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Biomedical subjects

Ellen L Goode

Publications and source records attributed to Ellen L Goode.

14 recordsLinked to original sources
PubMed2006

Age-related lobular involution and risk of breast cancer.

BACKGROUND: As women age, the lobules in their breasts undergo involution or regression. We investigated whether lobular involution in women with benign breast disease was associated with subsequent breast cancer risk. METHODS: We examined biopsy specimens of 8736 women in the Mayo Benign Breast Disease Cohort from whom biopsy samples were taken between January 1, 1967, and December 31, 1991. Median follow-up for breast cancer outcomes was 17 years. We classified lobular involution in the background breast tissue as none (0% involuted lobules), partial (1%-74%), or complete (> or = 75%). Subsequent breast cancer events and data on other risk factors were obtained from medical records and follow-up questionnaires. To estimate relative risks (RRs), standardized incidence ratios were calculated by use of incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) Registry. All statistical tests were two-sided. RESULTS: Distribution of extent of involution was none among 1627 (18.6%) women, partial among 5197 (59.5%), and complete among 1912 (21.9%). Increased involution was positively associated with increased age and inversely associated with parity (both P<.001). The relative risk for the entire cohort of 8736 women, compared with the Iowa SEER population, was 1.40 (95% CI = 1.30 to 1.51). Risk of breast cancer was associated with the extent of involution (for no involution, RR [i.e., observed versus expected] = 1.88, 95% confidence interval [CI] = 1.59 to 2.21; for partial involution, RR = 1.47, 95% CI = 1.33 to 1.61; and for complete involution, RR = 0.91, 95% CI = 0.75 to 1.10; test for heterogeneity P<.001). Lobular involution modified risk in all subsets (e.g., among women with atypia, for no involution, RR = 7.79, 95% CI = 3.56 to 14.81; for partial involution, RR = 4.06, 95% CI = 3.03 to 5.33; and for complete involution, RR = 1.49, 95% CI = 0.41 to 3.82; P = .003). CONCLUSIONS: In this large cohort of women with benign breast disease, lobular involution was associated with reduced risk of breast cancer. Aberrant involution may be a biologically important phenomenon in breast cancer biology.

Adult↗
PubMed2006

Inherited variation in carcinogen-metabolizing enzymes and risk of colorectal polyps.

Exposures such as cigarette smoke and meat contain a variety of procarcinogens, which are thought to play a role in elevation of risk for colorectal polyps and/or cancer. These procarcinogens (including heterocyclic amines and polycyclic aromatic hydrocarbons) are metabolized by a variety of polymorphic enzymes including N-acetyltransferases, sulfotransferases, cytochrome P450 enzymes and epoxide hydrolase. We hypothesized that genetic variation in the encoding genes NAT1, NAT2, SULT1A1, SULT1A2, CYP1A1 or EPHX1 is associated with risk of colorectal polyps and interacts with cigarette use or meat intake to modify risk of colorectal polyps. We examined the role of these genes in a clinic-based study of 651 Caucasian cases with hyperplastic polyps, adenomatous polyps or both types of polyps and 556 polyp-free controls. We found evidence for interaction between NAT acetylator status and SULT1A1 genotype in risk of hyperplastic polyps: individuals with SULT1A1 638AA genotype and NAT1 and NAT2 intermediate/fast phenotypes had 3.5-fold increased risk (95% CI 1.2-10.3) compared with individuals with SULT1A1 638GG genotype and NAT1 and NAT2 slow phenotypes. Data were also consistent with interactions between smoking and variation in SULT1A1, CYP1A1 and EPHX1 and between meat intake and variation in CYP1A1 and EPHX1. No interactions were statistically significant. Although results should be interpreted with caution considering sample size and the number of hypotheses examined, our study suggests future avenues of investigation in larger investigations of genetic and lifestyle factors in the pathway to colorectal cancer.

Adult↗
PubMed2005

The role of parametric linkage methods in complex trait analyses using microsatellites.

Many investigators of complexly inherited familial traits bypass classical segregation analysis to perform model-free genome-wide linkage scans. Because model-based or parametric linkage analysis may be the most powerful means to localize genes when a model can be approximated, model-free statistics may result in a loss of power to detect linkage. We performed limited segregation analyses on the electrophysiological measurements that have been collected for the Collaborative Study on the Genetics of Alcoholism. The resulting models are used in whole-genome scans. Four genomic regions provided a model-based LOD > 2 and only 3 of these were detected (p < 0.05) by a model-free approach. We conclude that parametric methods, using even over-simplified models of complex phenotypes, may complement nonparametric methods and decrease false positives.

Chromosome Mapping↗
PubMed2005

Bias of allele-sharing linkage statistics in the presence of intermarker linkage disequilibrium.

Current genome-wide linkage-mapping single-nucleotide polymorphism (SNP) panels with densities of 0.3 cM are likely to have increased intermarker linkage disequilibrium (LD) compared to 5-cM microsatellite panels. The resulting difference in haplotype frequencies versus that predicted may affect multipoint linkage analysis with ungenotyped founders; a common haplotype may be assumed to be rare, leading to inflation of identical-by-descent (IBD) allele-sharing estimates and evidence for linkage. Using data simulated for the Genetic Analysis Workshop 14, we assessed bias in allele-sharing measures and nonparametric linkage (NPL all) and Kong and Cox LOD (KC-LOD) scores in a targeted analysis of regions with and without LD and with and without genes. Using over 100 replicates, we found that if founders were not genotyped, multipoint IBD estimates and delta parameters were modestly inflated and NPL all and KC-LOD scores were biased upwards in the region with LD and no gene; rather than centering on the null, the mean NPL all and KC-LOD scores were 0.51 +/- 0.91 and 0.19 +/- 0.38, respectively. Reduction of LD by dropping markers reduced this upward bias. These trends were not seen in the non-LD region with no gene. In regions with genes (with and without LD), a slight loss in power with dropping markers was suggested. These results indicate that LD should be considered in dense scans; removal of markers in LD may reduce false-positive results although information may also be lost. Methods to address LD in a high-throughput manner are needed for efficient, robust genomic scans with dense SNPs.

Alleles↗
PubMed2005

Assessment and implications of linkage disequilibrium in genome-wide single-nucleotide polymorphism and microsatellite panels.

Linkage disequilibrium (LD) between markers is more likely to exist in dense genome-wide single-nucleotide polymorphism (SNP) panels than in microsatellite panels. As part of Genetic Analysis Workshop 14 (GAW14), the extent of LD in the Illumina linkage panel III and the Affymetrix Genechip 10 K mapping array was assessed, using data from the Collaborative Study on the Genetics of Alcoholism (COGA). The impact of LD on linkage results was examined in COGA and simulated data, and characteristics of SNPs were assessed for their ability to detect population substructure and predict haplotypes. The authors of the papers summarized here observed greater LD in the Affymetrix than in the Illumina panel, possibly due to increased marker density in the Affymetrix panel, and found greater LD on chromosome X than on the autosomes. Simulation analyses suggest that intermarker LD can cause an upward bias in linkage statistics; however, the impact of LD on linkage analysis depends on the proportion of ungenotyped founders and the extent of LD. No large effect of LD on linkage peaks was observed in COGA analyses. In addition, the papers summarized here found that SNPs with high minor allele frequencies were the most informative compared with microsatellites for the detection of population substructure, and that SNPs in higher LD, and small numbers of SNPs, were the most reliable for haplotype prediction. As ease of genotyping continues to increase, study design and SNP selection for linkage and association studies (including genome-wide association studies) will be improved with consideration of LD in the particular populations studied.

Alcoholism↗
PubMed2004

Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk.

Methionine synthase [5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR)] is involved in folate-mediated one-carbon metabolism, a pathway known to play a role in colorectal carcinogenesis. We investigated whether the MTR D919G polymorphism was associated with risk of colorectal adenoma in a colonoscopy-based study of 513 cases and 609 controls from Minneapolis, MN. Adenoma risk appeared nonsignificantly increased among women with DG or GG genotype [adjusted odds ratio (OR) versus DD, 1.4; 95% confidence interval (CI), 0.9-2.1] but not men (OR, 1.0; 95% CI, 0.7-1.5). An interaction with methionine intake was observed among women, such that low versus high intake was associated with a 2.3-fold increased risk only among those with DG or GG genotype (95% CI, 1.1-4.9; P for interaction = 0.05). Similarly, risk associated with alcohol intake was not elevated among women with the DD genotype; however, consumption of >7 g of alcohol/day versus none was associated with an increased risk among women with DG or GG genotype (adjusted OR, 2.5; 95% CI, 1.4-4.4; P for interaction = 0.03). An interaction between MTR D919G and the thymidylate synthase (TS or TYMS) 3'-untranslated region polymorphism 1494del6 was also observed among women (P for interaction = 0.007). No evidence of interaction with intake of folate, vitamin B(12), or vitamin B(6) or with genotype at MTHFR C677T or the TS enhancer region 28-bp repeat polymorphism was seen. These findings add to what is known about the complexities of genetic variations in one-carbon-metabolizing enzymes in relation to colorectal carcinogenesis.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2004

Polymorphisms in PTGS1 (=COX-1) and risk of colorectal polyps.

Two isoforms of prostaglandin H synthase (PTGS = COX) are key enzymes in prostaglandin synthesis and primary targets for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Use of aspirin or other NSAIDs is associated with a lower risk and reduced recurrence of colorectal adenomas, established precursors of adenocarcinoma. This study investigated risk of colorectal adenomatous and hyperplastic polyps associated with several polymorphisms in the coding region of PTGS1. Within the Minnesota polyp case-control study, patients with colorectal adenomatous (n = 521) or hyperplastic (n = 194) polyps and n = 621 polyp-free controls were genotyped for four PTGS1 polymorphisms (R8W, L15-L16del, P17L, L237M); these had been predicted to affect protein function based on sequence-homology software. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed. Whereas there was no appreciable difference in adenoma or hyperplastic polyp risk associated with R8W, P17L, and L237M, an increased risk was observed for individuals heterozygous for the L15-L16del polymorphism (OR = 3.6, 95% CI 1.2-11.2). The variant L15-L16del allele appeared to be associated with a stronger increase in adenoma risk among nonusers of aspirin/other NSAIDs. The reduced risk observed with aspirin/other NSAID use was limited to those wild type for P17L [PP users: OR = 0.6 (0.5-0.8) versus PP nonusers: 1.0 (referent) (P interaction = 0.03)]. To our knowledge, this study represents the first investigation of polymorphisms in PTGS1 and risk of colorectal polyps. The L15-L16del variant allele may result in an increased risk of colorectal adenomas, whereas P17L may be relevant to the pharmacogenetics of aspirin. These preliminary findings require confirmation in larger studies of colorectal neoplasia.

Adenomatous Polyps↗
PubMed2003

Multiple genome-wide analyses of smoking behavior in the Framingham Heart Study.

BACKGROUND: Cigarette smoking behavior may have a genetic basis. We assessed evidence for quantitative trait loci (QTLs) affecting the maximum number of cigarettes smoked per day, a trait meant to quantify this behavior, using data collected over 40 years as part of the Framingham Heart Study's original and offspring cohorts. RESULTS: Heritability was estimated to be approximately 21% using variance components (VC) methods (SOLAR), while oligogenic linkage and segregation analysis based on Bayesian Markov chain Monte Carlo (MCMC) methods (LOKI) estimated a mean of two large QTLs contributing approximately 28% and 20%, respectively, to the trait's variance. Genome-wide parametric (FASTLINK) and VC linkage analyses (SOLAR) revealed several LOD scores greater than 1.0, with peak LOD scores using both methods on chromosomes 2, 17, and 20; multi-point MCMC methods followed up on these chromosomes. The most robust linkage results were for a QTL between 65 and 84 cM on chromosome 20 with signals from multiple sex- and age-adjusted analyses including two-point LOD scores of 1.30 (parametric) and 1.07 (heritability = 0.17, VC) at 70.51 cM, a multi-point LOD score of 1.50 (heritability = 0.20, VC) at 84 cM, and an intensity ratio of 12.0 (MCMC) at 65 cM. CONCLUSION: Familial aggregation of the maximum number of cigarettes smoked per day was consistent with a genetic component to this behavior, and oligogenic segregation analyses using MCMC suggested two important QTLs. Linkage signals on chromosome 20 between 65 and 84 cM were seen using multiple analytical methods. No linkage result, however, met genome-wide statistical significance criteria, and the true relationship between these regions and smoking behavior remains unclear.

Adolescent↗
PubMed2003

Genomic scan of 254 hereditary prostate cancer families.

Hereditary prostate cancer (HPC) is a genetically heterogeneous disease, complicating efforts to map and clone susceptibility loci. We have used stratification of a large dataset of 254 HPC families in an effort to improve power to detect HPC loci and to understand what types of family features may improve locus identification. The strongest result is that of a dominant locus at 6p22.3 (heterogeneity LOD (HLOD) = 2.51), the evidence for which is increased by consideration of the age of PC onset (HLOD = 3.43 in 214 families with median age-of-onset 56-72 years) and co-occurrence of primary brain cancer (HLOD = 2.34 in 21 families) in the families. Additional regions for which we observe modest evidence for linkage include chromosome 7q and 17p. Only weak evidence of several previously implicated HPC regions is detected. These analyses support the existence of multiple HPC loci, whose presence may be best identified by analyses of large, including pooled, datasets which consider locus heterogeneity.

Aged↗
PubMed2003

Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset.

Previous studies have suggested strong evidence for a hereditary component to prostate cancer (PC) susceptibility. Here, we analyze 3,796 individuals in 263 PC families recruited as part of the ongoing Prostate Cancer Genetic Research Study (PROGRESS). We use Markov chain Monte Carlo (MCMC) oligogenic segregation analysis to estimate the number of quantitative trait loci (QTLs) and their contribution to the variance in age at onset of hereditary PC (HPC). We estimate 2 covariate effects: diagnosis of PC before and after prostate-specific antigen (PSA) test availability, and presence/absence of at least 1 blood relative with primary neuroepithelial brain cancer (BC). We find evidence that 2 to 3 QTLs contribute to the variance in age at onset of HPC. The 2 QTLs with the largest contribution to the total variance are both effectively dominant loci. We find that the covariate for diagnosis before and after PSA test availability is important. Our findings for the number of QTLs contributing to HPC and the variance contribution of these QTLs will be instructive in mapping and identifying these genes.

Adenocarcinoma↗
PubMed2003

Genetic analysis workshop 13: Summary of analyses of alcohol and cigarette use phenotypes in the Framingham Heart Study.

Data from the Framingham Heart Study were provided for Genetic Analysis Workshop 13. This paper summarizes six contributed papers that focused on the analysis of the longitudinal alcohol and/or cigarette use phenotypes available in these data, with the goal of detecting genes influencing these traits. For several of these contributions, the primary phenotype was maximum daily substance use reported over the longitudinal data. Others focused on a cross section by taking the daily use reported at a fixed time interval for all individuals, and others considered dichotomous phenotypes defined by thresholds of use. A variety of covariates were considered, including age (or year of birth) and sex. Most studies included unexposed individuals (those reporting no alcohol/cigarette use at all available assessments) in the linkage analyses, though one study compared results when defining the phenotype for unexposed individuals to be zero vs. defining the phenotype for unexposed individuals to be unknown. Linkage findings varied across studies. However, there was some concordance of evidence on chromosome 9 for alcohol traits, and of weaker evidence on chromosome 20 for cigarette traits. Analytical issues arose which may be crucial for genetic studies of substance use and dependence, including the choice of how to handle unexposed or substance-naive individuals, use of dichotomous vs. quantitative traits, and consideration of transformations and covariates.

Alcohol Drinking↗
PubMed2002

Effect of germ-line genetic variation on breast cancer survival in a population-based study.

Somatic genetic alterations in tumors are known to correlate with survival, but little is known about the prognostic significance of germ-line variation. We assessed the effect of germ-line variation on survival among women with breast cancer participating in a British population-based study. Up to 2430 cases for whom current vital status data were available were screened for BRCA1/2 mutations and genotyped for polymorphisms in 22 DNA repair, hormone metabolism, carcinogen metabolism, and other genes. The effect of genotype on outcome was assessed by Cox regression analysis. The largest effect was observed for the silent polymorphism D501D (t>c) in LIG4, a gene involved in DNA double-strand break repair. The estimated hazard ratio (HR) in cc homozygotes relative to tt homozygotes was 4.0 (95% confidence interval, 2.1-7.7; P = 0.002), and this effect remained after stratification by stage, grade, and tumor type [HR, 4.2 (1.8-9.4); P = 0.01]. Total length of a CYP19 IVS4 (ttta)(n) repeat was also associated with survival [HR, 0.9 (0.8-1.0); P = 0.01], but this became nonsignificant after stratification by stage, grade, and tumor type. Poorer survival was observed for 10 BRCA1 mutation carriers [HR, 4.1 (1.3-13); P = 0.047]; however, after adjustment for known prognostic factors, the HR estimate decreased to 2.0 and became nonsignificant (P = 0.4). CYP17 (P = 0.05) and TP53 (P = 0.06) polymorphisms showed marginally significant associations in unstratified analyses. No effect on survival was seen for polymorphisms in ATM, BRCA1/2, CHK2, KU70, NBS1, RAD51, RAD52, XRCC3, AR, COMT, NQO1, VDR, ADH3, CYP1A1, GSTP1, TGF-beta, or CDH1. Even if confirmed, the prognostic markers identified in this study are unlikely to replace current markers of prognosis such as estrogen receptor status. However, our results demonstrate the potential of the analysis of germ-line variation to provide insight into the biological determinants of response to treatment and prognosis in breast cancer.

Aged↗
PubMed2002

Polymorphisms in DNA repair genes and associations with cancer risk.

Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. To establish our overall understanding of possible in vivo relationships between DNA repair polymorphisms and the development of cancer, we performed a literature review of epidemiological studies that assessed associations between such polymorphisms and risk of cancer. Thirty studies of polymorphisms in OGG1, XRCC1, ERCC1, XPC, XPD, XPF, BRCA2, and XRCC3 were identified in the April 30, 2002 MEDLINE database (National Center for Biotechnology Information. PubMed Database: http://www.ncbi.nlm.nih.gov/entrez). These studies focused on adult glioma, bladder cancer, breast cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head and neck, and stomach cancer. We found that a small proportion of the published studies were large and population-based. Nonetheless, published data were consistent with associations between: (a) the OGG1 S326C variant and increased risk of various types of cancer; (b) the XRCC1 R194W variant and reduced risk of various types of cancer; and (c) the BRCA2 N372H variant and increased risk of breast cancer. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings. We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of cancer in the presence of reduced DNA repair capacity.

DNA Repair↗