Skip Navigation
Grant Details

Grant Number: 5U19CA148065-04 Interpret this number
Primary Investigator: Hunter, David
Organization: Harvard School Of Public Health
Project Title: Discovery, Biology and Risk of Inherited Variants in Breast Cancer
Fiscal Year: 2013
Back to top


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.

Back to top


Publications

Postmenopausal hormone therapy and the risks of coronary heart disease, breast cancer, and stroke.
Authors: Prentice RL
Source: Semin Reprod Med, 2014 Nov;32(6), p. 419-25.
EPub date: 2014 Oct 16.
PMID: 25321418
Related Citations

Back to top


Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.
Authors: Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, Shi J, Long J, Wen W, Choi JY, Noh DY, Shen CY, Matsuo K, Teo SH, Kim MK, Khoo US, Iwasaki M, Hartman M, Takahashi A, Ashikawa K, Matsuda K, Shin MH, Park MH, Zheng Y, Xiang YB, Ji BT, Park SK, Wu PE, Hsiung CN, Ito H, Kasuga Y, Kang P, Mariapun S, Ahn SH, Kang HS, Chan KY, Man EP, Iwata H, Tsugane S, Miao H, Liao J, Nakamura Y, Kubo M, DRIVE GAME-ON Consortium, Delahanty RJ, Zhang Y, Li B, Li C, Gao YT, Shu XO, Kang D, Zheng W
Source: Nat Genet, 2014 Aug;46(8), p. 886-90.
EPub date: 2014 Jul 20.
PMID: 25038754
Related Citations

Back to top


Enhancing reproducibility in cancer drug screening: how do we move forward?
Authors: Hatzis C, Bedard PL, Birkbak NJ, Beck AH, Aerts HJ, Stem DF, Shi L, Clarke R, Quackenbush J, Haibe-Kains B
Source: Cancer Res, 2014 Aug 1;74(15), p. 4016-23.
EPub date: 2014 Jul 11.
PMID: 25015668
Related Citations

Back to top


2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.
Authors: Li J, Lindström LS, Foo JN, Rafiq S, Schmidt MK, Pharoah PD, Michailidou K, Dennis J, Bolla MK, Wang Q, Van 't Veer LJ, Cornelissen S, Rutgers E, Southey MC, Apicella C, Dite GS, Hopper JL, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Blomqvist C, Muranen TA, Aittomäki K, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Hartikainen JM, Kataja V, Chenevix-Trench G, kConFab Investigators, Phillips KA, McLachlan SA, Lambrechts D, Thienpont B, Smeets A, Wildiers H, Chang-Claude J, Flesch-Janys D, Seibold P, Rudolph A, Giles GG, Baglietto L, Severi G, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Kristensen V, Alnæs GI, Borresen-Dale AL, Nord S, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Devilee P, Tollenaar R, Seynaeve C, Hooning M, Kriege M, Hollestelle A, van den Ouweland A, Li Y, Hamann U, Torres D, Ulmer HU, Rüdiger T, Shen CY, Hsiung CN, Wu PE, Chen ST, Teo SH, Taib NA, Har Yip C, Fuang Ho G, Matsuo K, Ito H, Iwata H, Tajima K, Kang D, Choi JY, Park SK, Yoo KY, Maishman T, Tapper WJ, Dunning A, Shah M, Luben R, Brown J, Khor CC, Eccles DM, Nevanlinna H, Easton D, Humphreys K, Liu J, Hall P, Czene K
Source: Nat Commun, 2014 Jun 17;5, p. 4051.
EPub date: 2014 Jun 17.
PMID: 24937182
Related Citations

Back to top


Expression QTL-based analyses reveal candidate causal genes and loci across five tumor types.
Authors: Li Q, Stram A, Chen C, Kar S, Gayther S, Pharoah P, Haiman C, Stranger B, Kraft P, Freedman ML
Source: Hum Mol Genet, 2014 Oct 1;23(19), p. 5294-302.
EPub date: 2014 Jun 6.
PMID: 24907074
Related Citations

Back to top


Post-GWAS gene-environment interplay in breast cancer: results from the Breast and Prostate Cancer Cohort Consortium and a meta-analysis on 79,000 women.
Authors: Barrdahl M, Canzian F, Joshi AD, Travis RC, Chang-Claude J, Auer PL, Gapstur SM, Gaudet M, Diver WR, Henderson BE, Haiman CA, Schumacher FR, Le Marchand L, Berg CD, Chanock SJ, Hoover RN, Rudolph A, Ziegler RG, Giles GG, Baglietto L, Severi G, Hankinson SE, Lindström S, Willet W, Hunter DJ, Buring JE, Lee IM, Zhang S, Dossus L, Cox DG, Khaw KT, Lund E, Naccarati A, Peeters PH, Quirós JR, Riboli E, Sund M, Trichopoulos D, Prentice RL, Kraft P, Kaaks R, Campa D
Source: Hum Mol Genet, 2014 Oct 1;23(19), p. 5260-70.
EPub date: 2014 May 8.
PMID: 24895409
Related Citations

Back to top


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
Related Citations

Back to top


A comprehensive examination of breast cancer risk loci in African American women.
Authors: Feng Y, Stram DO, Rhie SK, Millikan RC, Ambrosone CB, John EM, Bernstein L, Zheng W, Olshan AF, Hu JJ, Ziegler RG, Nyante S, Bandera EV, Ingles SA, Press MF, Deming SL, Rodriguez-Gil JL, Palmer JR, Olopade OI, Huo D, Adebamowo CA, Ogundiran T, Chen GK, Stram A, Park K, Rand KA, Chanock SJ, Le Marchand L, Kolonel LN, Conti DV, Easton D, Henderson BE, Haiman CA
Source: Hum Mol Genet, 2014 Oct 15;23(20), p. 5518-26.
EPub date: 2014 May 22.
PMID: 24852375
Related Citations

Back to top


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
Related Citations

Back to top


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
Related Citations

Back to top


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
Related Citations

Back to top


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
Related Citations

Back to top


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, Alnæs GG, Kristensen V, Børresen-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
Related Citations