Integrative eQTL-Based Analyses Reveal the Biology of Breast Cancer Risk Loci

被引：264

作者：

Li, Qiyuan ^{[1
,2
,4
]}

Seo, Ji-Heui ^{[1
,2
]}

Stranger, Barbara ^{[6
,7
]}

McKenna, Aaron ^{[5
,8
]}

Pe'er, Itsik ^{[9
]}

LaFramboise, Thomas ^{[10
]}

Brown, Myles ^{[1
]}

Tyekucheva, Svitlana ^{[3
,11
]}

Freedman, Matthew L. ^{[1
,2
,4
]}

机构：

[1] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Dept Med Oncol, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA

[3] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA

[4] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[5] Broad Inst, Canc Program, Cambridge, MA 02142 USA

[6] Harvard Univ, Div Genet, Dept Med, Sch Med, Boston, MA 02115 USA

[7] Brigham & Womens Hosp, Boston, MA 02115 USA

[8] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[9] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA

[10] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA

[11] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA

来源：

CELL | 2013年 / 152卷 / 03期

基金：

美国国家卫生研究院;

关键词：

ALLELIC EXPRESSION IMBALANCE; LONG-RANGE INTERACTION; GENOME-WIDE ANALYSIS; GENE-EXPRESSION; FGFR2; EXPRESSION; CIS; CELLS; GROWTH; MYC; IDENTIFICATION;

D O I：

10.1016/j.cell.2012.12.034

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Germline determinants of gene expression in tumors are infrequently studied due to the complexity of transcript regulation caused by somatically acquired alterations. We performed expression quantitative trait locus (eQTL)-based analyses using the multi-level information provided in The Cancer Genome Atlas (TCGA). Of the factors we measured, cis-acting eQTLs accounted for 1.2% of the total variation of tumor gene expression, while somatic copy-number alteration and CpG methylation accounted for 7.3% and 3.3%, respectively. eQTL analyses of 15 previously reported breast cancer risk loci resulted in the discovery of three variants that are significantly associated with transcript levels (false discovery rate [FDR] < 0.1). Our trans-based analysis identified an additional three risk loci to act through ESR1, MYC, and KLF4. These findings provide a more comprehensive picture of gene expression determinants in breast cancer as well as insights into the underlying biology of breast cancer risk loci.

引用

页码：633 / 641

页数：9

共 47 条

[1]

8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC [J].

Ahmadiyeh, Nasim ;

Pomerantz, Mark M. ;

Grisanzio, Chiara ;

Herman, Paula ;

Jia, Li ;

Almendro, Vanessa ;

He, Housheng Hansen ;

Brown, Myles ;

Liu, X. Shirley ;

Davis, Matt ;

Caswell, Jennifer L. ;

Beckwith, Christine A. ;

Hills, Adam ;

MacConaill, Laura ;

Coetzee, Gerhard A. ;

Regan, Meredith M. ;

Freedman, Matthew L. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (21) :9742-9746

[2]

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα [J].

Akaogi, K. ;

Nakajima, Y. ;

Ito, I. ;

Kawasaki, S. ;

Oie, S-H ;

Murayama, A. ;

Kimura, K. ;

Yanagisawa, J. .

ONCOGENE, 2009, 28 (32) :2894-2902

[3]

Genetic validation of whole-transcriptome sequencing for mapping expression affected by cis-regulatory variation [J].

Babak, Tomas ;

Garrett-Engele, Philip ;

Armour, Christopher D. ;

Raymond, Christopher K. ;

Keller, Mark P. ;

Chen, Ronghua ;

Rohl, Carol A. ;

Johnson, Jason M. ;

Attie, Alan D. ;

Fraser, Hunter B. ;

Schadt, Eric E. .

BMC GENOMICS, 2010, 11

[4]

IGFBP Ratio Confers Resistance to IGF Targeting and Correlates with Increased Invasion and Poor Outcome in Breast Tumors [J].

Becker, Marc A. ;

Hou, Xiaonan ;

Harrington, Sean C. ;

Weroha, S. John ;

Gonzalez, Sergio E. ;

Jacob, Kristina A. ;

Carboni, Joan M. ;

Gottardis, Marco M. ;

Haluska, Paul .

CLINICAL CANCER RESEARCH, 2012, 18 (06) :1808-1817

[5]

Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project [J].

Birney, Ewan ;

Stamatoyannopoulos, John A. ;

Dutta, Anindya ;

Guigo, Roderic ;

Gingeras, Thomas R. ;

Margulies, Elliott H. ;

Weng, Zhiping ;

Snyder, Michael ;

Dermitzakis, Emmanouil T. ;

Stamatoyannopoulos, John A. ;

Thurman, Robert E. ;

Kuehn, Michael S. ;

Taylor, Christopher M. ;

Neph, Shane ;

Koch, Christoph M. ;

Asthana, Saurabh ;

Malhotra, Ankit ;

Adzhubei, Ivan ;

Greenbaum, Jason A. ;

Andrews, Robert M. ;

Flicek, Paul ;

Boyle, Patrick J. ;

Cao, Hua ;

Carter, Nigel P. ;

Clelland, Gayle K. ;

Davis, Sean ;

Day, Nathan ;

Dhami, Pawandeep ;

Dillon, Shane C. ;

Dorschner, Michael O. ;

Fiegler, Heike ;

Giresi, Paul G. ;

Goldy, Jeff ;

Hawrylycz, Michael ;

Haydock, Andrew ;

Humbert, Richard ;

James, Keith D. ;

Johnson, Brett E. ;

Johnson, Ericka M. ;

Frum, Tristan T. ;

Rosenzweig, Elizabeth R. ;

Karnani, Neerja ;

Lee, Kirsten ;

Lefebvre, Gregory C. ;

Navas, Patrick A. ;

Neri, Fidencio ;

Parker, Stephen C. J. ;

Sabo, Peter J. ;

Sandstrom, Richard ;

Shafer, Anthony .

NATURE, 2007, 447 (7146) :799-816

[6]

Insulin-like growth factor-binding protein-5 inhibits the growth of human breast cancer cells in vitro and in vivo [J].

Butt, AJ ;

Dickson, KA ;

McDougall, F ;

Baxter, RC .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (32) :29676-29685

[7]

Validating Discovered Cis-Acting Regulatory Genetic Variants: Application of an Allele Specific Expression Approach to HapMap Populations [J].

Campino, Susana ;

Forton, Julian ;

Raj, Srilakshmi ;

Mohr, Bert ;

Auburn, Sarah ;

Fry, Andrew ;

Mangano, Valentina D. ;

Vandiedonck, Claire ;

Richardson, Anna ;

Rockett, Kirk ;

Clark, Taane G. ;

Kwiatkowski, Dominic P. .

PLOS ONE, 2008, 3 (12)

[8]

Genome-wide analysis of estrogen receptor binding sites [J].

Carroll, Jason S. ;

Meyer, Clifford A. ;

Song, Jun ;

Li, Wei ;

Geistlinger, Timothy R. ;

Eeckhoute, Jerome ;

Brodsky, Alexander S. ;

Keeton, Erika Krasnickas ;

Fertuck, Kirsten C. ;

Hall, Giles F. ;

Wang, Qianben ;

Bekiranov, Stefan ;

Sementchenko, Victor ;

Fox, Edward A. ;

Silver, Pamela A. ;

Gingeras, Thomas R. ;

Liu, X. Shirley ;

Brown, Myles .

NATURE GENETICS, 2006, 38 (11) :1289-1297

[9]

Natural variation in human gene expression assessed in lymphoblastoid cells [J].

Cheung, VG ;

Conlin, LK ;

Weber, TM ;

Arcaro, M ;

Jen, KY ;

Morley, M ;

Spielman, RS .

NATURE GENETICS, 2003, 33 (03) :422-425

[10]

Mapping complex disease traits with global gene expression [J].

Cookson, William ;

Liang, Liming ;

Abecasis, Goncalo ;

Moffatt, Miriam ;

Lathrop, Mark .

NATURE REVIEWS GENETICS, 2009, 10 (03) :184-194

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