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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review focuses on etiologic factors and hormonal correlates of the three major gynecologic cancers-uterine cervix, uterine corpus and ovary- and breast cancer. The incidence rate of the three gynecologic cancers combined is only 40 percent of the breast cancer rate (43.6 vs 109.5 per 100,000), whereas the combined mortality rate is half that for breast cancer (14.3 vs 27.3 per 100,000). Cervical cancer is distinctive in that it's hormonal correlates are few; it exhibits the epidemiologic characteristics of a sexually transmitted disease. Integration of Human Papilloma Virus DNA types 16, 18 (or other) within the cellular genome has been identified in more than 80% of high grade cervical intraepithelial neoplasias and invasive carcinomas. Epithelial ovarian cancers occur most commonly in nulliparous, infertile women and familial carriers of BRCA1. Oral contraceptive (OC) use reduces ovarian cancer risk by at least one-half, a benefit which increases with increasing duration of use and persists for at least 15 years after discontinuation. Pregnancy and OCs suppress gonadotropin secretion, whereas fertility drugs enhance follicle-stimulating hormone production. These indicators of alterations in the hypothalmic-pituitary-ovarian axis provide some support for both the excess gonadotropin and the incessant ovulation theories of ovarian carcinogenesis. Endometrial carcinoma is the prototype hormonally-determined disease. Increased estrogen from either endogenous or exogenous sources increases risk. Lowering the estrogen load or adding progestin reduces risk. This explains the marked protection achieved by combined estrogen/progestin OC's and the dramatic increased risk uncurred by long-term estrogen replacement therapy (ERT). Breast tissue, also a target for sex steroid hormones, displays a more complex risk profile. Current ERT use increases breast cancer risk by about 30%; adding a progestin to the estrogen does not improve the situation (40% increased risk). Furthermore, OCs do not reduce breast cancer risk, but may increase it for current OC users under age 45. The magnitude of these hormonal effects is much smaller than that exhibited with endometrial cancer.
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PMID:Epidemiologic analysis of breast and gynecologic cancers. 910 87

As inherited germ line mutations, such as loss of BRCA1 or AT, account for less than 5% of all breast cancer, most cases involve acquired somatic perturbations. Cumulative lifetime exposure to bioavailable estradiol links most known risk factors (except radiation) for breast cancer. Based on a series of recent experimental and epidemiologic findings, we hypothesize that the multistep process of breast carcinogenesis results from exposure to endogenous or exogenous hormones, including phytoestrogens that directly or indirectly alter estrogen metabolism. Xenohormones are defined as xenobiotic materials that modify hormonal production; they can work bifunctionally, through genetic or hormonal paths, depending on the periods and extent of exposure. As for genetic paths, xenohormones can modify DNA structure or function. As for hormonal paths, two distinct mechanisms can influence the potential for aberrant cell growth: compounds can directly bind with endogenous hormone or growth factor receptors affecting cell proliferation or compounds can modify breast cell proliferation altering the formation of hormone metabolites that influence epithelial-stromal interaction and growth regulation. Beneficial xenohormones, such as indole-3-carbinol, genistein, and other bioflavonoids, may reduce aberrant breast cell proliferation, and influence the rate of DNA repair or apoptosis and thereby influence the genetic or hormonal microenvironments. Upon validation with appropriate in vitro and in vivo studies, biologic markers of the risk for breast cancer, such as hormone metabolites, total bioavailable estradiol, and free radical generators can enhance cancer detection and prevention.
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PMID:Medical hypothesis: bifunctional genetic-hormonal pathways to breast cancer. 916 97

We analyzed the alteration of BRCA1 in DNA obtained from 83 individuals of 13 Japanese site-specific ovarian cancer families and 6 breast-ovarian cancer families. Six germline mutations were detected in 7 families, which consisted of 4 breast-ovarian cancer and 3 site-specific ovarian cancer families, by single-strand conformation polymorphism analysis, followed by direct sequence determination. The mutations included three frameshifts, two nonsense mutations, and one missense mutation causing loss of a zinc-binding motif. The frequency of loss of heterozygosity at the microsatellite markers on the BRCA1 gene was 57% (8 of 14 cases) in site-specific ovarian cancer families, and 100% (6 of 6 cases) in breast-ovarian cancer families. All tumors of the patients carrying a mutation of BRCA1 showed deletion of wild-type alleles, implicating BRCA1 as a tumor suppressor gene. These results suggest that germline mutations of the BRCA1 gene play an important role in the carcinogenesis of breast and/or ovarian cancer in a majority of breast-ovarian cancer families and in some site-specific ovarian cancer families.
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PMID:Mutational analysis of BRCA1 gene in ovarian and breast-ovarian cancer families in Japan. 919 34

Cancer incidence varies markedly by ethnicity and geographic location. Ethnic variation in cancer occurrence has traditionally been ascribed to differences in social, cultural, economic, and physical environments. However, this interpretation of the epidemiologic evidence may need to be revised as a result of new biological evidence and theories of carcinogenesis. Carcinogenesis is now recognized to be a multistep process during which mutations or heritable changes in expression occur in genes involved in cellular growth control and genome stability. Inherited cancer susceptibility may be a stronger determinant of ethnic differences in cancer incidence than is currently appreciated. To examine the potential role of inherited susceptibility, the theoretical contribution of inherited susceptibility to ethnic differences in rates in considered using a simple probability model. Germline mutations in tumor suppressor genes BRCA1 and p53 are used to illustrate the magnitude of the ethnic differences for breast cancer that might arise from differences in inherited susceptibility. Our simple model suggests that ethnic differences in cancer occurrence can result from differences in genetic susceptibility. However, the magnitude of ethnic relative risk is likely to more strongly reflect differences in the distribution of susceptibility genotypes between groups than the magnitude of the disease risk associated with the genotypes. For many scenarios, the ethnic relative risk arising from differences in susceptibility may be bounded by the ratio of the proportion of susceptible individuals in each group.
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PMID:Ethnic differences in cancer incidence: a marker for inherited susceptibility? 925 77

Epidemiologic studies have shown that the risk of cancer in the ovarian surface epithelium is decreased by factors that suppress ovulation, whereas uninterrupted ovulation has been associated with increased risk. This suggests that ovulation may play a critical role in ovarian carcinogenesis. More recently, molecular studies have demonstrated alterations in specific oncogenes and tumor suppressor genes in ovarian cancers. Overexpression of the HER-2/neu oncogene occurs in approximately 30% of ovarian cancers and correlates with poor survival. Although mutation of the K-ras oncogene has been found in some mucinous ovarian cancers, mutations in this gene appear to be more common in borderline ovarian tumors. Amplification of c-myc occurs in approximately 30% of ovarian cancers and is more frequently seen in serous cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 50% of stage III/IV and 15% of stage I/II ovarian cancers. Most p53 mutations in ovarian cancers are transitions, which suggests that they arise spontaneously rather than due to exogenous carcinogens. In contrast to the acquired genetic alterations described above that are a feature of sporadic ovarian cancers, 5-10% of ovarian cancers probably arise due to inherited genetic defects. Recently, the BRCA1 tumor suppressor gene has heen identified and shown to be responsible for most cases of hereditary ovarian cancer. Further studies are needed to augment our understanding of the molecular pathogenesis of ovarian cancer.
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PMID:Human ovarian cancer of the surface epithelium. 933 69

Breast cancer is a leading women's health issue. Continued advances in understanding the temporal sequencing of relevant exposures promises to shed light on the continuum of breast carcinogenesis. Oral contraceptive use and the transient increase in risk following childbirth are exposures that affect the near-term risk of breast cancer. The availability of commercial testing for inherited susceptibility to breast cancer has accelerated the need for data to develop sound policy for implementing gene testing. The risks associated with BRCA1 and BRCA2 mutations may be less than previously estimated. Antiestrogens with lesser risks than tamoxifen hold promise for chemoprevention, but await testing. Not enough is known to formulate primary prevention strategies based on lifestyle interventions. Further understanding lifestyle factors that may be involved in the etiology of breast cancer and are amenable to preventive intervention thus remains a top priority, with diet and physical activity of greatest interest.
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PMID:Epidemiology, prevention, and early detection of breast cancer. 937 70

To investigate the coordinated occurrence of loss of heterozygosity (LOH) at the BRCA1 locus and microsatellite instability (MI) in sporadic breast carcinomas, 56 tumors were analysed for both genetic alterations. The comparison of clinicopathological features with the obtained data revealed that LOH at the BRCA1 locus was significantly correlated with features specific for familial BRCA1 tumors and with absence of hormone receptors. No correlation was found between LOH and MI. These results suggest that sporadic and familial breast tumors, where BRCA1 is altered, could display similar clinicopathological features and that LOH and MI are distinct genetic events in sporadic breast carcinogenesis.
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PMID:Pathology of sporadic breast tumors with LOH at the BRCA1 locus: correlation with histopathological features specific to familial BRCA1 tumors and absence of microsatellite instability. 959 2

BRCA1 is considered to be a tumor-suppressor gene, yet mutations in this gene are uncommon in sporadic breast tumors. We investigated whether mechanisms other than DNA mutations that affect the coding region might be involved in breast carcinogenesis. Since loss of expression of the BRCA1 gene would lead to lack of protein, we evaluated the level of BRCA1 mRNA in 21 normal epithelial specimens and in 74 breast carcinomas using quantitative reverse-transcription-polymerase-chain-reaction (RT-PCR). All normal breast epithelial samples expressed BRCA1 mRNA. On the other hand, the tumor specimens exhibited approximately 10-fold range of levels of BRCA1, with some specimens expressing barely detectable amounts of BRCA1 mRNA. The distribution in levels was significantly higher in normal breast epithelial cells than in tumor specimens (p = 0.004). Examination of the BRCA1 locus indicated that deletion of the BRCA1 gene may account for low levels of BRCA1 in a number of specimens. In addition, analysis of samples with relatively reduced levels of BRCA1 expression revealed preferential allele-specific expression in a number of cases, suggesting the presence of regulatory mutations. Our data suggest that the BRCA1 gene may be involved in sporadic breast carcinogenesis through a reduction in gene expression.
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PMID:Preferential allelic expression can lead to reduced expression of BRCA1 in sporadic breast cancers. 963 85

DNA repair is an important factor of stability of pro- and eukaryotic genomes which plays a central role in mutagenesis and carcinogenesis. Genetic control of nucleotide excision repair (NER) in mammalian cells is well studied, but little is known about molecular mechanisms of postreplication repair (PRR) which allows bypass of base lesions in template strands after DNA replication. In Saccharomyces cerevisiae PRR is controlled by the RAD61RAD18 pathway which involves POL30 gene encoding proliferating cell nuclear antigen (PCNA), and in human cells PCNA is known to be closely associated with the newly replicated chromatin where PRR probably takes place. In UV-irradiated human cells distinct PCNA foci may be detected in some cells which accumulate phosphorylated breast cancer susceptibility protein BRCA1 and another protein BARD1. Human PCNA is also known to be phosphorylated after UV-irradiation. In this study we found that the known inhibitor of protein kinases staurosporine supresses PRR in NER-deficient cells which is consistent with the view that BRCA1 and PCNA are required for PRR. We also have shown that the distinct PCNA foci in UV-irradiated NER-deficient cells are actually associated with the newly replicated chromatin. Since RAD18 protein is not essential for normal DNA replication and directly controls PRR in yeast, we analysed whether this protein as well as its human homologs (HR18A and HR18B) have common domains with BRCA1 and BARD1. It is found that HR18A has a subregion of homology to BARD1 and HR18A-to BRCA1. Taken together the results indicate that BRCA1 and BARD1 may be involved in PRR in human cells.
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PMID:Staurosporine-sensitive protein phosphorylation is required for postreplication DNA repair in human cells. 964 67

Subsets of patients with common cancers belong to families in which the predisposition is inherited in a regular Mendelian fashion. Genes underlying these cancers are now recognized in colorectal cancer (APC, mismatch repair genes, LKB1) and in breast cancer (BRCA1, BRCA2) whereas, in prostate cancer, a locus in chromosome 1 (HPC1) has been proposed on the basis of linkage analysis. Major challenges are to determine the population incidence of these mutations, their penetrance, phenotypic expression, and the effects of modifier genes and epigenetic factors. Finally, the role of encoded proteins in carcinogenesis is a matter of major interest.
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PMID:The genetics of hereditary common cancers. 969 Sep 90


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