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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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ABSTRACT: AIMS: Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins which interact with vascular endothelial growth factor (VEGF) to prevent tumour cell apoptosis and regulate angiogenesis. However, the precise role of NRP1 and NRP2 in the adenoma-carcinoma sequence (ACS) of colorectal cancer remains unclear, and we aimed to determine this in surgical specimens comprising the ACS. METHODS AND RESULTS: Histological analysis demonstrated that epithelial NRP1 expression increased significantly across the ACS (P = 0.0007), and correlated with microvessel density (MVD; r = 0.505, P = 0.0003) and weakly with VEGF (r = 0.251, P = 0.001). In contrast, although NRP2 epithelial expression was increased significantly in all carcinomas (P < 0.002), there was no correlation with MVD, VEGF or NRP1. Furthermore, patients showing coexpression of NRP1 and NRP2 had a potentially worse prognosis than those expressing a single neuropilin or neither one. Although vascular expression of NRP1 increased significantly across the ACS (P = 0.0004) and correlated with MVD (r = 0.361, P = 0.0006), NRP2 vascular expression decreased significantly (P = 0.0001) and showed an inverse correlation with MVD (r=-0.506, P = 0.0001), suggesting differential roles for neuropilins in the angiogenic process during colorectal cancer development. CONCLUSIONS: These data suggest that an increase in NRP1 and NRP2 epithelial/tumour expression, as well as in NRP1 vascular expression, may be associated with disease progression in colorectal cancer.
Histopathology 01/2013; · 3.08 Impact Factor
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Maren Weischer,
Børge G Nordestgaard,
Paul Pharoah,
Manjeet K Bolla,
Heli Nevanlinna,
Laura J Van't Veer,
Montserrat Garcia-Closas,
John L Hopper,
Per Hall,
Irene L Andrulis, [......],
Simon S Cross,
Laura Baglietto,
Christof Sohn,
Xianshu Wang,
Vesa Kataja,
Anne-Lise Børresen-Dale,
Andreas Meyer,
Douglas F Easton,
Marjanka K Schmidt,
Stig E Bojesen
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ABSTRACT: PURPOSEWe tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. PATIENTS AND METHODS
From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.ResultsCHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only. CONCLUSION
Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.
Journal of Clinical Oncology 10/2012; · 18.37 Impact Factor
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Helen Warren,
Frank Dudbridge,
Olivia Fletcher,
Nick Orr,
Nichola Johnson,
John L Hopper,
Carmel Apicella,
Melissa C Southey,
Maryam Mahmoodi,
Marjanka K Schmidt, [......],
Maya Ghoussaini,
Alan Ashworth,
Anthony Swerdlow,
Michael Jones,
Minouk Schoemaker,
Douglas F Easton,
Manjeet Humphreys,
Qin Wang,
Julian Peto,
Isabel Dos-Santos-Silva
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ABSTRACT: BACKGROUND: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). METHODS: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). RESULTS: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors. CONCLUSIONS: This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783-. ©2012 AACR.
Cancer Epidemiology Biomarkers & Prevention 08/2012; 21(10):1783-1791. · 4.12 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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Peter A Fasching,
Paul D P Pharoah,
Angela Cox,
Heli Nevanlinna,
Stig E Bojesen,
Thomas Karn,
Annegien Broeks,
Flora E van Leeuwen,
Laura J van't Veer,
Renate Udo, [......],
Sara J Schonfeld,
Hoda Anton-Culver,
Peter Devilee,
Matthias W Beckmann,
Dennis J Slamon,
Kelly-Anne Phillips,
Jonine D Figueroa,
Manjeet K Humphreys,
Douglas F Easton,
Marjanka K Schmidt
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ABSTRACT: Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.
Human Molecular Genetics 04/2012; 21(17):3926-39. · 7.64 Impact Factor
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ABSTRACT: This study evaluated four fluorescent-protein conjugates to monitor microcirculatory variables using the murine cremaster muscle and determined acute and long-term responses to repeated administration of FITC-BSA [conjugated at the University of Sheffield (UoS)] within a dorsal microcirculatory chamber (DMC) in rats. For analysis of the cremaster muscle, male C3H/HeN mice were anaesthetized, the cremaster muscle was exteriorized, then TRITC-BSA, TRITC-dextran, FITC-BSA, FITC-BSA (UoS) or FITC-dextran (0.25 ml/100 g) were administered systemically. The microcirculation was viewed with epi-illumination every 10 min for 120 min. For analysis of the DMC, male Wistar rats were implanted with the chamber. Three weeks later, FITC-BSA (UoS) was administered systemically, and the microcirculation response was monitored using three different protocols. In addition, in vitro stability of fluorescent conjugates was measured over 8 h. With regard to the cremaster muscle, initially no differences in interstitial fluorescence or vessel diameter were observed between the four fluorescent conjugates. By the end of the study, interstitial fluorescence from TRITC-dextran, FITC-dextran and FITC-BSA (Sigma) was significantly (p < 0.05) increased compared to FITC-BSA (UoS). With regard to the DMC, there was no interstitial fluorescence leakage after 180 min or 5 weeks despite repeated administration, but a significant (p < 0.05) leak was detected between 4 and 24 h. FITC-BSA (UoS) was the most stable fluorescent conjugate both in vitro and in vivo and was comparable with other conjugates for evaluating skeletal muscle microcirculation using fluorescent in vivo microscopy.
Journal of Vascular Research 01/2012; 49(2):132-43. · 2.65 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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Rebecca Hein,
Melanie Maranian,
John L Hopper,
Miroslaw K Kapuscinski,
Melissa C Southey,
Daniel J Park,
Marjanka K Schmidt,
Annegien Broeks,
Frans B L Hogervorst,
H Bas Bueno-de-Mesquit, [......],
Polly A Newcomb,
Linda Titus,
Kathleen M Egan,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Manjeet K Humphreys,
Jonathan Morrison,
Jenny Chang-Claude,
Douglas F Easton,
Alison M Dunning
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ABSTRACT: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
PLoS ONE 01/2012; 7(8):e42380. · 4.09 Impact Factor
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Rebecca Hein,
Melanie Maranian,
John L Hopper,
Miroslaw K Kapuscinski,
Melissa C Southey,
Daniel J Park,
Marjanka K Schmidt,
Annegien Broeks,
Frans B L Hogervorst,
H Bas Bueno-de-Mesquit, [......],
Polly A Newcomb,
Linda Titus,
Kathleen M Egan,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Manjeet K Humphreys,
Jonathan Morrison,
Jenny Chang-Claude,
Douglas F Easton,
Alison M Dunning
PLoS ONE 01/2012; 7(10). · 4.09 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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Nicola J Camp,
Marina Parry,
Stacey Knight,
Ryan Abo,
Graeme Elliott,
Sushilaben H Rigas,
Sabapathy P Balasubramanian, Malcolm W R Reed,
Helen McBurney,
Ayse Latif,
William G Newman,
Lisa A Cannon-Albright,
D Gareth Evans,
Angela Cox
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ABSTRACT: Multiple genome-wide and candidate gene association studies have been conducted in search of common risk variants for breast cancer. Recent large meta analyses, consolidating evidence from these studies, have been consistent in highlighting the caspase-8 (CASP8) gene as important in this regard. To define a risk haplotype and map the CASP8 gene region with respect to underlying susceptibility variant/s, we screened four genes in the CASP8 region on 2q33-q34 for breast cancer risk.
Two independent data sets from the United Kingdom and the United States, including 3,888 breast cancer cases and controls, were genotyped for 45 tagging single nucleotide polymorphisms (tSNP) in the expanded CASP8 region. SNP and haplotype association tests were carried out using Monte Carlo-based methods.
We identified a three-SNP haplotype across rs3834129, rs6723097, and rs3817578 that was significantly associated with breast cancer (P < 5 × 10(-6)), with a dominant risk ratio and 95% CI of 1.28 (1.21-1.35) and frequency of 0.29 in controls. Evidence for this risk haplotype was extremely consistent across the two study sites and also consistent with previous data.
This three-SNP risk haplotype represents the best characterization so far of the chromosome upon which the susceptibility variant resides.
Characterization of the risk haplotype provides a strong foundation for resequencing efforts to identify the underlying risk variant, which may prove useful for individual-level risk prediction, and provide novel insights into breast carcinogenesis.
Cancer Epidemiology Biomarkers & Prevention 11/2011; 21(1):176-81. · 4.12 Impact Factor
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Roger L Milne,
Justo Lorenzo-Bermejo,
Barbara Burwinkel,
Núria Malats,
Jose Ignacio Arias,
M Pilar Zamora,
Javier Benítez,
Manjeet K Humphreys,
Montserrat García-Closas,
Stephen J Chanock, [......],
Carmel Apicella,
John L Hopper,
Alison M Dunning,
Karen A Pooley,
Paul D P Pharoah,
Ute Hamann,
Beate Pesch,
Yon-Dschun Ko,
Douglas F Easton,
Georgia Chenevix-Trench
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ABSTRACT: Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case-control studies.
The authors genotyped 14,843 invasive case patients and 19,852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression.
For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p = 0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33,376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p = 0.001). The OR was greater at younger ages (p trend = 0.01).
This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.
Journal of Medical Genetics 10/2011; 48(10):698-702. · 6.36 Impact Factor
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Jonine D Figueroa,
Montserrat Garcia-Closas,
Manjeet Humphreys,
Radka Platte,
John L Hopper,
Melissa C Southey,
Carmel Apicella,
Fleur Hammet,
Marjanka K Schmidt,
Annegien Broeks, [......],
Alan Ashworth,
Anthony Swerdlow,
Michael Jones,
Nick Orr,
Amy Trentham-Dietz,
Kathleen Egan,
Polly Newcomb,
Linda Titus-Ernstoff,
Doug Easton,
Amanda B Spurdle
[show abstract]
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ABSTRACT: A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.
Human Molecular Genetics 08/2011; 20(23):4693-706. · 7.64 Impact Factor
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Wei-Yu Lin,
Nicola J Camp,
Lisa A Cannon-Albright,
Kristina Allen-Brady,
Sabapathy Balasubramanian, Malcolm W R Reed,
John L Hopper,
Carmel Apicella,
Graham G Giles,
Melissa C Southey, [......],
Jolanta Lissowska,
Douglas F Easton,
Alison M Dunning,
Preetha Rajaraman,
Alice J Sigurdson,
Michele M Doody,
Martha S Linet,
Paul D Pharoah,
Marjanka K Schmidt,
Angela Cox
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ABSTRACT: The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer.
The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% CIs. Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8074 cases) from the Breast Cancer Association Consortium (BCAC).
The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10(-4), minor allele frequency (MAF)=0.23). This SNP yielded an OR(rec) of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-OR(rec) of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01).
These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.
Journal of Medical Genetics 07/2011; 48(7):477-84. · 6.36 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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ABSTRACT: Physiological wound healing is a complex process requiring the temporal and spatial co-ordination of various signaling networks, biomechanical forces, and biochemical signaling pathways in both hypoxic and non-hypoxic conditions. Although a plethora of factors are required for successful physiological tissue repair, transforming growth factor beta (TGF-β) expression has been demonstrated throughout wound healing and shown to regulate many processes involved in tissue repair, including production of ECM, proteases, protease inhibitors, migration, chemotaxis, and proliferation of macrophages, fibroblasts of the granulation tissue, epithelial and capillary endothelial cells. TGF-β mediates these effects by stimulating signaling pathways through a receptor complex which contains Endoglin. Endoglin is expressed in a broad spectrum of proliferating and stem cells with elevated expression during hypoxia, and regulates important cellular functions such as proliferation and adhesion via Smad signaling. This review focuses on how the TGF-β family and Endoglin, regulate stem cell availability, and modulate cellular behavior within the wound microenvironment, includes current knowledge of the signaling pathways involved, and explores how this information may be applicable to inflammatory and/or angiogenic diseases such as fibrosis, rheumatoid arthritis and metastatic cancer.
Frontiers in physiology. 01/2011; 2:89.
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Olivia Fletcher,
Nichola Johnson,
Isabel dos Santos Silva,
Nick Orr,
Alan Ashworth,
Heli Nevanlinna,
Tuomas Heikkinen,
Kristiina Aittomäki,
Carl Blomqvist,
Barbara Burwinkel, [......],
Marjanka K Schmidt,
Flora E van Leeuwen,
Laura J Van't Veer,
Sara Margolin,
Annika Lindblom,
Manjeet K Humphreys,
Jonathan Morrison,
Radka Platte,
Douglas F Easton,
Julian Peto
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ABSTRACT: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.
We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium.
Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (P(trend) = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; P(trend) = 0.02).
In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.
Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.
Cancer Epidemiology Biomarkers & Prevention 09/2010; 19(9):2143-51. · 4.12 Impact Factor
