Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias

被引：292

作者：

Dunford, Andrew ^{[1
]}

Weinstock, David M. ^{[1
,2
]}

Savova, Virginia ^{[3
,4
]}

Schumacher, Steven E. ^{[1
,3
]}

Cleary, John P. ^{[2
]}

Yoda, Akinori ^{[2
]}

Sullivan, Timothy J. ^{[1
]}

Hess, Julian M. ^{[1
]}

Gimelbrant, Alexander A. ^{[1
,3
,4
]}

Beroukhim, Rameen ^{[1
,2
,3
]}

Lawrence, Michael S. ^{[5
,6
]}

Getz, Gad ^{[1
,5
,6
]}

Lane, Andrew A. ^{[1
,2
]}

机构：

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

[2] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Harvard Med Sch, Dept Genet, Boston, MA USA

[5] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA

[6] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

来源：

NATURE GENETICS | 2017年 / 49卷 / 01期

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; H3K27ME3 DEMETHYLASE UTX; CHROMOSOME INACTIVATION; Y-CHROMOSOME; SOMATIC MUTATIONS; MOSAIC LOSS; EXPRESSION; DISPARITIES; DISORDERS; EVOLUTION;

D O I：

10.1038/ng.3726

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

There is a striking and unexplained male predominance across many cancer types. A subset of X-chromosome genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative 'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males (based on a false discovery rate < 0.1), in comparison to zero of 18,055 autosomal and PAR genes (Fisher's exact P < 0.0001). Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.

引用

页码：10 / 16

页数：7

共 50 条

[1] A cross-species comparison of escape from X inactivation in Eutheria: implications for evolution of X chromosome inactivation [J].

Al Nadaf, Shafagh ;

Deakin, Janine E. ;

Gilbert, Clement ;

Robinson, Terence J. ;

Graves, Jennifer A. M. ;

Waters, Paul D. .

CHROMOSOMA, 2012, 121 (01) :71-78

[2] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[3] RBM5, 6, and 10 Differentially Regulate NUMB Alternative Splicing to Control Cancer Cell Proliferation [J].

Bechara, Elias G. ;

Sebestyen, Endre ;

Bernardis, Isabella ;

Eyras, Eduardo ;

Valcarcel, Juan .

MOLECULAR CELL, 2013, 52 (05) :720-733

[4] Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators [J].

Bellott, Daniel W. ;

Hughes, Jennifer F. ;

Skaletsky, Helen ;

Brown, Laura G. ;

Pyntikova, Tatyana ;

Cho, Ting-Jan ;

Koutseva, Natalia ;

Zaghlul, Sara ;

Graves, Tina ;

Rock, Susie ;

Kremitzki, Colin ;

Fulton, Robert S. ;

Dugan, Shannon ;

Ding, Yan ;

Morton, Donna ;

Khan, Ziad ;

Lewis, Lora ;

Buhay, Christian ;

Wang, Qiaoyan ;

Watt, Jennifer ;

Holder, Michael ;

Lee, Sandy ;

Nazareth, Lynne ;

Rozen, Steve ;

Muzny, Donna M. ;

Warren, Wesley C. ;

Gibbs, Richard A. ;

Wilson, Richard K. ;

Page, David C. .

NATURE, 2014, 508 (7497) :494-+

[5] Escape from X Inactivation Varies in Mouse Tissues [J].

Berletch, Joel B. ;

Ma, Wenxiu ;

Yang, Fan ;

Shendure, Jay ;

Noble, William S. ;

Disteche, Christine M. ;

Deng, Xinxian .

PLOS GENETICS, 2015, 11 (03)

[6] Genes that escape from X inactivation [J].

Berletch, Joel B. ;

Yang, Fan ;

Xu, Jun ;

Carrel, Laura ;

Disteche, Christine M. .

HUMAN GENETICS, 2011, 130 (02) :237-245

[7] Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling [J].

Blok, Lot Snijders ;

Madsen, Erik ;

Juusola, Jane ;

Gilissen, Christian ;

Baralle, Diana ;

Reijnders, Margot R. F. ;

Venselaar, Hanka ;

Helsmoorte, Celine ;

Cho, Megan T. ;

Hoischen, Alexander ;

Vissers, Lisenka E. L. M. ;

Koemans, Tom S. ;

Wissink-Lindhout, Willemijn ;

Eichler, Evan E. ;

Romano, Corrado ;

Van Esch, Hilde ;

Stumpel, Connie ;

Vreeburg, Maaike ;

Smeets, Eric ;

Obemdorff, Karin ;

van Bon, Bregje W. M. ;

Shaw, Marie ;

Gecz, Jozef ;

Haan, Eric ;

Bienek, Melanie ;

Jensen, Corinna ;

Loeys, Bart L. ;

Van Diick, Anke ;

Innes, A. Micheil ;

Racher, Hilary ;

Vermeer, Sascha ;

Di Donato, Nataliya ;

Rump, Andreas ;

Tatton-Brown, Katrina ;

Parker, Michael J. ;

Henderson, Alex ;

Lynch, Sally A. ;

Fryer, Alan ;

Ross, Alison ;

Vasudevan, Pradeep ;

Kini, Usha ;

Newbury-Ecob, Ruth ;

Chandler, Kate ;

Male, Alison ;

Dijkstra, Sybe ;

Schieving, Jolanda ;

Giltay, Jacques ;

Van Gassen, Koen L. I. ;

Schuurs-Hoeijmakers, Janneke ;

Tan, Perciliz L. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2015, 97 (02) :343-352

[8] 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

[9] X-inactivation profile reveals extensive variability in X-linked gene expression in females [J].

Carrel, L ;

Willard, HF .

NATURE, 2005, 434 (7031) :400-404

[10] The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer [J].

Chaligne, Ronan ;

Popova, Tatiana ;

Mendoza-Parra, Marco-Antonio ;

Saleem, Mohamed-Ashick M. ;

Gentien, David ;

Ban, Kristen ;

Piolot, Tristan ;

Leroy, Olivier ;

Mariani, Odette ;

Gronemeyer, Hinrich ;

Vincent-Salomon, Anne ;

Stern, Marc-Henri ;

Heard, Edith .

GENOME RESEARCH, 2015, 25 (04) :488-503

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