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Hui Shen,
Brooke L Fridley,
Honglin Song,
Kate Lawrenson,
Julie M Cunningham,
Susan J Ramus,
Mine S Cicek,
Jonathan Tyrer,
Douglas Stram,
Melissa C Larson, [......],
Joellen M Schildkraut,
Thomas A Sellers,
David Huntsman,
Andrew Berchuck,
Georgia Chenevix-Trench,
Simon A Gayther,
Paul D P Pharoah,
Peter W Laird,
Ellen L Goode,
Celeste Leigh Pearce
[show abstract]
[hide abstract]
ABSTRACT: HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
Nature Communications 03/2013; 4:1628. · 7.40 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
[show abstract]
[hide abstract]
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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[show abstract]
[hide abstract]
ABSTRACT: Tea materials are widely consumed beverages in the world and they are rich source of dietary polyphenols. Catechins in tea materials showed excellent antioxidant properties, which is beneficial for many diseases such as cancers and cardiovascular diseases. Tea catechins can interact with plasma proteins to form soluble or insoluble complexes, which are responsible for their bioactivities in vivo. However, there are no reviews published in the recent time which focused on tea catechins-plasma protein interaction (TcPI), despite numerous articles have been appeared in this field. This review summarizes the recent trend in TcPI studies focusing on metabolism, structure-affinity relationship, influence on antioxidant activity, and molecular docking aspects.
Current Drug Metabolism 01/2013; · 5.11 Impact Factor
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Hui Shen,
Brooke L. Fridley,
Honglin Song,
Kate Lawrenson,
Julie M. Cunningham,
Susan J. Ramus,
Mine S. Cicek,
Jonathan Tyrer,
Douglas Stram,
Melissa C. Larson, [......],
Joellen M. Schildkraut,
Thomas A. Sellers,
David Huntsman,
Andrew Berchuck,
Georgia Chenevix-Trench,
Simon A. Gayther,
Paul D. P. Pharoah,
Peter W. Laird,
Ellen L. Goode,
Celeste Leigh Pearce
Nat Commun. 01/2013; 4:1628.
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Kristen N Stevens,
Xianshu Wang,
Zachary Fredericksen,
Vernon S Pankratz,
Mark H Greene,
Irene L Andrulis,
Mads Thomassen,
Maria Caligo,
Katherine L Nathanson,
Anna Jakubowska, [......],
Jacques Simard,
Amanda B Spurdle,
Sue Healey, Xiaoqing Chen,
Timothy R Rebbeck,
Douglas F Easton,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Fergus J Couch,
Hans Ehrencrona
[show abstract]
[hide abstract]
ABSTRACT: Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.
Breast Cancer Research and Treatment 09/2012; 136(1):295-302. · 4.43 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
[show abstract]
[hide abstract]
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, pheterogeneity = 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 08/2012; 7(8). · 4.09 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
[show abstract]
[hide abstract]
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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Yi Lu, Xiaoqing Chen,
Jonathan Beesley,
Sharon E Johnatty,
Anna Defazio,
Sandrina Lambrechts,
Diether Lambrechts,
Evelyn Despierre,
Ignace Vergotes,
Jenny Chang-Claude, [......],
Susan Ramus,
Usha Menon,
Alexandra Gentry-Maharaj,
Simon A Gayther,
Elisa V Bandera,
Sara H Olson,
Irene Orlow,
Lorna Rodriguez-Rodriguez,
Stuart Macgregor,
Georgia Chenevix-Trench
[show abstract]
[hide abstract]
ABSTRACT: Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.
Twin Research and Human Genetics 07/2012; 15(5):615-23. · 1.70 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, [......],
Fiona Douglas,
Shirley Hodgson,
D. Gareth Evans,
Rosalind Eeles,
Bert Gold,
Paul D.P. Pharoah,
Kenneth Offit,
Georgia Chenevix-Trench,
Douglas F. Easton,
on behalf of BCAC/CIMBA
[show abstract]
[hide abstract]
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 (I2 = 49.3%; p =
PLoS ONE 06/2012; 7(6). · 4.09 Impact Factor
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Yuan C Ding,
Lesley McGuffog,
Sue Healey,
Eitan Friedman,
Yael Laitman,
Shani- Paluch-Shimon,
Bella Kaufman,
Annelie Liljegren,
Annika Lindblom,
Håkan Olsson, [......],
Hilmi Ozcelik,
Anne-Marie Gerdes,
Mads Thomassen,
Uffe Birk Jensen,
Anne-Bine Skytte,
Maria A Caligo,
Andrew Lee,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Susan L Neuhausen
[show abstract]
[hide abstract]
ABSTRACT: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.
IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.
Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).
The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.
These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
Cancer Epidemiology Biomarkers & Prevention 06/2012; 21(8):1362-70. · 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
[show abstract]
[hide abstract]
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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Amanda B. Spurdle,
Andrew J. Deans,
David Duffy,
David E. Goldgar, Xiaoqing Chen,
Jonathan Beesley,
kConFaB,
Douglas F. Easton,
Antonis C. Antoniou,
Susan Peock,
Margaret Cook,
EMBRACE Study Collaborators,
Katherine L. Nathanson,
Susan M. Domchek,
Grant A. MacArthur,
Georgia Chenevix-Trench
[show abstract]
[hide abstract]
ABSTRACT: The p27kip1 protein functions as an inhibitor of cyclin dependent kinase-2, and shows loss of expression in a large percentage of BRCA1 and BRCA2 breast cancer cases. We investigated the association between CDKN1B gene variants and breast cancer risk in 2359 female BRCA1 and BRCA2 mutation carriers from Australia, the UK, and the USA. Samples were genotyped for five single nucleotide polymorphisms, including
coding variant rs2066827 (V109G). Cox regression provided no convincing evidence that any of the polymorphisms modified disease
risk for BRCA1 or BRCA2 carriers, either alone or as a haplotype. Borderline associations were observed for homozygote carriers of the rs3759216
rare allele, but were opposite in effect for BRCA1 and BRCA2 carriers (adjusted hazard ratio (HR) 0.72 (95% CI=0.53–0.99; P=0.04 for BRCA1, HR 1.47 (95% CI=0.99–2.18; P=0.06 for BRCA2). The 95% confidence intervals for per allele risk estimates excluded a twofold risk, indicating that common CDKN1B polymorphisms do not markedly modify breast cancer risk among BRCA1 or BRCA2 carriers.
Breast Cancer Research and Treatment 04/2012; 115(2):307-313. · 4.43 Impact Factor
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Sharon E. Johnatty,
Jonathan Beesley, Xiaoqing Chen,
John L. Hopper,
Melissa C. Southey,
Graham G. Giles,
David E. Goldgar,
Georgia Chenevix-Trench,
Amanda B. Spurdle,
The Australian Ovarian Cancer Study Group,
The Kathleen Cuningham Consortium for Research in Familial Breast Cancer
[show abstract]
[hide abstract]
ABSTRACT: BARD1 was first identified as a BRCA1-interacting protein with tumour-suppressor functions. Some association studies suggested
that the BARD1 Cys557Ser variant might be associated with increased risk of breast cancer, but the evidence remains uncertain. We found
that the BARD1 Cys557Ser variant was carried by 50 of 1,136 cases (4.4%) and 30 of 623 controls (5.0%) from the population-based Australian
Breast Cancer Family Study, 14 of 324 (4.3%) cases from the Kathleen Cuningham Foundation Consortium for Research into Familial
Breast Cancer (kConFab), and 30 of 760 controls (4.0%) from the Australian Ovarian Cancer Study. Case–control comparisons
showed no evidence that the variant frequency differed by case–control status (P≥0.3). Segregation analysis of 14 kConFab variant-carrying families containing 157 genotyped individuals provided no evidence
of segregation with disease. We conclude that the BARD1 Cys557Ser variant is not associated with breast cancer risk.
Breast Cancer Research and Treatment 04/2012; 115(1):145-150. · 4.43 Impact Factor
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James G. Dowty,
Felicity Lose,
Mark A. Jenkins,
Jiun-Horng Chang, XiaoQing Chen,
Jonathan Beesley,
Gillian S. Dite,
Melissa C. Southey,
Graham B. Byrnes,
Andrea Tesoriero,
Graham G. Giles,
kConFab Investigators,
Australian Breast Cancer Family Study (ABCFS,
John L. Hopper,
Amanda B. Spurdle
[show abstract]
[hide abstract]
ABSTRACT: RAD51D is a homolog of the RAD51 protein, which is known to be an important component of the DNA repair pathway. A rare missense
variant in the RAD51D gene, E233G (c.A>G), has been reported to be more prevalent in breast cancer cases from specific multiple-case breast cancer
families, with an odds ratio of 2.6 (95% confidence interval (CI): 1.12–6.03). We assessed whether this variant was associated
with breast cancer risk using two studies: a population-based case–control-family study based on 1,110 cases and 629 controls,
and a clinic-based study based on 390 cases from multiple-case breast cancer families. We conducted case–control analyses
and modified segregation analyses of carrier families. The carrier frequencies (95% CI) of the RAD51D variant were 4.1% (2.4–6.6) for clinic-based cases, 3.9% (2.8–5.2) for population-based cases, and 3.7% (2.3–5.4) for population-based
controls, and were not significantly higher in case groups than controls (P=0.7 and P=0.8, respectively). After genotyping the relatives of cases who carried the variant, modified segregation analyses of these
families were conducted, and the estimated hazard ratio for breast cancer corresponding to the E233G variant was 1.30 (95%
CI: 0.66–2.58; P=0.4) for familial breast cancer families and 1.28 (95% CI: 0.47–3.43; P=0.6) for families unselected for family history. Therefore, despite being well powered to detect moderate risks, no evidence
for an association between the E233G variant and breast cancer risk was observed in any setting. Larger studies would be required
to determine if this variant is associated with a smaller risk of breast cancer.
Breast Cancer Research and Treatment 04/2012; 112(1):35-39. · 4.43 Impact Factor
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Ana-Teresa Maia,
Antonis C Antoniou,
Martin O'Reilly,
Shamith Samarajiwa,
Mark Dunning,
Christiana Kartsonaki,
Suet-Feung Chin,
Christina N Curtis,
Lesley McGuffog,
Susan M Domchek, [......],
Fergus J Couch,
Andrew K Godwin,
Maria Adelaide Caligo,
Rosa B Barkardottir, Xiaoqing Chen,
Jonathan Beesley,
Sue Healey,
Carlos Caldas,
Georgia Chenevix-Trench,
Bruce Aj Ponder
[show abstract]
[hide abstract]
ABSTRACT: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism.
We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers.
We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBPα, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048).
Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.
Breast cancer research: BCR 04/2012; 14(2):R63. · 5.24 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Association studies aimed at identifying breast cancer susceptibility variants in the progesterone receptor (PGR) gene have been previously reported in the literature with conflicting results, ranging from a protective effect conferred
by the PROGINS allele in German Caucasian women, to an increased risk for the leucine variant of the Val660Leu (rs1042838)
polymorphism in East Anglian cases. We report the results of genotype and haplotype analyses of five PGR polymorphisms, +44C/T
(rs518162), +331G/A (rs10895068), V660L (rs1042838), H770H (rs1042839) and Q886Q (rs500760), conducted on 1,847 Australian
breast cancer cases (including 276 cases from a cohort of multiple-case breast cancer families) and 833 controls. Genotype
and haplotype analyses of the five polymorphisms showed no evidence of an association with breast cancer (p>0.3). We also conducted a meta-analysis of the V660L (rs1042838) polymorphism on our and six other published studies including
10,205 cases and 11,320 controls. Compared to the VV homozygotes, VL heterozygotes and LL homozygotes were associated with
a non-significant increased risk for breast cancer [Odds ratio (OR)VL, 1.06; 95% confidence intervals (95% CI), 0.97–1.15, ORLL, 1.05; 95% CI, 0.75–1.49]. Analysis of a per-leucine allele risk under a codominant model, however, suggested a significant
leucine-allele dose effect, ORper-L, 1.07; 95% CI, 1.02–1.13, p=0.01. We conclude that the leucine allele of the V660L SNP may be associated with a small increase in breast cancer risk,
while the other four PGR SNPs, +44C/T (rs518162), +331G/A (rs10895068), H770H (rs1042839) and Q886Q (rs500760), do not substantially
increase breast cancer risk.
Breast Cancer Research and Treatment 04/2012; 109(1):91-99. · 4.43 Impact Factor
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Jianjun Liu,
Kartiki Vasant Desai,
Yuqing Li,
Shakeela Banu,
Yew Kok Lee,
Dianbo Qu,
Tuomas Heikkinen,
Kirsimari Aaltonen,
Taru A. Muranen,
Tasneem Shabbir Kajiji, [......],
Georgia Chenevix-Trench,
Jonathan Beesley,
Amanda B. Spurdle, Xiaoqing Chen,
Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer,
Australian Ovarian Cancer Study Group,
Kamila Czene,
Per Hall,
Heli Nevanlinna,
Edison T. Liu
[show abstract]
[hide abstract]
ABSTRACT: Multiple lines of evidence suggest regulatory variation to play an important role in phenotypic evolution and disease development,
but few regulatory polymorphisms have been characterized genetically and molecularly. Recent technological advances have made
it possible to identify bona fide regulatory sequences experimentally on a genome-wide scale and opened the window for the
biological interrogation of germ-line polymorphisms within these sequences. In this study, through a forward genetic analysis
of bona fide p53 binding sites identified by a genome-wide chromatin immunoprecipitation and sequence analysis, we discovered
a SNP (rs1860746) within the motif sequence of a p53 binding site where p53 can function as a regulator of transcription.
We found that the minor allele (T) binds p53 poorly and has low transcriptional regulation activity as compared to the major
allele (G). Significantly, the homozygosity of the minor allele was found to be associated with an increased risk of ER negative
breast cancer (OR=1.47, P=0.038) from the analysis of five independent breast cancer samples of European origin consisting of 6,127 breast cancer
patients and 5,197 controls. rs1860746 resides in the third intron of the PRKAG2 gene that encodes the γ subunit of the AMPK
protein, a major sensor of metabolic stress and a modulator of p53 action. However, this gene does not appear to be regulated
by p53 in lymphoblastoid cell lines nor in a cancer cell line. These results suggest that either the rs1860746 locus regulates
another gene through distant interactions, or that this locus is in linkage disequilibrium with a second causal mutation.
This study shows the feasibility of using genomic scale molecular data to uncover disease associated SNPs, but underscores
the complexity of determining the function of regulatory variants in human populations.
Keywordsp53 binding sites-PRKAG2 gene-Polymorphism-ER negative tumors-Breast cancer susceptibility
HUGO Journal 04/2012; 3(1):31-40.
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Diether Lambrechts,
Therese Truong,
Christina Justenhoven,
Manjeet K Humphreys,
Jean Wang,
John L Hopper,
Gillian S Dite,
Carmel Apicella,
Melissa C Southey,
Marjanka K Schmidt, [......],
Daehee Kang,
Keun-Young Yoo,
Dong-Young Noh,
Annika Lindblom,
Sara Margolin,
Alison M Dunning,
Paul D P Pharoah,
Douglas F Easton,
Pascal Guénel,
Hiltrud Brauch
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ABSTRACT: A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
Human Mutation 03/2012; 33(7):1123-32. · 5.69 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Diabetes is characterized by an elevated level of glucose in the blood. This glucose can form covalent adducts with plasma proteins through a non-enzymatic process known as glycation. It has been suggested that the increasing glycation can influence the ability of plasma proteins to bind to small molecules. Herein, the difference between healthy human plasma proteins (HPP) and type II diabetes plasma proteins (TPP) in binding small molecules was investigated. TPP showed about 1-10 times lower affinities for polyphenols than HPP. The values of lg K(a)(HPP) are positive proportional to the values of lg K(a)(TPP) with excellent linear relationship. The glycation of HPP decreased the affinities for HPP by about 1.17 to 16.6 times. The difference between HPP-polyphenol interaction and TPP-polyphenol interaction was bigger for the more lipophilic polyphenols. The affinities for TPP or HPP slightly decreased with increasing hydrogen bond donor numbers of polyphenols and hardly changed with hydrogen bond acceptor numbers.
Integrative Biology 03/2012; 4(5):502-7. · 4.51 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Puerariae lobata flower (Willdenow) has a long history used to treat alcoholic intoxication in China, which contains a series of isoflavones as its chief pharmacologically active constituents. In this study, bovine serum albumin (BSA) functionalized iron oxide magnetic nanoparticles (Fe₃O₄ MNPs) coupled with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) were used to screen and identify active compounds from ethanolic extract of P. lobata flower. Thirteen active isoflavones were screened and identified as glycitin (1), tectoridin (2), daidzin (3), 3'-methoxy daidzin (4), ononin (5), 3'-hydroxyl daidzein (6), tectorigenin (7), biochanin A (8), prunetin (9), genistein (10), 3'-methoxy daidzein (11), irisolidone (12) and 5,7-dihydroxy-3',4'-methylenedioxyisoflavone (13), while compounds 4, 6, 9, 11 and 13 were identified from this plant for the first time. Furthermore, the activity of each bound ligand was evaluated on-line. The results indicated that the binding affinities of compounds with BSA were highly dependent on chemical structures and the methoxylation and hydroxylation on B-ring could improve the activity. The effective method could be widely applied for rapid screening and identification of active compounds from complex mixtures.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 03/2012; 887-888:55-60. · 2.78 Impact Factor
