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Cell Rep. 2018 Apr 3;23(1):239-254.e6. doi: 10.1016/j.celrep.2018.03.076.

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.

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

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.

KEYWORDS:

DNA damage footprints; DNA damage repair; The Cancer Genome Atlas PanCanAtlas project; epigenetic silencing; integrative statistical analysis; mutational signatures; protein structure analysis; somatic copy-number alterations; somatic mutations

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