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Grant Details

Grant Number: 5U19CA148065-04 Interpret this number
Primary Investigator: Hunter, David
Organization: Harvard College
Project Title: Discovery, Biology and Risk of Inherited Variants in Breast Cancer
Fiscal Year: 2013
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Abstract

DESCRIPTION (provided by applicant): We propose an integrated multiple-PI Project to systematically discover and replicate additional common genetic variants associated with breast cancer, assess their biological significance, and develop evidence based assessments of the clinical validity of prediction algorithms using these variants, and their suitability for translation into clinical practice. In sub-Project 1 we will combine the resources of (a) major GWAS for breast cancer amounting to >15,000 cases and (b) three pre-existing Consortia with over 48,000 additional cases to provide the large sample size needs necessary in the replication phase of GWAS. We will fine map the associated loci in collaboration with the major Consortia conducting GWAS for breast cancer in Asian and African-American women. In sub-Project 2 we will conduct a series of investigations to (a) assign a gene function to each replicated risk variant by measuring expression of 24,000 RNA transcripts in breast tumor tissue and normal tissue, from women for whom we also have an lllumina 540 GWAS available; by identifying networks of genes in which alterations of expression can be linked to specific germline risk variants; and by using Chromosomal Conformation Capture assays to examine whether associated intergenic regions fold physically in a way that brings them into contact with distant genie regions. We will also (b) examine whether loss or gain of function of the genes implicated in (a) in breast epithelial cells or stromal cells alter phenotypes in vitro in a 3-D model of breast morphogenesis and oncogenesis. In sub- Project 3, we will develop breast cancer prediction models that can be used to stratify women according to breast cancer risk. We will attempt to discover gene-gene interactions by reanalyzing the GWAS data, and we will systematically examine the genome-wide significant gene variants for effect modification by established breast cancer risk factors, using the largest set of prospective studies available. We will develop and refine risk models that incorporate both the germline risk factors and the established non-genetic risk factors, and also assess these in a cohort of women with higher familial risk of breast cancer (to specifically address the clinical needs of women at high risk due to a strong family history of breast cancer). Finally, we will analyze data from the major trials of primary prevention of breast cancer to address the question of whether the protective effect of tamoxifen is altered by risk status for our prediction models, data with a direct bearing on clinical decision-making with respect to chemoprevention for women at known high risk.

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Publications

Enhancing Reproducibility in Cancer Drug Screening: How Do We Move Forward?
Authors: Hatzis C, Bedard PL, Juul Birkbak N, Beck AH, Aerts HJ, Stern DF, Shi L, Clarke R, Quackenbush J, Haibe-Kains B
Source: Cancer Res, 2014 Jul 11;null, p. null.
EPub date: 2014 Jul 11.
PMID: 25015668
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A multivariate approach to the integration of multi-omics datasets.
Authors: Meng C, Kuster B, Culhane AC, Gholami AM
Source: BMC Bioinformatics, 2014 May 29;15, p. 162.
EPub date: 2014 May 29.
PMID: 24884486
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FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.
Authors: Agarwal D, Pineda S, Michailidou K, Herranz J, Pita G, Moreno LT, Alonso MR, Dennis J, Wang Q, Bolla MK, Meyer KB, Menéndez-Rodríguez P, Hardisson D, Mendiola M, González-Neira A, Lindblom A, Margolin S, Swerdlow A, Ashworth A, Orr N, Jones M, Matsuo K, Ito H, Iwata H, Kondo N, kConFab Investigators, Australian Ovarian Cancer Study Group, Hartman M, Hui M, Lim WY, Iau PT, Sawyer E, Tomlinson I, Kerin M, Miller N, Kang D, Choi J-, Park SK, Noh D-, Hopper JL, Schmidt DF, Makalic E, Southey MC, Teo SH, Yip CH, Sivanandan K, Tay W-, Brauch H, Brüning T, Hamann U, GENICA Network, Dunning AM, Shah M, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Schmidt MK, Broeks A, Rosenberg EH, van't Veer LJ, Fasching PA, Renner SP, Ekici AB, Beckmann MW, Shen C-, Hsiung C-, Yu J-, Hou M-, Blot W, Cai Q, Wu AH, Tseng C-, Van Den Berg D, Stram DO, Cox A, Brock IW, Reed MW, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Zheng W, Deming-Halverson S, Shrubsole MJ, Long J, Shu X-, Lu W, Gao Y-, Zhang B, Radice P, Peterlongo P, Manoukian S, Mariette F, Sangrajrang S, McKay J, Couch FJ, Toland AE, TNBCC, Yannoukakos D, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Marme F, Burwinkel B, Guénel P, Truong T, Sanchez M, Mulot C, Bojesen SE, Nordestgaard BG, Flyer H, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Mannermaa A, Kataja V, Kosma V-, Hartikainen JM, Lambrechts D, Yesilyurt BT, Floris G, Leunen K, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Wang X, Olson JE, Vachon C, Purrington K, Giles GG, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Marchand LL, Simard J, Dumont M, Goldberg MS, Labréche F, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Devilee P, Tollenaar RA, Seynaeve C, García-Closas M, Chanock SJ, Lissowska J, Figueroa JD, Czene K, Eriksson M, Humphreys K, Darabi H, Hooning MJ, Kriege M, Collée JM, Tilanus-Linthorst M, Li J, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Bogdanova N, Dörk T, Hall P, Chenevix-Trench G, Easton DF, Pharroah PD, Arias-Perez JI, Zamora P, Benítez J, Milne RL
Source: Br J Cancer, 2014 Feb 18;110(4), p. 1088-100.
PMID: 24548884
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A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age.
Authors: Ahsan H, Halpern J, Kibriya MG, Pierce BL, Tong L, Gamazon E, McGuire V, Felberg A, Shi J, Jasmine F, Roy S, Brutus R, Argos M, Melkonian S, Chang-Claude J, Andrulis I, Hopper JL, John EM, Malone K, Ursin G, Gammon MD, Thomas DC, Seminara D, Casey G, Knight JA, Southey MC, Giles GG, Santella RM, Lee E, Conti D, Duggan D, Gallinger S, Haile R, Jenkins M, Lindor NM, Newcomb P, Michailidou K, Apicella C, Park DJ, Peto J, Fletcher O, dos Santos Silva I, Lathrop M, Hunter DJ, Chanock SJ, Meindl A, Schmutzler RK, Müller-Myhsok B, Lochmann M, Beckmann L, Hein R, Makalic E, Schmidt DF, Bui QM, Stone J, Flesch-Janys D, Dahmen N, Nevanlinna H, Aittomäki K, Blomqvist C, Hall P, Czene K, Irwanto A, Liu J, Rahman N, Turnbull C, Familial Breast Cancer Study, Dunning AM, Pharoah P, Waisfisz Q, Meijers-Heijboer H, Uitterlinden AG, Rivadeneira F, Nicolae D, Easton DF, Cox NJ, Whittemore AS
Source: Cancer Epidemiol Biomarkers Prev, 2014 Apr;23(4), p. 658-69.
EPub date: 2014 Feb 3.
PMID: 24493630
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Inconsistency in large pharmacogenomic studies.
Authors: Haibe-Kains B, El-Hachem N, Birkbak NJ, Jin AC, Beck AH, Aerts HJ, Quackenbush J
Source: Nature, 2013 Dec 19;504(7480), p. 389-93.
EPub date: 2013 Nov 27.
PMID: 24284626
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Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions.
Authors: Schoeps A, Rudolph A, Seibold P, Dunning AM, Milne RL, Bojesen SE, Swerdlow A, Andrulis I, Brenner H, Behrens S, Orr N, Jones M, Ashworth A, Li J, Cramp H, Connley D, Czene K, Darabi H, Chanock SJ, Lissowska J, Figueroa JD, Knight J, Glendon G, Mulligan AM, Dumont M, Severi G, Baglietto L, Olson J, Vachon C, Purrington K, Moisse M, Neven P, Wildiers H, Spurdle A, Kosma VM, Kataja V, Hartikainen JM, Hamann U, Ko YD, Dieffenbach AK, Arndt V, Stegmaier C, Malats N, Arias Perez JI, Benítez J, Flyger H, Nordestgaard BG, Truong T, Cordina-Duverger E, Menegaux F, dos Santos Silva I, Fletcher O, Johnson N, Häberle L, Beckmann MW, Ekici AB, Braaf L, Atsma F, van den Broek AJ, Makalic E, Schmidt DF, Southey MC, Cox A, Simard J, Giles GG, Lambrechts D, Mannermaa A, Brauch H, Guénel P, Peto J, Fasching PA, Hopper J, Flesch-Janys D, Couch F, Chenevix-Trench G, Pharoah PD, Garcia-Closas M, Schmidt MK, Hall P, Easton DF, Chang-Claude J
Source: Genet Epidemiol, 2014 Jan;38(1), p. 84-93.
EPub date: 2013 Nov 18.
PMID: 24248812
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A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium.
Authors: Milne RL, Herranz J, Michailidou K, Dennis J, Tyrer JP, Zamora MP, Arias-Perez JI, González-Neira A, Pita G, Alonso MR, Wang Q, Bolla MK, Czene K, Eriksson M, Humphreys K, Darabi H, Li J, Anton-Culver H, Neuhausen SL, Ziogas A, Clarke CA, Hopper JL, Dite GS, Apicella C, Southey MC, Chenevix-Trench G, kConFab Investigators, Australian Ovarian Cancer Study Group, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Bojesen SE, Nordestgaard BG, Flyger H, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Wang X, Olson JE, Vachon C, Purrington K, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Dunning AM, Shah M, Guénel P, Truong T, Sanchez M, Mulot C, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Lindblom A, Margolin S, Hooning MJ, Hollestelle A, Collée JM, Jager A, Cox A, Brock IW, Reed MW, Devilee P, Tollenaar RA, Seynaeve C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Dumont M, Soucy P, Dörk T, Bogdanova NV, Hamann U, Försti A, Rüdiger T, Ulmer HU, Fasching PA, Häberle L, Ekici AB, Beckmann MW, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Radice P, Peterlongo P, Peissel B, Mariani P, Giles GG, Severi G, Baglietto L, Sawyer E, Tomlinson I, Kerin M, Miller N, Marme F, Burwinkel B, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Lambrechts D, Yesilyurt BT, Floris G, Leunen K, Alnćs GG, Kristensen V, Břrresen-Dale AL, García-Closas M, Chanock SJ, Lissowska J, Figueroa JD, Schmidt MK, Broeks A, Verhoef S, Rutgers EJ, Brauch H, Brüning T, Ko YD, GENICA Network, Couch FJ, Toland AE, TNBCC, Yannoukakos D, Pharoah PD, Hall P, Benítez J, Malats N, Easton DF
Source: Hum Mol Genet, 2014 Apr 1;23(7), p. 1934-46.
EPub date: 2013 Nov 15.
PMID: 24242184
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Lessons from postgenome-wide association studies: functional analysis of cancer predisposition loci.
Authors: Monteiro AN, Freedman ML
Source: J Intern Med, 2013 Nov;274(5), p. 414-24.
PMID: 24127939
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Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study.
Authors: Rudolph A, Hein R, Lindström S, Beckmann L, Behrens S, Liu J, Aschard H, Bolla MK, Wang J, Truong T, Cordina-Duverger E, Menegaux F, Brüning T, Harth V, GENICA Network, Severi G, Baglietto L, Southey M, Chanock SJ, Lissowska J, Figueroa JD, Eriksson M, Humpreys K, Darabi H, Olson JE, Stevens KN, Vachon CM, Knight JA, Glendon G, Mulligan AM, Ashworth A, Orr N, Schoemaker M, Webb PM, kConFab Investigators, AOCS Management Group, Guénel P, Brauch H, Giles G, García-Closas M, Czene K, Chenevix-Trench G, Couch FJ, Andrulis IL, Swerdlow A, Hunter DJ, Flesch-Janys D, Easton DF, Hall P, Nevanlinna H, Kraft P, Chang-Claude J, Breast Cancer Association Consortium
Source: Endocr Relat Cancer, 2013 Dec;20(6), p. 875-87.
EPub date: 2013 Nov 4.
PMID: 24080446
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Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans.
Authors: Wang H, Haiman CA, Burnett T, Fortini BK, Kolonel LN, Henderson BE, Signorello LB, Blot WJ, Keku TO, Berndt SI, Newcomb PA, Pande M, Amos CI, West DW, Casey G, Sandler RS, Haile R, Stram DO, Le Marchand L
Source: Hum Mol Genet, 2013 Dec 15;22(24), p. 5048-55.
EPub date: 2013 Jul 12.
PMID: 23851122
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Large-scale genotyping identifies a new locus at 22q13.2 associated with female breast size.
Authors: Li J, Foo JN, Schoof N, Varghese JS, Fernandez-Navarro P, Gierach GL, Quek ST, Hartman M, Nord S, Kristensen VN, Pollán M, Figueroa JD, Thompson DJ, Li Y, Khor CC, Humphreys K, Liu J, Czene K, Hall P
Source: J Med Genet, 2013 Oct;50(10), p. 666-73.
EPub date: 2013 Jul 3.
PMID: 23825393
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New breast cancer risk variant discovered at 10q25 in East Asian women.
Authors: Shi J, Sung H, Zhang B, Lu W, Choi JY, Xiang YB, Kim MK, Iwasaki M, Long J, Ji BT, Park SK, Zheng Y, Tsugane S, Yoo KY, Wang W, Noh DY, Han W, Kim SW, Lee MH, Lee JW, Lee JY, Shen CY, Matsuo K, Ahn SH, Gao YT, Shu XO, Cai Q, Kang D, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2013 Jul;22(7), p. 1297-303.
EPub date: 2013 May 15.
PMID: 23677579
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The case-only test for gene-environment interaction is not uniformly powerful: an empirical example.
Authors: Wu C, Chang J, Ma B, Miao X, Zhou Y, Liu Y, Li Y, Wu T, Hu Z, Shen H, Jia W, Zeng Y, Lin D, Kraft P
Source: Genet Epidemiol, 2013 May;37(4), p. 402-7.
EPub date: 2013 Mar 13.
PMID: 23595356
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Evaluating genome-wide association study-identified breast cancer risk variants in African-American women.
Authors: Long J, Zhang B, Signorello LB, Cai Q, Deming-Halverson S, Shrubsole MJ, Sanderson M, Dennis J, Michailiou K, Easton DF, Shu XO, Blot WJ, Zheng W
Source: PLoS One, 2013;8(4), p. e58350.
EPub date: 2013 Apr 8.
PMID: 23593120
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