly to geographic regions in the United States. The NCI's national special population networks have been formed to consider factors related to these and other issues.
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