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Montserrat Garcia-Closas,
Fergus J Couch,
Sara Lindstrom,
Kyriaki Michailidou,
Marjanka K Schmidt,
Mark N Brook,
Nick Orr,
Suhn Kyong Rhie,
Elio Riboli,
Heather S Feigelson, [......],
Alison M Dunning,
Mark E Sherman,
Georgia Chenevix-Trench,
Stephen J Chanock,
Per Hall,
Paul D P Pharoah,
Celine Vachon,
Douglas F Easton,
Christopher A Haiman,
Peter Kraft
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ABSTRACT: Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
Nature Genetics 03/2013; 45(4):392-398. · 35.53 Impact Factor
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Kyriaki Michailidou,
Per Hall,
Anna Gonzalez-Neira,
Maya Ghoussaini,
Joe Dennis,
Roger L Milne,
Marjanka K Schmidt,
Jenny Chang-Claude,
Stig E Bojesen,
Manjeet K Bolla, [......],
Sandra Deming-Halverson,
Martha Shrubsole,
Jirong Long,
Jacques Simard,
Montse Garcia-Closas,
Paul D P Pharoah,
Georgia Chenevix-Trench,
Alison M Dunning,
Javier Benitez,
Douglas F Easton
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ABSTRACT: Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
Nature Genetics 03/2013; 45(4):353-361. · 35.53 Impact Factor
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Stig E Bojesen,
Karen A Pooley,
Sharon E Johnatty,
Jonathan Beesley,
Kyriaki Michailidou,
Jonathan P Tyrer,
Stacey L Edwards,
Hilda A Pickett,
Howard C Shen,
Chanel E Smart, [......],
Simon A Gayther,
Paul D P Pharoah,
Roger R Reddel,
Ellen L Goode,
Mark H Greene,
Douglas F Easton,
Andrew Berchuck,
Antonis C Antoniou,
Georgia Chenevix-Trench,
Alison M Dunning
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ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Nature Genetics 03/2013; 45(4):371-384. · 35.53 Impact Factor
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Juliet D French,
Maya Ghoussaini,
Stacey L Edwards,
Kerstin B Meyer,
Kyriaki Michailidou,
Shahana Ahmed,
Sofia Khan,
Mel J Maranian,
Martin O'Reilly,
Kristine M Hillman, [......],
Anthony Swerdlow,
Alan Ashworth,
Nick Orr,
Minouk J Schoemaker,
Bruce A J Ponder,
Heli Nevanlinna,
Melissa A Brown,
Georgia Chenevix-Trench,
Douglas F Easton,
Alison M Dunning
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ABSTRACT: Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
The American Journal of Human Genetics 03/2013; · 10.60 Impact Factor
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ABSTRACT: BACKGROUND: To investigate markers for predicting breast cancer progression, we performed a candidate gene-based study that assessed expression change of three genes, cyclin D1, β-catenin, and metastasis-associated protein-1 (MTA1), involving in aggressive phenotypes of cancerous cells, namely hyperproliferation, epithelial-mesenchymal transition, and global transcriptional regulation. METHODS: Specimens were from 150 enrolled female patients, with invasive ductal carcinoma, followed up for more than 10 years. mRNA expression of cyclin D1, β-catenin, and MTA1 in cancerous and noncancerous cells microdissected from the primary tumor site was determined by quantitative real-time PCR. The relationship between mRNA expression levels of the genes and clinicopathologic features was assessed by statistical analysis. Disease-free and overall survival (DFS and OS) were analyzed by Kaplan-Meier analysis with log-rank test and a multivariate Cox regression model. RESULTS: Cyclin D1 was shown to be overexpressed in late-stage breast cancer (stage III/IV). Breast cancer with lymph node metastasis (LNM) showed significantly higher frequency of overexpressed cyclin D1, β-catenin, and MTA1 (P < 0.05). Patients carrying greater numbers of overexpressed genes had joint effects on increased risk in tumors of advanced stages (P ( trend ) = 0.03) and LNM (P ( trend ) < 0.01). In the LNM-negative group, patients whose tumors with greater number of cyclin D1, β-catenin, and MTA1 overexpressions were associated with poorer clinical outcomes, with hazard ratio of 14.79 for OS (P = 0.015) and 7.54 for DFS (P = 0.015) using multivariate Cox regression analysis during the 10-year follow-up. CONCLUSIONS: Higher expression of cyclin D1, β-catenin, and MTA1 mRNAs in breast cancers may prove effective in predicting unfavorable outcomes of breast cancer.
Annals of Surgical Oncology 08/2012; · 4.17 Impact Factor
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Tomas Kirchhoff,
Mia M Gaudet,
Antonis C Antoniou,
Lesley Mcguffog,
Manjeet K Humphreys,
Alison M Dunning,
Stig E Bojesen,
Børge G Nordestgaard,
Henrik Flyger,
Daehee Kang, [......],
Jackie Cook,
Fiona Douglas,
Shirley Hodgson,
D Gareth Evans,
Rosalind Eeles,
Bert Gold,
Paul D P Pharoah,
Kenneth Offit,
Georgia Chenevix-Trench,
Douglas F Easton
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ABSTRACT: AM), 9 Gene Environment Interaction and Breast Cancer in Germany (GENICA): Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University Tü bingen, Stuttgart and Tü bingen, Germany (HB, Christina Justenhoven); Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum, Heidelberg, Germany (UH); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (YDK,); Institute of Pathology, Medical Faculty of the University of Bonn, Bonn, Germany (Hans-Peter Fischer); Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Bochum, Germany (Thomas Brü ning, Beate Pesch, Volker Harth, Sylvia Rabstein), 10 Amsterdam Breast Cancer Study (ABCS): Netherlands Cancer Institute, Departments of Experimental Therapy, Epidemiology and Molecular Pathology, Amsterdam, The Netherlands (AB, MKS, LJVV, LMB), 11 British Breast Cancer Study (BBCS):
PLoS ONE 06/2012; 6(7). · 4.09 Impact Factor
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Kristen N Stevens,
Zachary Fredericksen,
Celine M Vachon,
Xianshu Wang,
Sara Margolin,
Annika Lindblom,
Heli Nevanlinna,
Dario Greco,
Kristiina Aittomäki,
Carl Blomqvist, [......],
Marie-Rose Christiaens,
Georgia Chenevix-Trench,
Jonathan Beesley,
Xiaoqing Chen,
Arto Mannermaa,
Veli-Matti Kosma,
Jaana M Hartikainen,
Ylermi Soini,
Douglas F Easton,
Fergus J Couch
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ABSTRACT: The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.
Cancer Research 02/2012; 72(7):1795-803. · 7.86 Impact Factor
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Maya Ghoussaini,
Olivia Fletcher,
Kyriaki Michailidou,
Clare Turnbull,
Marjanka K Schmidt,
Ed Dicks,
Joe Dennis,
Qin Wang,
Manjeet K Humphreys,
Craig Luccarini, [......],
Susan M Gerty,
Nikki J Graham,
Bruce A J Ponder,
Georgia Chenevix-Trench,
Paul D P Pharoah,
Mark Lathrop,
Alison M Dunning,
Nazneen Rahman,
Julian Peto,
Douglas F Easton
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ABSTRACT: Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
Nature Genetics 01/2012; 44(3):312-8. · 35.53 Impact Factor
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Tomas Kirchhoff,
Mia M Gaudet,
Antonis C Antoniou,
Lesley McGuffog,
Manjeet K Humphreys,
Alison M Dunning,
Stig E Bojesen,
Børge G Nordestgaard,
Henrik Flyger,
Daehee Kang, [......],
Jackie Cook,
Fiona Douglas,
Shirley Hodgson,
D Gareth Evans,
Rosalind Eeles,
Bert Gold,
Paul D P Pharoah,
Kenneth Offit,
Georgia Chenevix-Trench,
Douglas F Easton
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ABSTRACT: Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
PLoS ONE 01/2012; 7(6):e35706. · 4.09 Impact Factor
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Annegien Broeks,
Marjanka K Schmidt,
Mark E Sherman,
Fergus J Couch,
John L Hopper,
Gillian S Dite,
Carmel Apicella,
Letitia D Smith,
Fleur Hammet,
Melissa C Southey, [......], Chia-Ni Hsiung,
Jyh-Cherng Yu,
Shou-Tung Chen,
Giu-Cheng Hsu,
Ming-Feng Hou,
Chiun-Sheng Huang,
Hoda Anton-Culver,
Argyrios Ziogas,
Paul D P Pharoah,
Montserrat Garcia-Closas
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ABSTRACT: Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10(-18)), rs3803662 (16q12) (P = 3.7 × 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10(-6) and P = 4.1 × 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.
Human Molecular Genetics 06/2011; 20(16):3289-303. · 7.64 Impact Factor
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Xiaohong R Yang,
Jenny Chang-Claude,
Ellen L Goode,
Fergus J Couch,
Heli Nevanlinna,
Roger L Milne,
Mia Gaudet,
Marjanka K Schmidt,
Annegien Broeks,
Angela Cox, [......],
John L Hopper,
Fleur Hammet,
Helen Tsimiklis,
Letitia D Smith,
Melissa C Southey,
Manjeet K Humphreys,
Douglas Easton,
Paul Pharoah,
Mark E Sherman,
Montserrat Garcia-Closas
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ABSTRACT: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.
In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.
This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
CancerSpectrum Knowledge Environment 02/2011; 103(3):250-63. · 14.07 Impact Factor
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Jyh-Cherng Yu, Chia-Ni Hsiung,
Huan-Ming Hsu,
Bo-Ying Bao,
Shou-Tung Chen,
Giu-Cheng Hsu,
Wen-Cheng Chou,
Ling-Yueh Hu,
Shian-Ling Ding,
Chun-Wen Cheng,
Pei-Ei Wu,
Chen-Yang Shen
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ABSTRACT: Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the promoter region of estrogen-responsive genes, regulates their transcription, and consequently mediates physiological or tumorigenic effects. Thus, sequence variants in EREs have the potential to affect the estrogen-ER-ERE interaction. In this study, we examined the hypothesis that genetic variations of EREs are associated with breast cancer development.
This case-control study involved 815 patients of Asian descent with incident breast cancer and 821 healthy female controls. A total of 13,737 ERE sites in the whole genome predicted by a genome-wide computational algorithm were blasted with single-nucleotide polymorphism (SNP) sequences. Twenty-one SNPs located within 2,000 bp upstream or within introns 1 and 2 of putative genes and with a minor allele frequency greater than 5% were identified and genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility.
A significant combined effect of rs12539530, an ERE SNP in intron 2 of NRCAM which codes for a cell adhesion molecule, and SNPs of ESR1, the gene coding for ER, on breast cancer risk was found. Interestingly, this combined effect was more significant in women who had experienced a longer period of lifetime estrogen exposure, supporting a hormonal etiology of this SNP in breast tumorigenesis.
Our findings provide support for a role of genetic variation in ERE-ESR1 in determining susceptibility of breast cancer development.
Breast cancer research: BCR 01/2011; 13(1):R13. · 5.24 Impact Factor
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ABSTRACT: Endogenous estrogen is suggested to initiate cell proliferation and cause oxidative DNA damage during breast tumorigenesis. Cells eliminate DNA damage by means of repair enzymes. Genotypic variants of DNA damage repair genes, participating in base excision repair (BER) and nucleotide excision repair (NER) pathways, may act as modifiers that affect the association between estrogen exposure and breast cancer.
In a hospital-based case-control study of female breast cancer, DNA samples were obtained from 401 cases and 533 enrolled healthy controls, all of whom were Chinese women in Taiwan. Genotyping of polymorphisms of XRCC1 (Arg194Trp and Arg399Gln), OGG1 (Ser326Cys and Arg229Gln), ERCC2 Lys751Gln, ERCC4 Ser662Pro, and ERCC5 His1104Asp was performed and used to evaluate breast cancer susceptibility.
Of the nonsynonymous polymorphisms, the ERCC5 1104Asp variant was significantly associated with breast cancer (odds ratio = 1.42; 95% confidence interval = 1.08-1.97), and this association was more pronounced in women with lengthy estrogen exposure. A trend toward an increased risk of developing breast cancer was observed in women who carried greater numbers of combined high-risk genotypes of BER and NER genes (P(trend) = .038). The synergistic effect of multiple genes on the increase of risk was significant in women with a longer period of estrogen exposure (>26 years), greater age at first full-term pregnancy (>26 years), a longer menarche-to-first full-term pregnancy interval (>11 years), and higher body mass index (>22) (all P<.05).
This study demonstrates that genotype polymorphisms related to DNA damage repair confer greater susceptibility to endogenous estrogen in the development of breast cancer in women.
Annals of Surgical Oncology 03/2010; 17(3):760-71. · 4.17 Impact Factor
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Miriam S Udler,
Shahana Ahmed,
Catherine S Healey,
Kerstin Meyer,
Jeffrey Struewing,
Melanie Maranian,
Erika M Kwon,
Jinghui Zhang,
Jonathan Tyrer,
Eric Karlins, [......],
Keun-Young Yoo,
Dong-Young Noh,
Sei-Hyun Ahn,
Kathleen E Malone,
Christopher A Haiman,
Paul D Pharoah,
Bruce A J Ponder,
Elaine A Ostrander,
Douglas F Easton,
Alison M Dunning
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ABSTRACT: Recent genome-wide association studies have identified a breast cancer susceptibility locus on 16q12 with an unknown biological basis. We used a set of single nucleotide polymorphism (SNP) markers to generate a fine-scale map and narrowed the region of association to a 133 kb DNA segment containing the largely uncharacterized hypothetical gene LOC643714, a short intergenic region and the 5' end of TOX3. Re-sequencing this segment in European subjects identified 293 common polymorphisms, including a set of 26 highly correlated candidate causal variants. By evaluation of these SNPs in five breast cancer case-control studies involving more than 23 000 subjects from populations of European and Southeast Asian ancestry, all but 14 variants could be excluded at odds of <1:100. Most of the remaining variants lie in the intergenic region, which exhibits evolutionary conservation and open chromatin conformation, consistent with a regulatory function. African-American case-control studies exhibit a different pattern of association suggestive of an additional causative variant.
Human Molecular Genetics 03/2010; 19(12):2507-15. · 7.64 Impact Factor
