Recurrent and functional regulatory mutations in breast cancer

被引：223

作者：

Rheinbay, Esther ^{[1
,2
]}

Parasuraman, Prasanna ^{[2
]}

Grimsby, Jonna ^{[1
]}

Tiao, Grace ^{[1
]}

Engreitz, Jesse M. ^{[1
,3
]}

Kim, Jaegil ^{[1
]}

Lawrence, Michael S. ^{[1
,2
]}

Taylor-Weiner, Amaro ^{[1
]}

Rodriguez-Cuevas, Sergio ^{[4
]}

Rosenberg, Mara ^{[1
]}

Hess, Julian ^{[1
]}

Stewart, Chip ^{[1
]}

Maruvka, Yosef E. ^{[1
,2
]}

Stojanov, Petar ^{[1
]}

Cortes, Maria L. ^{[1
]}

Seepo, Sara ^{[1
]}

Cibulskis, Carrie ^{[1
]}

Tracy, Adam ^{[1
]}

Pugh, Trevor J. ^{[5
,6
]}

Lee, Jesse ^{[2
]}

Zheng, Zongli ^{[2
]}

Ellisen, Leif W. ^{[2
,7
]}

Iafrate, A. John ^{[2
]}

Boehm, Jesse S. ^{[1
]}

Gabriel, Stacey B. ^{[1
]}

Meyerson, Matthew ^{[1
,7
,8
]}

Golub, Todd R. ^{[1
,7
,8
]}

Baselga, Jose ^{[9
]}

Hidalgo-Miranda, Alfredo ^{[10
]}

Shioda, Toshi ^{[2
]}

Bernards, Andre ^{[2
]}

Lander, Eric S. ^{[1
]}

Getz, Gad ^{[1
,2
,7
,11
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02124 USA

[2] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA

[3] MIT, Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[4] Inst Enfermedades Mama FUCAM AC, Mexico City 04980, DF, Mexico

[5] Univ Toronto, Princess Margaret Canc Ctr, Univ Hlth Network, Toronto, ON M5G 1L7, Canada

[6] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada

[7] Harvard Med Sch, Boston, MA 02115 USA

[8] Dana Farber Canc Inst, Boston, MA 02115 USA

[9] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[10] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico

[11] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

来源：

NATURE | 2017年 / 547卷 / 7661期

关键词：

ESTROGEN-RECEPTOR BINDING; TERT PROMOTER MUTATIONS; GENOME-WIDE ANALYSIS; SOMATIC MUTATIONS; LUMINAL SUBTYPE; EXPRESSION; FOXA1; LANDSCAPE; DISCOVERY; PROTEIN;

D O I：

10.1038/nature22992

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.

引用

页码：55 / +

页数：20

共 69 条

[1] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[2] Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations [J].

Araya, Carlos L. ;

Cenik, Can ;

Reuters, Jason A. ;

Kiss, Gert ;

Pande, Vijay S. ;

Snyder, Michael P. ;

Greenleaf, William J. .

NATURE GENETICS, 2016, 48 (02) :117-125

[3] FOXA1 expression in breast cancer - Correlation with luminal subtype A and survival [J].

Badve, Sunil ;

Turbin, Dmitry ;

Thorat, Mangesh A. ;

Morimiya, Akira ;

Nielsen, Torsten O. ;

Perou, Charles M. ;

Dunn, Sandi ;

Huntsman, David G. ;

Nakshatri, Harikrishna .

CLINICAL CANCER RESEARCH, 2007, 13 (15) :4415-4421

[4] Sequence analysis of mutations and translocations across breast cancer subtypes [J].

Banerji, Shantanu ;

Cibulskis, Kristian ;

Rangel-Escareno, Claudia ;

Brown, Kristin K. ;

Carter, Scott L. ;

Frederick, Abbie M. ;

Lawrence, Michael S. ;

Sivachenko, Andrey Y. ;

Sougnez, Carrie ;

Zou, Lihua ;

Cortes, Maria L. ;

Fernandez-Lopez, Juan C. ;

Peng, Shouyong ;

Ardlie, Kristin G. ;

Auclair, Daniel ;

Bautista-Pina, Veronica ;

Duke, Fujiko ;

Francis, Joshua ;

Jung, Joonil ;

Maffuz-Aziz, Antonio ;

Onofrio, Robert C. ;

Parkin, Melissa ;

Pho, Nam H. ;

Quintanar-Jurado, Valeria ;

Ramos, Alex H. ;

Rebollar-Vega, Rosa ;

Rodriguez-Cuevas, Sergio ;

Romero-Cordoba, Sandra L. ;

Schumacher, Steven E. ;

Stransky, Nicolas ;

Thompson, Kristin M. ;

Uribe-Figueroa, Laura ;

Baselga, Jose ;

Beroukhim, Rameen ;

Polyak, Kornelia ;

Sgroi, Dennis C. ;

Richardson, Andrea L. ;

Jimenez-Sanchez, Gerardo ;

Lander, Eric S. ;

Gabriel, Stacey B. ;

Garraway, Levi A. ;

Golub, Todd R. ;

Melendez-Zajgla, Jorge ;

Toker, Alex ;

Getz, Gad ;

Hidalgo-Miranda, Alfredo ;

Meyerson, Matthew .

NATURE, 2012, 486 (7403) :405-409

[5] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[6] Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas [J].

Brat, Daniel J. ;

Verhaak, Roel G. W. ;

Al-dape, Kenneth D. ;

Yung, W. K. Alfred ;

Salama, Sofie R. ;

Cooper, Lee A. D. ;

Rheinbay, Esther ;

Miller, C. Ryan ;

Vitucci, Mark ;

Morozova, Olena ;

Robertson, A. Gordon ;

Noushmehr, Houtan ;

Laird, Peter W. ;

Cherniack, Andrew D. ;

Akbani, Rehan ;

Huse, Jason T. ;

Ciriello, Giovanni ;

Poisson, Laila M. ;

Barnholtz-Sloan, Jill S. ;

Berger, Mitchel S. ;

Brennan, Cameron ;

Colen, Rivka R. ;

Colman, Howard ;

Flanders, Adam E. ;

Giannini, Caterina ;

Grifford, Mia ;

Iavarone, Antonio ;

Jain, Rajan ;

Joseph, Isaac ;

Kim, Jaegil ;

Kasaian, Katayoon ;

Mikkelsen, Tom ;

Murray, Bradley A. ;

O'Neill, Brian Patrick ;

Pachter, Lior ;

Parsons, Donald W. ;

Sougnez, Carrie ;

Sulman, Erik P. ;

Vandenberg, Scott R. ;

Van Meir, Erwin G. ;

von Deimling, Andreas ;

Zhang, Hailei ;

Crain, Daniel ;

Lau, Kevin ;

Mallery, David ;

Morris, Scott ;

Paulauskis, Joseph ;

Penny, Robert ;

Shelton, Troy ;

Sherman, Mark .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (26) :2481-2498

[7] INDEPENDENT BINDING OF THE RETINOBLASTOMA PROTEIN AND P107 TO THE TRANSCRIPTION FACTOR E2F [J].

CAO, L ;

FAHA, B ;

DEMBSKI, M ;

TSAI, LH ;

HARLOW, E ;

DYSON, N .

NATURE, 1992, 355 (6356) :176-179

[8] Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1 [J].

Carroll, JS ;

Liu, XS ;

Brodsky, AS ;

Li, W ;

Meyer, CA ;

Szary, AJ ;

Eeckhoute, J ;

Shao, WL ;

Hestermann, EV ;

Geistlinger, TR ;

Fox, EA ;

Silver, PA ;

Brown, M .

CELL, 2005, 122 (01) :33-43

[9] Absolute quantification of somatic DNA alterations in human cancer [J].

Carter, Scott L. ;

Cibulskis, Kristian ;

Helman, Elena ;

McKenna, Aaron ;

Shen, Hui ;

Zack, Travis ;

Laird, Peter W. ;

Onofrio, Robert C. ;

Winckler, Wendy ;

Weir, Barbara A. ;

Beroukhim, Rameen ;

Pellman, David ;

Levine, Douglas A. ;

Lander, Eric S. ;

Meyerson, Matthew ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2012, 30 (05) :413-+

[10] Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples [J].

Cibulskis, Kristian ;

Lawrence, Michael S. ;

Carter, Scott L. ;

Sivachenko, Andrey ;

Jaffe, David ;

Sougnez, Carrie ;

Gabriel, Stacey ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2013, 31 (03) :213-219

← 1 2 3 4 5 6 7 →