Showing papers by "Nichola Johnson published in 2009"
University of Cambridge1, National Institutes of Health2, Princess Anne Hospital3, St Mary's Hospital4, Wellcome Trust Sanger Institute5, Science Applications International Corporation6, Fred Hutchinson Cancer Research Center7, Baylor College of Medicine8, University of Hawaii at Manoa9, University of Utah10, Marshfield Clinic11, American Cancer Society12, University of Copenhagen13, Hannover Medical School14, Russian Academy15, Seoul National University16, Leiden University17, Erasmus University Rotterdam18, Curie Institute19, Nofer Institute of Occupational Medicine20, University of Helsinki21, University of Melbourne22, QIMR Berghofer Medical Research Institute23, Netherlands Cancer Institute24, Carlos III Health Institute25, University of Cologne26, German Cancer Research Center27, Heidelberg University28, Technische Universität München29, Bosch30, University of Tübingen31, University of Ulm32, Karolinska Institutet33, University of Eastern Finland34, Mayo Clinic35, Cancer Council Victoria36, Harvard University37, Norwegian University of Science and Technology38, University of Minnesota39, Agency for Science, Technology and Research40, University of Sheffield41, China Medical University (Taiwan)42, Academia Sinica43, National Defense Medical Center44, University of California, Irvine45, University of Toronto46, Cancer Research UK47
TL;DR: Strong evidence is found for additional susceptibility loci on 3p and 17q and potential causative genes include SLC4A7 and NEK10 on3p and COX11 on 17q.
Abstract: Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
480 citations
TL;DR: The potential for gene-body epigenetic misregulation of ATM and other cancer-related genes in peripheral blood DNA that may be useful as a novel marker to estimate breast cancer risk is demonstrated.
Abstract: Bilaterality of breast cancer is an indicator of constitutional cancer susceptibility; however, the molecular causes underlying this predisposition in the majority of cases is not known. We hypothesize that epigenetic misregulation of cancer-related genes could partially account for this predisposition. We have performed methylation microarray analysis of peripheral blood DNA from 14 women with bilateral breast cancer compared with 14 unaffected matched controls throughout 17 candidate breast cancer susceptibility genes including BRCA1, BRCA2, CHEK2, ATM, ESR1, SFN, CDKN2A, TP53, GSTP1, CDH1, CDH13, HIC1, PGR, SFRP1, MLH1, RARB and HSD17B4. We show that the majority of methylation variability is associated with intragenic repetitive elements. Detailed validation of the tiled region around ATM was performed by bisulphite modification and pyrosequencing of the same samples and in a second set of peripheral blood DNA from 190 bilateral breast cancer patients compared with 190 controls. We show significant hypermethylation of one intragenic repetitive element in breast cancer cases compared with controls (P = 0.0017), with the highest quartile of methylation associated with a 3-fold increased risk of breast cancer (OR 3.20, 95% CI 1.78-5.86, P = 0.000083). Increased methylation of this locus is associated with lower steady-state ATM mRNA level and correlates with age of cancer patients but not controls, suggesting a combined age-phenotype-related association. This research demonstrates the potential for gene-body epigenetic misregulation of ATM and other cancer-related genes in peripheral blood DNA that may be useful as a novel marker to estimate breast cancer risk. ACCESSION NUMBERS: The microarray data and associated .BED and .WIG files can be accessed through Gene Expression Omnibus accession number: GSE14603.
129 citations
Carlos III Health Institute1, University of Helsinki2, Autonomous University of Madrid3, Heidelberg University4, German Cancer Research Center5, Technische Universität München6, University of Cologne7, University of Sheffield8, University of Melbourne9, Mayo Clinic10, Hannover Medical School11, Leiden University12, Erasmus University Rotterdam13, Karolinska Institutet14, Agency for Science, Technology and Research15, University of Cambridge16, University of California, Irvine17, Bosch18, University of Tübingen19, University of Bonn20, University of Erlangen-Nuremberg21, University of California, Los Angeles22, Cancer Council Victoria23, University of London24, University of Copenhagen25, Seoul National University26, University of Eastern Finland27, National Institutes of Health28, Curie Institute29, University of Ulm30, Academia Sinica31, National Defense Medical Center32, Russian Academy33
TL;DR: There is strong evidence of association between rs13387042 and breast cancer in white women of European origin and an association was observed for both ER-positive and ER-negative breast cancers in European women.
Abstract: Background: A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium. Methods: 2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided. Results: We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 x 10–19). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10–15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)–positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10–14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002). Conclusion: The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women. Roger L. Milne, Javier Benitez, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomaki, Carl Blomqvist, Jose Ignacio Arias, M. Pilar Zamora, Barbara Burwinkel, Claus R. Bartram, Alfons Meindl, Rita K. Schmutzler, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W. R. Reed, Melissa C. Southey, Letitia Smith, Amanda B. Spurdle, John L. Hopper, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Zachary Fredericksen, Peter Schurmann, Michael Bremer, Peter Hillemanns, Thilo Dork, Peter Devilee, Christie J. van Asperen, Rob A. E. M. Tollenaar, Caroline Seynaeve, Per Hall, Kamila Czene, Jianjun Liu, Yuqing Li, Shahana Ahmed, Alison M. Dunning, Melanie Maranian, Paul D. P. Pharoah, Georgia Chenevix-Trench, Jonathan Beesley, kConFab Investigators,, AOCS Group, Natalia V. Bogdanova, Natalia N. Antonenkova, Iosif V. Zalutsky, Hoda Anton-Culver, Argyrios Ziogas, Hiltrud Brauch, Christina Justenhoven, Yon-Dschun Ko, Susanne Haas, Peter A. Fasching, Reiner Strick, Arif B. Ekici, Matthias W. Beckmann, Graham G. Giles, Gianluca Severi, Laura Baglietto, Dallas R. English, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Clare Turnbull, Sarah Hines, Anthony Renwick, Nazneen Rahman, Borge G. Nordestgaard, Stig E. Bojesen, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Montserrat Garcia-Closas, Stephen Chanock, Jolanta Lissowska, Louise A. Brinton, Jenny Chang-Claude, Shan Wang-Gohrke, Chen-Yang Shen, Hui-Chun Wang, Jyh-Cherng Yu, Sou-Tong Chen, Marina Bermisheva, Tatjana Nikolaeva, Elza Khusnutdinova, Manjeet K. Humphreys, Jonathan Morrison, Radka Platte, Douglas F. Easton, on behalf of the Breast Cancer Association Consortium
115 citations
University of Cambridge1, University of Southern California2, University of Hawaii at Manoa3, Netherlands Cancer Institute4, University of Melbourne5, University of Erlangen-Nuremberg6, University of California, Los Angeles7, University of London8, University of Copenhagen9, Carlos III Health Institute10, German Cancer Research Center11, University of Cologne12, Hannover Medical School13, University of Helsinki14, Karolinska Institutet15, University of Eastern Finland16, Royal Brisbane and Women's Hospital17, University of Hamburg18, Mayo Clinic19, Cancer Council Victoria20, University of Oslo21, Oslo University Hospital22, Harvard University23, Leiden University24, Curie Institute25, National Institutes of Health26, Genome Institute of Singapore27, Seoul National University28, Academia Sinica29, National Defense Medical Center30, Tri-Service General Hospital31, University of California, Irvine32, Peter MacCallum Cancer Centre33
TL;DR: SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations and appears largely confined to oestrogen receptor-positive tumour risk.
Abstract: We have conducted a three-stage, comprehensive single nucleotide polymorphism (SNP)-tagging association study of ESR1 gene variants (SNPs) in more than 55,000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an odds ratio (OR) of 1.05 [95% Confidence Intervals (CI) 1.02-1.09] relative to t-allele homozygotes, P = 0.004. There is significant heterogeneity between studies, P = 0.002. The increased risk appears largely confined to oestrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, and it may subtly alter the ratio of two mRNA splice forms.
95 citations
TL;DR: The study shows a positive association between estrogen levels and density and suggests that the mean level throughout the cycle is the most biologically relevant measure, which supports the hypothesis that endogenous hormones affect density in premenopausal women.
Abstract: Mammographic density is strongly associated with breast cancer risk, and endogenous hormones, which are risk factors for breast cancer, may be involved in the mechanism. This cross-sectional study of 494 premenopausal women is the first to account for cyclic variations in estrogen levels, by measuring urinary estrone glucuronide (E1G) in the periovulatory and luteal phases of the menstrual cycle, and to assess the role of androgens. Computer-assisted density readings were obtained from digitized mammograms. Mean ovulatory E1G level and daily E1G load were both positively associated with percent density before adjustment for body mass index (BMI), with women in the top fourth having 10.2% (95% CI: 2.9%, 18.1%) and 8.9% (1.7%, 16.7%), respectively, higher density than those in the bottom fourth (Ptrend before/after BMI adjustment=0.006/0.11 and 0.01/0.13, respectively). Neither the peak nor luteal E1G levels were predictive of density after adjustment for E1G levels at other points in the cycle. The plasma androgens testosterone, androstenedione, and dehydroepiandrosterone sulfate were negatively associated with density. In mutually adjusted analyses, density was positively associated with insulin-like growth factor (IGF)-I and negatively with IGF-II (Ptrend=0.006 for both) but not with IGF binding protein-3. There was also weak evidence of a positive association of prolactin with density. The study supports the hypothesis that endogenous hormones affect density in premenopausal women; in particular, it shows a positive association between estrogen levels and density and suggests that the mean level throughout the cycle is the most biologically relevant measure. Most of these hormone-density associations were attenuated with further adjustment for BMI.
68 citations
TL;DR: The results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2*1100delC carrier status, and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk.
Abstract: If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2 1100delC should be approximately 5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be approximately 9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2 1100delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (P(trend) = 0.0003) and Finland (P(trend) = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2 1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2 1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2 1100delC and other moderate penetrance alleles in women with a family history of breast cancer.
48 citations
01 Jan 2009
TL;DR: Five variants within SMAD7 and GREM1 and two variants in CRAC1 are signaling components on the transforming growth factor-β pathway, which regulates normal mammary gland development and has been implicated in breast tumor invasion and metastasis, which suggest that the effects of these alleles are cancer site–specific.
Abstract: SMAD7 and GREM1 are signaling components on the transforming growth factor-β pathway, which regulates normal mammary gland development and has been implicated in breast tumor invasion and metastasis. Three variants within SMAD7 and two variants in CRAC1 (a colorectal cancer–associated region on chromosome 15 in which GREM1 is located) have been associated with colorectal cancer risks [odds ratios (OR), 0.85-1.26; all P 1.08. One or more of these variants may be associated with a very small OR for breast cancer, but our data suggest that the effects of these alleles are cancer site–specific. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1934–6)
5 citations
TL;DR: In this paper, three variants within SMAD7 and two variants in CRAC1 have been associated with colorectal cancer risks [odds ratios (OR), 0.85-1.26; all P 1.08.
Abstract: SMAD7 and GREM1 are signaling components on the transforming growth factor-β pathway, which regulates normal mammary gland development and has been implicated in breast tumor invasion and metastasis. Three variants within SMAD7 and two variants in CRAC1 (a colorectal cancer–associated region on chromosome 15 in which GREM1 is located) have been associated with colorectal cancer risks [odds ratios (OR), 0.85-1.26; all P 1.08. One or more of these variants may be associated with a very small OR for breast cancer, but our data suggest that the effects of these alleles are cancer site–specific. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1934–6)
4 citations
TL;DR: The variant genotype of SNP rs2046210 is associated with increased ERα expression, and while the increase contributed by the variant allele is relatively modest, this may partly explain why the SNP isassociated with increased breast cancer risk.
Abstract: Aim: To identify whether breast cancer-associated SNP rs2046210 is associated with ERα level in invasive breast tumours.BackgroundA recent genome-wide association study identified SNP rs2046210 at 6q25.1 as having a strong association with breast cancer risk1. The SNP is located 29kb upstream of the first untranslated exon of ESR1 and 180kb upstream of the transcription start site2. Rs2046210 is not in linkage disequilibrium (LD) with two of the most widely studied polymorphisms in ESR1. We test here the hypothesis that rs2046210 may be associated with altered ESR1 expression.MethodsPatients with both leukocyte DNA and invasive breast tumour paraffin blocks available were identified from two of our ongoing tissue collections: Femara Anastrazole Clinical Evaluation (FACE) and the British Breast Cancer (BBC) study. Germline DNA was extracted from bloods using the QIAamp DNA Blood Mini Kit. PCR was performed with primers spanning the SNP site, with a single basepair mismatch in the reverse sequence to generate an HhaI restriction site in the presence of the C allele. PCR product was run on a 3% agarose gel to confirm presence of a single 120bp band. Restriction digest with HhaI was then performed and products run on a 4% Metaphor agarose gel. Genotype was assigned as follows: 97bp band only = wild-type (C/C); 97bp and 120bp band = heterozygote (C/T); 120bp band only = variant (T/T). From corresponding invasive breast tumour, ERα was assessed on 4μm whole sections using clone 6F11 (Vector Labs) and quantified by H-score. Mean H-scores (left and right invasive breast tumours) were used for the BBC group. ERα- samples (H-score≤1.0) were excluded. Analysis was by ANOVA using non-parametric bias-corrected and accelerated 95% bootstrap confidence intervals (2000 replications), with genotype fitted as a score and study as a stratifying co-variate.ResultsMinor allele frequency was 33%, which is similar to the 38% previously reported in patients of European ancestry1. Within FACE, increased ERα was seen with presence of variant SNP. In the BBC group, variant SNP patients had higher ERα than both wild-type and heterozygote. Overall, there was a significant difference in ERα score per genotype group of 7.05, (95% CI 0.7-13.5, p=0.035). This was circa 4% difference in H-score per variant allele.ConclusionThe variant genotype of SNP rs2046210 is associated with increased ERα expression. While the increase contributed by the variant allele is relatively modest, this may partly explain why the SNP is associated with increased breast cancer risk. Similar studies should be conducted in normal breast tissue.1Zheng et al. (2009) Nat. Gen. 41(3): 324-3282Kos et al. (2001) Mol. Endocrinol. 15: 2057-2063 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4138.
2 citations
Journal Article•
1 citations