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Mia M Gaudet,
Karoline B Kuchenbaecker,
Joseph Vijai,
Robert J Klein, Tomas Kirchhoff,
Lesley McGuffog,
Daniel Barrowdale,
Alison M Dunning,
Andrew Lee,
Joe Dennis, [......],
Guillermo Pita,
M Rosario Alonso,
Per Hall,
Fergus J Couch,
Jacques Simard,
David Altshuler,
Douglas F Easton,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Kenneth Offit
[show abstract]
[hide abstract]
ABSTRACT: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
PLoS Genetics 03/2013; 9(3):e1003173. · 8.69 Impact Factor
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Joseph Vijai, Tomas Kirchhoff,
Kasmintan A Schrader,
Jennifer Brown,
Ana Virginia Dutra-Clarke,
Christopher Manschreck,
Nichole Hansen,
Rohini Rau-Murthy,
Kara Sarrel,
Jennifer Przybylo, [......],
Dina Ben-Yehuda,
Agnes Viale,
Carol Portlock,
David Straus,
Steven M Lipkin,
Mortimer Lacher,
Mark Robson,
Robert J Klein,
Andrew Zelenetz,
Kenneth Offit
[show abstract]
[hide abstract]
ABSTRACT: The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (P(LYM) = 3.89×10(-8), OR = 1.29) and rs948562 (P(LYM) = 5.85×10(-7), OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P(NHL) = 5.72×10(-7)) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P(FL) = 2.69×10(-12), OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
PLoS Genetics 01/2013; 9(1):e1003220. · 8.69 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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Kate M. Im, Tomas Kirchhoff,
Xianshu Wang,
Todd Green,
Clement Y. Chow,
Joseph Vijai,
Joshua Korn,
Mia M. Gaudet,
Zachary Fredericksen,
V. Shane Pankratz, [......],
Robert J. Klein,
Mark J. Daly,
Eitan Friedman,
Michael Dean,
Andrew G. Clark,
David M. Altshuler,
Antonis C. Antoniou,
Fergus J. Couch,
Kenneth Offit,
Bert Gold
[show abstract]
[hide abstract]
ABSTRACT: Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency
in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele
frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range
linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act
to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of
long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds
of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ
chromosomes with the BRCA1 185delAG mutation share an identical 2.1Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate
that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis
that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype
blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
Human Genetics 04/2012; 130(5):685-699. · 5.07 Impact Factor
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Penny Soucy,
Jonathan Beesley,
Xiaoqing Chen,
Lesley McGuffog,
Andrew Lee,
Daniel Barrowdale,
Sue Healey,
Niklas Loman,
Katja Harbst,
Annika Lindblom, [......],
Laura Papi,
Laura Ottini,
Paolo Radice,
Hilmi Ozcelik,
Gord Glendon,
Mads Thomassen,
Anne-Marie Gerdes,
Anne-Bine Skytte,
Georgia Chenevix-Trench,
Jacques Simard
[show abstract]
[hide abstract]
ABSTRACT: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
Breast cancer research: BCR 02/2012; 14(1):R33. · 5.24 Impact Factor
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Fergus J Couch,
Mia M Gaudet,
Antonis C Antoniou,
Susan J Ramus,
Karoline B Kuchenbaecker,
Penny Soucy,
Jonathan Beesley,
Xiaoqing Chen,
Xianshu Wang, Tomas Kirchhoff, [......],
Alessandra Viel,
Giuseppe Giannini,
Liliana Varesco,
Paolo Radice,
Mark H Greene,
Phuong L Mai,
Douglas F Easton,
Georgia Chenevix-Trench,
Kenneth Offit,
Jacques Simard
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.
We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)).
19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.
These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
Cancer Epidemiology Biomarkers & Prevention 02/2012; 21(4):645-57. · 4.12 Impact Factor
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Susan J Ramus,
Antonis C Antoniou,
Karoline B Kuchenbaecker,
Penny Soucy,
Jonathan Beesley,
Xiaoqing Chen,
Lesley McGuffog,
Olga M Sinilnikova,
Sue Healey,
Daniel Barrowdale, [......],
Irene L Andrulis,
Gord Glendon,
Hilmi Ozcelik,
Paul D P Pharoah,
Simon A Gayther,
Jacques Simard,
Douglas F Easton,
Fergus J Couch,
Georgia Chenevix-Trench,
Hans Ehrencrona
[show abstract]
[hide abstract]
ABSTRACT: Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.
Human Mutation 01/2012; 33(4):690-702. · 5.69 Impact Factor
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Yael Laitman,
Karoline B Kuchenbaecker,
Johanna Rantala,
Frans Hogervorst,
Susan Peock,
Andrew K Godwin,
Adalgeir Arason, Tomas Kirchhoff,
Kenneth Offit,
Claudine Isaacs, [......],
Katherine L Nathanson,
Maria Adelaide Caligo,
Susan L Neuhausen,
Patricia Ganz,
Olga M Sinilnikova,
Lesley McGuffog,
Douglas F Easton,
Antonis C Antoniou,
Ido Wolf,
Eitan Friedman
[show abstract]
[hide abstract]
ABSTRACT: Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan(®) allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93-1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82-1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84-1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66-1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.
Breast Cancer Research and Treatment 01/2012; 132(3):1119-26. · 4.43 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: 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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Antonis C Antoniou,
Christiana Kartsonaki,
Olga M Sinilnikova,
Penny Soucy,
Lesley McGuffog,
Sue Healey,
Andrew Lee,
Paolo Peterlongo,
Siranoush Manoukian,
Bernard Peissel, [......],
Amanda B Spurdle,
Susan L Neuhausen,
Yuan Chun Ding,
Zachary Fredericksen,
Xianshu Wang,
Vernon S Pankratz,
Fergus Couch,
Jacques Simard,
Douglas F Easton,
Georgia Chenevix-Trench
[show abstract]
[hide abstract]
ABSTRACT: Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
Human Molecular Genetics 06/2011; 20(16):3304-21. · 7.64 Impact Factor
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Kate M Im, Tomas Kirchhoff,
Xianshu Wang,
Todd Green,
Clement Y Chow,
Joseph Vijai,
Joshua Korn,
Mia M Gaudet,
Zachary Fredericksen,
V Shane Pankratz, [......],
Robert J Klein,
Mark J Daly,
Eitan Friedman,
Michael Dean,
Andrew G Clark,
David M Altshuler,
Antonis C Antoniou,
Fergus J Couch,
Kenneth Offit,
Bert Gold
[show abstract]
[hide abstract]
ABSTRACT: Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
Human Genetics 05/2011; 130(5):685-99. · 5.07 Impact Factor
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Susan J Ramus,
Christiana Kartsonaki,
Simon A Gayther,
Paul D P Pharoah,
Olga M Sinilnikova,
Jonathan Beesley,
Xiaoqing Chen,
Lesley McGuffog,
Sue Healey,
Fergus J Couch, [......],
Miguel de la Hoya,
Heli Nevanlinna,
Kristiina Aittomäki,
Jacques Simard,
Penny Soucy,
Amanda B Spurdle,
Helene Holland,
Georgia Chenevix-Trench,
Douglas F Easton,
Antonis C Antoniou
[show abstract]
[hide abstract]
ABSTRACT: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.
We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided.
The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%.
Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.
CancerSpectrum Knowledge Environment 01/2011; 103(2):105-16. · 14.07 Impact Factor
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Timothy Best,
Dalin Li,
Andrew D Skol, Tomas Kirchhoff,
Sarah A Jackson,
Yutaka Yasui,
Smita Bhatia,
Louise C Strong,
Susan M Domchek,
Katherine L Nathanson,
Olufunmilayo I Olopade,
R Stephanie Huang,
Thomas M Mack,
David V Conti,
Kenneth Offit,
Wendy Cozen,
Leslie L Robison,
Kenan Onel
[show abstract]
[hide abstract]
ABSTRACT: Survivors of pediatric Hodgkin's lymphoma are at risk for radiation therapy-induced second malignant neoplasms (SMNs). We identified two variants at chromosome 6q21 associated with SMNs in survivors of Hodgkin's lymphoma treated with radiation therapy as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 (encoding PR domain containing 1, with ZNF domain) and impaired induction of the PRDM1 protein after radiation exposure. These data suggest a new gene-exposure interaction that may implicate PRDM1 in the etiology of radiation therapy-induced SMNs.
Nature medicine 01/2011; 17(8):941-3. · 27.14 Impact Factor
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Antonis C Antoniou,
Jonathan Beesley,
Lesley McGuffog,
Olga M Sinilnikova,
Sue Healey,
Susan L Neuhausen,
Yuan Chun Ding,
Timothy R Rebbeck,
Jeffrey N Weitzel,
Henry T Lynch, [......],
Miguel de la Hoya,
Kristiina Aittomäki,
Heli Nevanlinna,
Jacques Simard,
Amanda B Spurdle,
Helene Holland,
Xiaoqing Chen,
Radka Platte,
Georgia Chenevix-Trench,
Douglas F Easton
[show abstract]
[hide abstract]
ABSTRACT: The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.
Cancer Research 12/2010; 70(23):9742-54. · 7.86 Impact Factor
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Antonis C Antoniou,
Xianshu Wang,
Zachary S Fredericksen,
Lesley McGuffog,
Robert Tarrell,
Olga M Sinilnikova,
Sue Healey,
Jonathan Morrison,
Christiana Kartsonaki,
Timothy Lesnick, [......],
Fiona Blows,
Kristy Driver,
Alison Dunning,
Paul P D Pharoah,
Kenneth Offit,
V Shane Pankratz,
Hakon Hakonarson,
Georgia Chenevix-Trench,
Douglas F Easton,
Fergus J Couch
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ABSTRACT: Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10⁻⁹ to P(trend) = 3.9 × 10⁻⁷), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 × 10⁻⁷) to P(trend) = 8 × 10⁻⁵; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 × 10⁻⁷
Nature Genetics 10/2010; 42(10):885-92. · 35.53 Impact Factor
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ABSTRACT: Genome-wide association studies (GWAS) have now been performed in nearly all common malignancies and have identified more than 100 common genetic risk variants that confer a modest increased risk of cancer. For most discovered germline risk variants, the per allele effect size is small (<1.5) and the biologic mechanism of the detected association remains unexplained. Exceptions are the risk variants identified in JAK2 in myeloproliferative neoplasm and in the KITLG gene in testicular cancer, which are each associated with nearly a 3-fold increased risk of disease. GWAS have provided an efficient approach to identifying common, low-penetrance risk variants, and have implicated several novel cancer susceptibility loci. However, the identified low-penetrance risk variants explain only a small fraction of the heritability of cancer and the clinical usefulness of using these variants for cancer-risk prediction is to date limited. Studies involving more heterogeneous populations, determination of the causal variants, and functional studies are now necessary to further elucidate the potential biologic and clinical significance of the observed associations.
Hematology/oncology clinics of North America 10/2010; 24(5):973-96. · 2.05 Impact Factor
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Antonis C Antoniou,
Xianshu Wang,
Zachary S Fredericksen,
Lesley McGuffog,
Robert Tarrell,
Olga M Sinilnikova,
Sue Healey,
Jonathan Morrison,
Christiana Kartsonaki,
Timothy Lesnick, [......],
Fiona Blows,
Kristy Driver,
Alison Dunning,
Paul P D Pharoah,
Kenneth Offit,
V Shane Pankratz,
Hakon Hakonarson,
Georgia Chenevix-Trench,
Douglas F Easton,
Fergus J Couch
Nature Genetics 09/2010; 42(10):885-892. · 35.53 Impact Factor
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David J Gallagher,
Joseph Vijai,
Angel M Cronin,
Jasmine Bhatia,
Andrew J Vickers,
Mia M Gaudet,
Samson Fine,
Victor Reuter,
Howard I Scher,
Christer Halldén,
Ana Dutra-Clarke,
Robert J Klein,
Peter T Scardino,
James A Eastham,
Hans Lilja, Tomas Kirchhoff,
Kenneth Offit
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ABSTRACT: Prostate cancer is a heterogeneous disease with a variable natural history that is not accurately predicted by currently used prognostic tools.
We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and prostate-specific antigen. We investigated associations between 29 single nucleotide polymorphisms (SNP) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we did an independent analysis using a high-resolution panel of 13 SNPs.
On univariate analysis, two SNPs were associated (P<0.05) with biochemical recurrence, three SNPs were associated with clinical metastases, and one SNP was associated with prostate cancer-specific mortality. Applying a Bonferroni correction (P<0.0017), one association with biochemical recurrence (P=0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (P<0.0005 by both univariate and multivariable analysis).
We identified associations between prostate cancer susceptibility SNPs and clinical end points. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region were strongly associated with prostate cancer-specific survival, and rs10486567 in the 7JAZF1 gene were associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models.
Clinical Cancer Research 05/2010; 16(10):2819-32. · 7.74 Impact Factor
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David J Gallagher,
Mia M Gaudet,
Prodipto Pal, Tomas Kirchhoff,
Lisa Balistreri,
Kinjal Vora,
Jasmine Bhatia,
Zsofia Stadler,
Samson W Fine,
Victor Reuter,
Michael Zelefsky,
Michael J Morris,
Howard I Scher,
Robert J Klein,
Larry Norton,
James A Eastham,
Peter T Scardino,
Mark E Robson,
Kenneth Offit
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ABSTRACT: Increased prostate cancer risk has been reported for BRCA mutation carriers, but BRCA-associated clinicopathologic features have not been clearly defined.
We determined BRCA mutation prevalence in 832 Ashkenazi Jewish men diagnosed with localized prostate cancer between 1988 and 2007 and 454 Ashkenazi Jewish controls and compared clinical outcome measures among 26 BRCA mutation carriers and 806 noncarriers. Kruskal-Wallis tests were used to compare age of diagnosis and Gleason score, and logistic regression models were used to determine associations between carrier status, prostate cancer risk, and Gleason score. Hazard ratios (HR) for clinical end points were estimated using Cox proportional hazards models.
BRCA2 mutations were associated with a 3-fold risk of prostate cancer [odds ratio, 3.18; 95% confidence interval (95% CI), 1.52-6.66; P = 0.002] and presented with more poorly differentiated (Gleason score > or =7) tumors (85% versus 57%; P = 0.0002) compared with non-BRCA-associated prostate cancer. BRCA1 mutations conferred no increased risk. After 7,254 person-years of follow-up, and adjusting for clinical stage, prostate-specific antigen, Gleason score, and treatment, BRCA2 and BRCA1 mutation carriers had a higher risk of recurrence [HR (95% CI), 2.41 (1.23-4.75) and 4.32 (1.31-13.62), respectively] and prostate cancer-specific death [HR (95% CI), 5.48 (2.03-14.79) and 5.16 (1.09-24.53), respectively] than noncarriers.
BRCA2 mutation carriers had an increased risk of prostate cancer and a higher histologic grade, and BRCA1 or BRCA2 mutations were associated with a more aggressive clinical course. These results may have implications for tailoring clinical management of this subset of hereditary prostate cancer.
Clinical Cancer Research 03/2010; 16(7):2115-21. · 7.74 Impact Factor
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Mia M Gaudet, Tomas Kirchhoff,
Todd Green,
Joseph Vijai,
Joshua M Korn,
Candace Guiducci,
Ayellet V Segrè,
Kate McGee,
Lesley McGuffog,
Christiana Kartsonaki, [......],
Michael Dean,
Bert Gold,
Robert J Klein,
Fergus J Couch,
Georgia Chenevix-Trench,
Douglas F Easton,
Mark J Daly,
Antonis C Antoniou,
David M Altshuler,
Kenneth Offit
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ABSTRACT: The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
PLoS Genetics 01/2010; 6(10):e1001183. · 8.69 Impact Factor
