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Cell. 2018 Apr 5;173(2):386-399.e12. doi: 10.1016/j.cell.2018.03.027.

A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples.

Collaborators (725)

Caesar-Johnson SJ, Demchok JA, Felau I, Kasapi M, Ferguson ML, Hutter CM, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang JJ, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Cho J, DeFreitas T, Frazer S, Gehlenborg N, Getz G, Heiman DI, Kim J, Lawrence MS, Lin P, Meier S, Noble MS, Saksena G, Voet D, Zhang H, Bernard B, Chambwe N, Dhankani V, Knijnenburg T, Kramer R, Leinonen K, Liu Y, Miller M, Reynolds S, Shmulevich I, Thorsson V, Zhang W, Akbani R, Broom BM, Hegde AM, Ju Z, Kanchi RS, Korkut A, Li J, Liang H, Ling S, Liu W, Lu Y, Mills GB, Ng KS, Rao A, Ryan M, Wang J, Weinstein JN, Zhang J, Abeshouse A, Armenia J, Chakravarty D, Chatila WK, de Bruijn I, Gao J, Gross BE, Heins ZJ, Kundra R, La K, Ladanyi M, Luna A, Nissan MG, Ochoa A, Phillips SM, Reznik E, Sanchez-Vega F, Sander C, Schultz N, Sheridan R, Sumer SO, Sun Y, Taylor BS, Wang J, Zhang H, Anur P, Peto M, Spellman P, Benz C, Stuart JM, Wong CK, Yau C, Hayes DN, Parker JS, Wilkerson MD, Ally A, Balasundaram M, Bowlby R, Brooks D, Carlsen R, Chuah E, Dhalla N, Holt R, Jones SJM, Kasaian K, Lee D, Ma Y, Marra MA, Mayo M, Moore RA, Mungall AJ, Mungall K, Robertson AG, Sadeghi S, Schein JE, Sipahimalani P, Tam A, Thiessen N, Tse K, Wong T, Berger AC, Beroukhim R, Cherniack AD, Cibulskis C, Gabriel SB, Gao GF, Ha G, Meyerson M, Schumacher SE, Shih J, Kucherlapati MH, Kucherlapati RS, Baylin S, Cope L, Danilova L, Bootwalla MS, Lai PH, Maglinte DT, Van Den Berg DJ, Weisenberger DJ, Auman JT, Balu S, Bodenheimer T, Fan C, Hoadley KA, Hoyle AP, Jefferys SR, Jones CD, Meng S, Mieczkowski PA, Mose LE, Perou AH, Perou CM, Roach J, Shi Y, Simons JV, Skelly T, Soloway MG, Tan D, Veluvolu U, Fan H, Hinoue T, Laird PW, Shen H, Zhou W, Bellair M, Chang K, Covington K, Creighton CJ, Dinh H, Doddapaneni H, Donehower LA, Drummond J, Gibbs RA, Glenn R, Hale W, Han Y, Hu J, Korchina V, Lee S, Lewis L, Li W, Liu X, Morgan M, Morton D, Muzny D, Santibanez J, Sheth M, Shinbrot E, Wang L, Wang M, Wheeler DA, Xi L, Zhao F, Hess J, Appelbaum EL, Bailey M, Cordes MG, Ding L, Fronick CC, Fulton LA, Fulton RS, Kandoth C, Mardis ER, McLellan MD, Miller CA, Schmidt HK, Wilson RK, Crain D, Curley E, Gardner J, Lau K, Mallery D, Morris S, Paulauskis J, Penny R, Shelton C, Shelton T, Sherman M, Thompson E, Yena P, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Wise L, Zmuda E, Corcoran N, Costello T, Hovens C, Carvalho AL, de Carvalho AC, Fregnani JH, Longatto-Filho A, Reis RM, Scapulatempo-Neto C, Silveira HCS, Vidal DO, Burnette A, Eschbacher J, Hermes B, Noss A, Singh R, Anderson ML, Castro PD, Ittmann M, Huntsman D, Kohl B, Le X, Thorp R, Andry C, Duffy ER, Lyadov V, Paklina O, Setdikova G, Shabunin A, Tavobilov M, McPherson C, Warnick R, Berkowitz R, Cramer D, Feltmate C, Horowitz N, Kibel A, Muto M, Raut CP, Malykh A, Barnholtz-Sloan JS, Barrett W, Devine K, Fulop J, Ostrom QT, Shimmel K, Wolinsky Y, Sloan AE, De Rose A, Giuliante F, Goodman M, Karlan BY, Hagedorn CH, Eckman J, Harr J, Myers J, Tucker K, Zach LA, Deyarmin B, Hu H, Kvecher L, Larson C, Mural RJ, Somiari S, Vicha A, Zelinka T, Bennett J, Iacocca M, Rabeno B, Swanson P, Latour M, Lacombe L, Têtu B, Bergeron A, McGraw M, Staugaitis SM, Chabot J, Hibshoosh H, Sepulveda A, Su T, Wang T, Potapova O, Voronina O, Desjardins L, Mariani O, Roman-Roman S, Sastre X, Stern MH, Cheng F, Signoretti S, Berchuck A, Bigner D, Lipp E, Marks J, McCall S, McLendon R, Secord A, Sharp A, Behera M, Brat DJ, Chen A, Delman K, Force S, Khuri F, Magliocca K, Maithel S, Olson JJ, Owonikoko T, Pickens A, Ramalingam S, Shin DM, Sica G, Van Meir EG, Zhang H, Eijckenboom W, Gillis A, Korpershoek E, Looijenga L, Oosterhuis W, Stoop H, van Kessel KE, Zwarthoff EC, Calatozzolo C, Cuppini L, Cuzzubbo S, DiMeco F, Finocchiaro G, Mattei L, Perin A, Pollo B, Chen C, Houck J, Lohavanichbutr P, Hartmann A, Stoehr C, Stoehr R, Taubert H, Wach S, Wullich B, Kycler W, Murawa D, Wiznerowicz M, Chung K, Edenfield WJ, Martin J, Baudin E, Bubley G, Bueno R, De Rienzo A, Richards WG, Kalkanis S, Mikkelsen T, Noushmehr H, Scarpace L, Girard N, Aymerich M, Campo E, Giné E, Guillermo AL, Van Bang N, Hanh PT, Phu BD, Tang Y, Colman H, Evason K, Dottino PR, Martignetti JA, Gabra H, Juhl H, Akeredolu T, Stepa S, Hoon D, Ahn K, Kang KJ, Beuschlein F, Breggia A, Birrer M, Bell D, Borad M, Bryce AH, Castle E, Chandan V, Cheville J, Copland JA, Farnell M, Flotte T, Giama N, Ho T, Kendrick M, Kocher JP, Kopp K, Moser C, Nagorney D, O'Brien D, O'Neill BP, Patel T, Petersen G, Que F, Rivera M, Roberts L, Smallridge R, Smyrk T, Stanton M, Thompson RH, Torbenson M, Yang JD, Zhang L, Brimo F, Ajani JA, Gonzalez AMA, Behrens C, Bondaruk J, Broaddus R, Czerniak B, Esmaeli B, Fujimoto J, Gershenwald J, Guo C, Lazar AJ, Logothetis C, Meric-Bernstam F, Moran C, Ramondetta L, Rice D, Sood A, Tamboli P, Thompson T, Troncoso P, Tsao A, Wistuba I, Carter C, Haydu L, Hersey P, Jakrot V, Kakavand H, Kefford R, Lee K, Long G, Mann G, Quinn M, Saw R, Scolyer R, Shannon K, Spillane A, Stretch J, Synott M, Thompson J, Wilmott J, Al-Ahmadie H, Chan TA, Ghossein R, Gopalan A, Levine DA, Reuter V, Singer S, Singh B, Tien NV, Broudy T, Mirsaidi C, Nair P, Drwiega P, Miller J, Smith J, Zaren H, Park JW, Hung NP, Kebebew E, Linehan WM, Metwalli AR, Pacak K, Pinto PA, Schiffman M, Schmidt LS, Vocke CD, Wentzensen N, Worrell R, Yang H, Moncrieff M, Goparaju C, Melamed J, Pass H, Botnariuc N, Caraman I, Cernat M, Chemencedji I, Clipca A, Doruc S, Gorincioi G, Mura S, Pirtac M, Stancul I, Tcaciuc D, Albert M, Alexopoulou I, Arnaout A, Bartlett J, Engel J, Gilbert S, Parfitt J, Sekhon H, Thomas G, Rassl DM, Rintoul RC, Bifulco C, Tamakawa R, Urba W, Hayward N, Timmers H, Antenucci A, Facciolo F, Grazi G, Marino M, Merola R, de Krijger R, Gimenez-Roqueplo AP, Piché A, Chevalier S, McKercher G, Birsoy K, Barnett G, Brewer C, Farver C, Naska T, Pennell NA, Raymond D, Schilero C, Smolenski K, Williams F, Morrison C, Borgia JA, Liptay MJ, Pool M, Seder CW, Junker K, Omberg L, Dinkin M, Manikhas G, Alvaro D, Bragazzi MC, Cardinale V, Carpino G, Gaudio E, Chesla D, Cottingham S, Dubina M, Moiseenko F, Dhanasekaran R, Becker KF, Janssen KP, Slotta-Huspenina J, Abdel-Rahman MH, Aziz D, Bell S, Cebulla CM, Davis A, Duell R, Elder JB, Hilty J, Kumar B, Lang J, Lehman NL, Mandt R, Nguyen P, Pilarski R, Rai K, Schoenfield L, Senecal K, Wakely P, Hansen P, Lechan R, Powers J, Tischler A, Grizzle WE, Sexton KC, Kastl A, Henderson J, Porten S, Waldmann J, Fassnacht M, Asa SL, Schadendorf D, Couce M, Graefen M, Huland H, Sauter G, Schlomm T, Simon R, Tennstedt P, Olabode O, Nelson M, Bathe O, Carroll PR, Chan JM, Disaia P, Glenn P, Kelley RK, Landen CN, Phillips J, Prados M, Simko J, Smith-McCune K, VandenBerg S, Roggin K, Fehrenbach A, Kendler A, Sifri S, Steele R, Jimeno A, Carey F, Forgie I, Mannelli M, Carney M, Hernandez B, Campos B, Herold-Mende C, Jungk C, Unterberg A, von Deimling A, Bossler A, Galbraith J, Jacobus L, Knudson M, Knutson T, Ma D, Milhem M, Sigmund R, Godwin AK, Madan R, Rosenthal HG, Adebamowo C, Adebamowo SN, Boussioutas A, Beer D, Giordano T, Mes-Masson AM, Saad F, Bocklage T, Landrum L, Mannel R, Moore K, Moxley K, Postier R, Walker J, Zuna R, Feldman M, Valdivieso F, Dhir R, Luketich J, Pinero EMM, Quintero-Aguilo M, Carlotti CG Jr, Dos Santos JS, Kemp R, Sankarankuty A, Tirapelli D, Catto J, Agnew K, Swisher E, Creaney J, Robinson B, Shelley CS, Godwin EM, Kendall S, Shipman C, Bradford C, Carey T, Haddad A, Moyer J, Peterson L, Prince M, Rozek L, Wolf G, Bowman R, Fong KM, Yang I, Korst R, Rathmell WK, Fantacone-Campbell JL, Hooke JA, Kovatich AJ, Shriver CD, DiPersio J, Drake B, Govindan R, Heath S, Ley T, Van Tine B, Westervelt P, Rubin MA, Lee JI, Aredes ND, Mariamidze A.

Abstract

The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on "chromatin-state" to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.

KEYWORDS:

PD-L1 expression; The Cancer Genome Atlas; aneuploidy; chromatin state; enhancer expression; mutation burden; pan-cancer analysis; prognostic markers

PMID:
29625054
PMCID:
PMC5890960
[Available on 2019-04-05]
DOI:
10.1016/j.cell.2018.03.027
[Indexed for MEDLINE]
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