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Search Results: 1 - 10 of 228046 matches for " Timothy R Rebbeck "
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The contribution of inherited genotype to breast cancer
Timothy R Rebbeck
Breast Cancer Research , 2002, DOI: 10.1186/bcr430
Abstract: The multistage model of carcinogenesis describes the progression of normal cells to initiated and preneoplastic cells, and finally to malignant and metastatic disease. Inherited genotypes are known to play a prominent role in the initiation of breast tumors. For example, it is well known that germline mutations in BRCA1 can initiate breast tumorigenesis [1]. However, inherited genotypes may also act at a variety of other steps in the multistage process of breast carcinogenesis. These genotypes may not only affect disease susceptibility, but also disease outcome.Figure 1 presents a number of classes of genes acting in multistage carcinogenesis. In this presentation, G denotes genotypes at a single locus. Subscripts to G are used to distinguish different classes of genes that may act at different points in the development and progression of a tumor. As described in detail below, GE are involved in metabolic pathways that determine propensity to be exposed to breast carcinogens. GP are involved in the metabolism of chemopreventive agents. These genes can determine the degree to which an individual's cancer risk may be modified, or the degree to which an individual will suffer adverse side effects from exposure to the agent. GD include genes that are directly involved in the etiology of a tumor. These genes are typically involved in studies addressing disease susceptibility, and generally represent those genes considered in evaluating cancer risk. GT are genes involved in the determination of drug dissemination and metabolism. Thus, GT determine in part the efficacy or toxicity of a drug. GO are determinants of a tumor's natural history, as it progresses from a more benign to a more advanced stage. Each of these classes of genes will be defined in this commentary, with examples that illustrate how inherited genotype information can be used to better understand the multistep carcinogenesis process and improve cancer detection, prevention, and treatment. It is important t
Variation in breast cancer risk in BRCA1 and BRCA2 mutation carriers
Timothy R Rebbeck, Susan M Domchek
Breast Cancer Research , 2008, DOI: 10.1186/bcr2115
Abstract: In 1995, Easton and colleagues [1] provided an estimate of greater than 80% for the lifetime risk of breast cancer in BRCA1 carriers. This estimate, the highest reported, was based on families with at least four individuals with breast and/or ovarian cancer collected for linkage analysis to identify genes associated with familial breast cancer. In contrast, studies of unselected breast cancer patients have estimated risks in the 40% to 60% range, while studies examining risk estimates in families attending high-risk clinics have intermediate risk estimates of 60% to 80% [2-5]. These wide-ranging risk estimates, as well as studies that suggest wide interindividual variability in risk even within families with the same BRCA1/2 mutation, suggest that there is no 'correct' risk estimate that can be applied to all women, and there are risk modifiers in BRCA1/2 mutation carriers. These modifiers are likely to include reproductive and environmental exposures, genes at other loci, and the nature of an individual's family history.In families with BRCA1/2 mutations, relatives of probands with ovarian cancer have a higher risk of ovarian cancer, and relatives of probands with breast cancer have a higher risk of breast cancer. For example, Lee and colleagues [6] examined the lifetime risk of cancer in first-degree relatives (FDRs) of BRCA1/2 mutation carriers with breast or ovarian cancers. The standardized incidence ratio for breast cancer was 10.6 (95% confidence interval 5.2 to 21.6) in FDRs of breast cancer probands and 3.3 (1.4 to 7.5) in FDRs of ovarian cancer probands (p = 0.02). Similarly, the standardized incidence ratio for ovarian cancer was 7.9 (1.2 to 5.3) for FDRs of breast cancer probands, and 11.3 (3.6 to 31.9) for FDRs of ovarian cancer probands, although this difference was not statistically significant (p = 0.37). Why should this be? Phenotype-genotype correlations of specific gene mutations exist that suggest that some mutations are more likely to confer ris
Germline Mutations and Polymorphisms in the Origins of Cancers in Women
Kim M. Hirshfield,Timothy R. Rebbeck,Arnold J. Levine
Journal of Oncology , 2010, DOI: 10.1155/2010/297671
Abstract: Several female malignancies including breast, ovarian, and endometrial cancers can be characterized based on known somatic and germline mutations. Initiation and propagation of tumors reflect underlying genomic alterations such as mutations, polymorphisms, and copy number variations found in genes of multiple cellular pathways. The contributions of any single genetic variation or mutation in a population depend on its frequency and penetrance as well as tissue-specific functionality. Genome wide association studies, fluorescence in situ hybridization, comparative genomic hybridization, and candidate gene studies have enumerated genetic contributors to cancers in women. These include p53, BRCA1, BRCA2, STK11, PTEN, CHEK2, ATM, BRIP1, PALB2, FGFR2, TGFB1, MDM2, MDM4 as well as several other chromosomal loci. Based on the heterogeneity within a specific tumor type, a combination of genomic alterations defines the cancer subtype, biologic behavior, and in some cases, response to therapeutics. Consideration of tumor heterogeneity is therefore important in the critical analysis of gene associations in cancer.
Clique-Finding for Heterogeneity and Multidimensionality in Biomarker Epidemiology Research: The CHAMBER Algorithm
Richard A. Mushlin, Stephen Gallagher, Aaron Kershenbaum, Timothy R. Rebbeck
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004862
Abstract: Background Commonly-occurring disease etiology may involve complex combinations of genes and exposures resulting in etiologic heterogeneity. We present a computational algorithm that employs clique-finding for heterogeneity and multidimensionality in biomedical and epidemiological research (the “CHAMBER” algorithm). Methodology/Principal Findings This algorithm uses graph-building to (1) identify genetic variants that influence disease risk and (2) predict individuals at risk for disease based on inherited genotype. We use a set-covering algorithm to identify optimal cliques and a Boolean function that identifies etiologically heterogeneous groups of individuals. We evaluated this approach using simulated case-control genotype-disease associations involving two- and four-gene patterns. The CHAMBER algorithm correctly identified these simulated etiologies. We also used two population-based case-control studies of breast and endometrial cancer in African American and Caucasian women considering data on genotypes involved in steroid hormone metabolism. We identified novel patterns in both cancer sites that involved genes that sulfate or glucuronidate estrogens or catecholestrogens. These associations were consistent with the hypothesized biological functions of these genes. We also identified cliques representing the joint effect of multiple candidate genes in all groups, suggesting the existence of biologically plausible combinations of hormone metabolism genes in both breast and endometrial cancer in both races. Conclusions The CHAMBER algorithm may have utility in exploring the multifactorial etiology and etiologic heterogeneity in complex disease.
Incorporating tumour pathology information into breast cancer risk prediction algorithms
Nasim Mavaddat, Timothy R Rebbeck, Sunil R Lakhani, Douglas F Easton, Antonis C Antoniou
Breast Cancer Research , 2010, DOI: 10.1186/bcr2576
Abstract: We extended BOADICEA by treating breast cancer subtypes as distinct disease end points. Age-specific expression of phenotypic markers in a series of tumours from 182 BRCA1 mutation carriers, 62 BRCA2 mutation carriers and 109 controls from the Breast Cancer Linkage Consortium, and over 300,000 tumours from the general population obtained from the Surveillance Epidemiology, and End Results database, were used to calculate age-specific and genotype-specific incidences of each disease end point. The probability that an individual carries a BRCA1 or BRCA2 mutation given their family history and tumour marker status of family members was computed in sample pedigrees.The cumulative risk of ER-negative breast cancer by age 70 for BRCA1 mutation carriers was estimated to be 55% and the risk of ER-positive disease was 18%. The corresponding risks for BRCA2 mutation carriers were 21% and 44% for ER-negative and ER-positive disease, respectively. The predicted BRCA1 carrier probabilities among ER-positive breast cancer cases were less than 1% at all ages. For women diagnosed with breast cancer below age 50 years, these probabilities rose to more than 5% in ER-negative breast cancer, 7% in TN disease and 24% in TN breast cancer expressing both CK5/6 and CK14 cytokeratins. Large differences in mutation probabilities were observed by combining ER status and other informative markers with family history.This approach combines both full pedigree and tumour subtype data to predict BRCA1/2 carrier probabilities. Prediction of BRCA1/2 carrier status, and hence selection of women for mutation screening, may be substantially improved by combining tumour pathology with family history of cancer.Genetic testing for BRCA1 and BRCA2 has important clinical implications: individuals found to carry mutations in these genes can be carefully monitored and receive preventive therapies including oophorectomy or mastectomy [1-6]. As genetic testing is expensive and may be associated with adverse psy
Prostate Cancer Severity Associations with Neighborhood Deprivation
Charnita M. Zeigler-Johnson,Ann Tierney,Timothy R. Rebbeck,Andrew Rundle
Prostate Cancer , 2011, DOI: 10.1155/2011/846263
Abstract: Background. The goal of this paper was to examine neighborhood deprivation and prostate cancer severity. Methods. We studied African American and Caucasian prostate cancer cases from the Pennsylvania State Cancer Registry. Census tract-level variables and deprivation scores were examined in relation to diagnosis stage, grade, and tumor aggressiveness. Results. We observed associations of low SES with high Gleason score among African Americans residing in neighborhoods with low educational attainment (OR?=?1.34, 95% CI?=?1.13–1.60), high poverty (OR?=?1.39, 95% CI?=?1.15–1.67), low car ownership (OR?=?1.46, 95% CI?=?1.20–1.78), and higher percentage of residents on public assistance (OR?=?1.32, 95%?=?1.08–1.62). The highest quartile of neighborhood deprivation was also associated with high Gleason score. For both Caucasians and African Americans, the highest quartile of neighborhood deprivation was associated with high Gleason score at diagnosis (OR?=?1.34, 95% CI?=?1.19–1.52; OR?=?1.71, 95% CI?=?1.21–2.40, resp.). Conclusion. Using a neighborhood deprivation index, we observed associations between high-grade prostate cancer and neighborhood deprivation in Caucasians and African-Americans. 1. Introduction Prostate cancer is the most prevalent malignant cancer among men in the U.S. 217,730 incident cases were expected in 2010 [1]. The advent of prostatic specific antigen (PSA) testing has driven large increases in diagnoses with dramatic increases observed between 1988 and 1993, coinciding with the advent of widespread PSA testing [2–4]. African Americans have a significantly higher risk of disease than Caucasian men, tend to be diagnosed with more aggressive disease, and suffer the greatest mortality associated with prostate cancer [5]. In spite of its common occurrence and strong racial disparities, modifiable risk factors for prostate cancer have not been confirmed. These disparities are believed to be a result of interactions among genes, health behaviors, and environmental factors. Economic, physical, and social characteristics of residential neighborhoods may influence health-related behaviors, screening behaviors and health conditions. Disadvantaged neighborhoods are often correlated with higher levels of environmental pollutants, overcrowding, violence, less social cohesion, and less access to services [6]. Of particular importance for diseases such as prostate cancer in which screening practices have had large effects on incidence, low-income neighborhoods often have fewer medical facilities and these facilities are often stressed due to higher
What stresses men? predictors of perceived stress in a population-based multi-ethnic cross sectional cohort
Timothy R Rebbeck, Anita L Weber, Elaine Spangler, Charnita M Zeigler-Johnson
BMC Public Health , 2013, DOI: 10.1186/1471-2458-13-113
Abstract: We used a population-based survey of 6,773 White, 1,681 Black, and 617 Hispanic men in Southeastern Pennsylvania to evaluate the relationship of self-reported PS and financial security, health status, social factors, and health behaviors. Interactions across levels of age and ethnicity were tested using logistic regression models adjusted for overall health status, education, and household poverty.High PS decreased significantly with age (p<0.0001) and varied by ethnicity (p=0.0001). Exposure to health-related and economic factors were more consistently associated with elevated PS in all ethnicities and ages, while social factors and health behaviors were less strongly or not at all associated with PS in most groups. Significant differences in the relationship of high PS by age and ethnicity were observed among men who are medically uninsured (p=0.0002), reported missing a meal due to cost (p<0.0001), or had spent a night in the hospital (p=0.020). In contrast, not filling a prescription due to cost and diagnosed with a mental health condition were associated with high PS but did not differ by age and ethnicity subgroup.These data suggest that some, but not all, factors associated with high PS differ by age and/or ethnicity. Research, clinical, or public health initiatives that involve social stressors should consider differences by age and ethnicity.
Genetic polymorphisms in human SULT1A1 and UGT1A1 genes associate with breast tumor characteristics: a case-series study
Ekaterina G Shatalova, Susan E Walther, Olga O Favorova, Timothy R Rebbeck, Rebecca L Blanchard
Breast Cancer Research , 2005, DOI: 10.1186/bcr1318
Abstract: The capacity for SULT1A1*2 to sulfate 17β-estradiol and the capacity for cells expressing SULT1A1*1 or SULT1A1*2 to proliferate in response to 17β-estradiol was evaluated. A case-series study was performed in a total of 210 women with incident breast cancer, including 177 Caucasians, 25 African-Americans and eight women of other ethnic background. The SULT1A1 and UGT1A1 genotypes were determined and a logistic regression model was used to analyze genotype–phenotype associations.We determined that the SULT1A1*1/*1 high-activity genotype was associated with tumor size ≤2 cm (odds ratio = 2.63, 95% confidence interval = 1.25–5.56, P = 0.02). Individuals with low-activity UGT1A1 genotypes (UGT1A1*28/*28 or UGT1A1*28/*34) were more likely to have an age at diagnosis ≥60 years (odds ratio = 3.70, 95% confidence interval = 1.33–10.00, P = 0.01). Individuals with both SULT1A1 and UGT1A1 high-activity genotypes had low tumor grade (odds ratio = 2.56, 95% confidence interval = 1.04–6.25, P = 0.05). Upon stratification by estrogen receptor status, significant associations were observed predominantly in estrogen receptor-negative tumors.The data suggest that genetic variation in SULT1A1 and UGT1A1 may influence breast cancer characteristics and might be important for breast cancer prognosis.Estrogens are involved in the development and progression of breast cancer [1-4]. Women experience various exposures to estrogens, including endogenous production, use of pharmacological estrogens (birth control medications and hormone replacement therapy) and through environmental contact. There are several mechanisms that are believed to be critical for estrogen-mediated carcinogenesis. Estrogens, being estrogen receptor (ER)-mediated mitogens, stimulate cell proliferation and promote the growth of estrogen-responsive transformed cells [5,6]. ER-independent activities of estrogens have recently been elucidated that include cell-signal transduction as well as mutagenicity [4,7-9]. Estrogens
Global Patterns of Prostate Cancer Incidence, Aggressiveness, and Mortality in Men of African Descent
Timothy R. Rebbeck,Susan S. Devesa,Bao-Li Chang,Clareann H. Bunker
Prostate Cancer , 2013, DOI: 10.1155/2013/560857
Dissecting the Within-Africa Ancestry of Populations of African Descent in the Americas
Klara Stefflova,Matthew C. Dulik,Jill S. Barnholtz-Sloan,Athma A. Pai,Amy H. Walker,Timothy R. Rebbeck
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014495
Abstract: The ancestry of African-descended Americans is known to be drawn from three distinct populations: African, European, and Native American. While many studies consider this continental admixture, few account for the genetically distinct sources of ancestry within Africa – the continent with the highest genetic variation. Here, we dissect the within-Africa genetic ancestry of various populations of the Americas self-identified as having primarily African ancestry using uniparentally inherited mitochondrial DNA.
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