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

Knijnenburg, T.A.; Wang, L.; Zimmermann, M.T.; Chambwe, N.; Gao, G.F.; Cherniack, A.D.; Fan, H.; Shen, H.; Way, G.P.; Greene, C.S.; Liu, Y.; Akbani, R.; Feng, B.; Donehower, L.A.; Miller, C.; Shen, Y.; Karimi, M.; Chen, H.; Kim, P.; Jia, P.; Shinbrot, E.; Zhang, S.; Liu, J.; Hai, H.; Bailey, M.H.; Yau, C.; Wolf, D.; Zhao, Z.; Weinstein, J.N.; Lei, L.; Ding, L.; Mills, G.B.; Laird, P.W.; Wheeler, D.A.; Shmulevich, I.; Monnat, R.J.; Xiao, Y.; Wang, C.; Caesar-Johnson, S.J.; Demchok, J.A.; Felau, I.; Kasapi, M.; Ferguson, M.L.; Hutter, C.M.; Sofia, H.J.; Tarnuzzer, R.; Wang, Z.; Yang, L.; Zenklusen, J.C.; Zhang, J.(.; Chudamani, S.; Liu, J.; Lolla, L.; Naresh, R.; Pihl, T.; Sun, Q.; Wan, Y.; Ye, W.; Cho, J.; Defreitas, T.; Frazer, S.; Gehlenborg, N.; Getz, G.; Heiman, D.I.; Kim, J.; Lawrence, M.S.; Lin, P.; Meier, S.; Noble, M.S.; 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, B.M.; Hegde, A.M.; Zhenlin, J.; Kanchi, R.S.; Korkut, A.; Jun, L.; Liang, H.; Ling, S.; Liu, W.; Yiling, L.; Mills, G.B.; Kwok-Shing, N.; Rao, A.; Ryan, M.; Wang, J.; Weinstein, J.N.; Zhang, J.; Abeshouse, A.; Armenia, J.; Chakravarty, D.; Chatila, W.K.; de Bruijn, I.; Gao, J.; Gross, B.E.; Heins, Z.J.; Kundra, R.; Konnor, L.; Ladanyi, M.; Luna, A.; Nissan, M.G.; Ochoa, A.; Phillips, S.M.; Reznik, E.; Sanchez-Vega, F.; Sander, C.; Schultz, N.; Sheridan, R.; Sumer, S.O.; Sun, Y.; Taylor, B.S.; Wang, J.; Zhang, H.; Anur, P.; Peto, M.; Spellman, P.; Benz, C.; Stuart, J.M.; Wong, C.K.; Yau, C.; Hayes, D.N.; Parker, J.S.; Wilkerson, M.D.; Ally, A.; Balasundaram, M.; Bowlby, R.; Brooks, D.; Carlsen, R.; Chuah, E.; Dhalla, N.; Holt, R.; Jones, S.J.M.; Kasaian, K.; Lee, D.; Yussanne, M.; Marra, M.A.; Mayo, M.; Moore, R.A.; Mungall, A.J.; Mungall, K.; Robertson, A.G.; Sadeghi, S.; Schein, J.E.; Sipahimalani, P.; Tam, A.; Thiessen, N.; Tse, K.; Wong, T.; Berger, A.C.; Beroukhim, R.; Cherniack, A.D.; Cibulskis, C.; Gabriel, S.B.; Gao, G.F.; Gavin, H.; Meyerson, M.; Schumacher, S.E.; Shih, J.; Kucherlapati, M.H.; Kucherlapati, R.S.; Baylin, S.; Cope, L.; Danilova, L.; Bootwalla, M.S.; Lai, P.H.; Maglinte, D.T.; Van Den Berg, D.J.; Weisenberger, D.J.; Auman, J.T.; Balu, S.; Bodenheimer, T.; Fan, C.; Hoadley, K.A.; Hoyle, A.P.; Jefferys, S.R.; Jones, C.D.; Meng, S.; Mieczkowski, P.A.; Mose, L.E.; Perou, A.H.; Perou, C.M.; Roach, J.; Shi, Y.; Simons, J.V.; Skelly, T.; Soloway, M.G.; Tan, D.; Veluvolu, U.; Fan, H.; Hinoue, T.; Laird, P.W.; Shen, H.; Zhou, W.; Bellair, M.; Chang, K.; Covington, K.; Creighton, C.J.; Dinh, H.; Doddapaneni, H.; Donehower, L.A.; Drummond, J.; Gibbs, R.A.; Glenn, R.; Hale, W.; Han, Y.; Jianhong, H.; Korchina, V.; Lee, S.; Lewis, L.; Wei, L.; Liu, X.; Morgan, M.; Morton, D.; Muzny, D.; Santibanez, J.; Sheth, M.; Shinbrot, E.; Wang, L.; Wang, M.; Wheeler, D.A.; Liu, X.; Zhao, F.; Hess, J.; Appelbaum, E.L.; Bailey, M.; Cordes, M.G.; Ding, L.; Fronick, C.C.; Fulton, L.A.; Fulton, R.S.; Kandoth, C.; Mardis, E.R.; Mclellan, M.D.; Miller, C.A.; Schmidt, H.K.; Wilson, R.K.; 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, J.M.; Gerken, M.; Leraas, K.M.; Lichtenberg, T.M.; Ramirez, N.C.; Wise, L.; Zmuda, E.; Corcoran, N.; Costello, T.; Hovens, C.; Carvalho, A.L.; de Carvalho, A.C.; Fregnani, J.H.; Longatto-Filho, A.; Reis, R.M.; Scapulatempo-Neto, C.; Silveira, H.C.S.; Vidal, D.O.; Burnette, A.; Eschbacher, J.; Hermes, B.; Noss, A.; Singh, R.; Anderson, M.L.; Castro, P.D.; Ittmann, M.; Huntsman, D.; Kohl, B.; Xuan, L.; Thorp, R.; Andry, C.; Duffy, E.R.; 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, C.P.; Malykh, A.; Barnholtz-Sloan, J.S.; Barrett, W.; Devine, K.; Fulop, J.; Ostrom, Q.T.; Shimmel, K.; Wolinsky, Y.; Sloan, A.E.; De Rose, A.; Giuliante, F.; Goodman, M.; Karlan, B.Y.; Hagedorn, C.H.; Eckman, J.; Harr, J.; Myers, J.; Tucker, K.; Zach, L.A.; Deyarmin, B.; Hai, H.; Kvecher, L.; Larson, C.; Mural, R.J.; 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, S.M.; Chabot, J.; Hibshoosh, H.; Sepulveda, A.; Tao, S.; Wang, T.; Potapova, O.; Voronina, O.; Desjardins, L.; Mariani, O.; Roman-Roman, S.; Sastre, X.; Stern, M.; Cheng, F.; Signoretti, S.; Berchuck, A.; Bigner, D.; Lipp, E.; Marks, J.; Mccall, S.; Mclendon, R.; Secord, A.; Sharp, A.; Behera, M.; Brat, D.J.; Chen, A.; Delman, K.; Force, S.; Khuri, F.; Magliocca, K.; Maithel, S.; Olson, J.J.; Owonikoko, T.; Pickens, A.; Ramalingam, S.; Shin, D.M.; Sica, G.; Van Meir, E.G.; Zhang, H.; Eijckenboom, W.; Gillis, A.; Korpershoek, E.; Looijenga, L.; Oosterhuis, W.; Stoop, H.; van Kessel, K.E.; Zwarthoff, E.C.; 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, W.J.; Martin, J.; Baudin, E.; Bubley, G.; Bueno, R.; De Rienzo, A.; Richards, W.G.; Kalkanis, S.; Mikkelsen, T.; Noushmehr, H.; Scarpace, L.; Girard, N.; Aymerich, M.; Campo, E.; Giné, E.; Guillermo, A.L.; Van Bang, N.; Hanh, P.T.; Phu, B.D.; Tang, Y.; Colman, H.; Evason, K.; Dottino, P.R.; Martignetti, J.A.; Gabra, H.; Juhl, H.; Akeredolu, T.; Stepa, S.; Hoon, D.; Ahn, K.; Kang, K.J.; Beuschlein, F.; Breggia, A.; Birrer, M.; Bell, D.; Borad, M.; Bryce, A.H.; Castle, E.; Chandan, V.; Cheville, J.; Copland, J.A.; Farnell, M.; Flotte, T.; Giama, N.; Thai, H.; Kendrick, M.; Kocher, J.; Kopp, K.; Moser, C.; Nagorney, D.; O’Brien, D.; O’Neill, B.P.; Patel, T.; Petersen, G.; Que, F.; Rivera, M.; Roberts, L.; Smallridge, R.; Smyrk, T.; Stanton, M.; Thompson, R.H.; Torbenson, M.; Yang, J.D.; Zhang, L.; Brimo, F.; Ajani, J.A.; Gonzalez, A.M.A.; Behrens, C.; Bondaruk, J.; Broaddus, R.; Czerniak, B.; Esmaeli, B.; Fujimoto, J.; Gershenwald, J.; Guo, C.; Lazar, A.J.; 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, T.A.; Ghossein, R.; Gopalan, A.; Levine, D.A.; Reuter, V.; Singer, S.; Singh, B.; Tien, N.V.; Broudy, T.; Mirsaidi, C.; Nair, P.; Drwiega, P.; Miller, J.; Smith, J.; Zaren, H.; Park, J.; Hung, N.P.; Kebebew, E.; Linehan, W.M.; Metwalli, A.R.; Pacak, K.; Pinto, P.A.; Schiffman, M.; Schmidt, L.S.; Vocke, C.D.; 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, D.M.; Rintoul, R.C.; 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, A.; Piché, A.; Chevalier, S.; Mckercher, G.; Birsoy, K.; Barnett, G.; Brewer, C.; Farver, C.; Naska, T.; Pennell, N.A.; Raymond, D.; Schilero, C.; Smolenski, K.; Williams, F.; Morrison, C.; Borgia, J.A.; Liptay, M.J.; Pool, M.; Seder, C.W.; Junker, K.; Omberg, L.; Dinkin, M.; Manikhas, G.; Alvaro, D.; Bragazzi, M.C.; Cardinale, V.; Carpino, G.; Gaudio, E.; Chesla, D.; Cottingham, S.; Dubina, M.; Moiseenko, F.; Dhanasekaran, R.; Becker, K.; Janssen, K.; Slotta-Huspenina, J.; Abdel-Rahman, M.H.; Aziz, D.; Bell, S.; Cebulla, C.M.; Davis, A.; Duell, R.; Elder, J.B.; Hilty, J.; Kumar, B.; Lang, J.; Lehman, N.L.; Mandt, R.; Nguyen, P.; Pilarski, R.; Rai, K.; Schoenfield, L.; Senecal, K.; Wakely, P.; Hansen, P.; Lechan, R.; Powers, J.; Tischler, A.; Grizzle, W.E.; Sexton, K.C.; Kastl, A.; Henderson, J.; Porten, S.; Waldmann, J.; Fassnacht, M.; Asa, S.L.; Schadendorf, D.; Couce, M.; Graefen, M.; Huland, H.; Sauter, G.; Schlomm, T.; Simon, R.; Tennstedt, P.; Olabode, O.; Nelson, M.; Bathe, O.; Carroll, P.R.; Chan, J.M.; Disaia, P.; Glenn, P.; Kelley, R.K.; Landen, C.N.; 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.; Deqin, M.; Milhem, M.; Sigmund, R.; Godwin, A.K.; Madan, R.; Rosenthal, H.G.; Adebamowo, C.; Adebamowo, S.N.; Boussioutas, A.; Beer, D.; Giordano, T.; Mes-Masson, A.; 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, E.M.M.; Quintero-Aguilo, M.; Carlotti, C.G.; Dos Santos, J.S.; Kemp, R.; Sankarankuty, A.; Tirapelli, D.; Catto, J.; Agnew, K.; Swisher, E.; Creaney, J.; Robinson, B.; Shelley, C.S.; Godwin, E.M.; Kendall, S.; Shipman, C.; Bradford, C.; Carey, T.; Haddad, A.; Moyer, J.; Peterson, L.; Prince, M.; Rozek, L.; Wolf, G.; Bowman, R.; Fong, K.M.; Yang, I.; Korst, R.; Rathmell, W.K.; Fantacone-Campbell, J.L.; Hooke, J.A.; Kovatich, A.J.; Shriver, C.D.; Dipersio, J.; Drake, B.; Govindan, R.; Heath, S.; Ley, T.; Van Tine, B.; Westervelt, P.; Rubin, M.A.; Lee, J.I.; Aredes, N.D.; Mariamidze, A.

doi:10.1016/j.celrep.2018.03.076

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. Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores.

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas / T.A. Knijnenburg, L. Wang, M.T. Zimmermann, N. Chambwe, G.F. Gao, A.D. Cherniack, H. Fan, H. Shen, G.P. Way, C.S. Greene, Y. Liu, R. Akbani, B. Feng, L.A. Donehower, C. Miller, Y. Shen, M. Karimi, H. Chen, P. Kim, P. Jia, E. Shinbrot, S. Zhang, J. Liu, H. Hai, M.H. Bailey, C. Yau, D. Wolf, Z. Zhao, J.N. Weinstein, L. Lei, L. Ding, G.B. Mills, P.W. Laird, D.A. Wheeler, I. Shmulevich, R.J. Monnat, Y. Xiao, C. Wang, S.J. Caesar-Johnson, J.A. Demchok, I. Felau, M. Kasapi, M.L. Ferguson, C.M. Hutter, H.J. Sofia, R. Tarnuzzer, Z. Wang, L. Yang, J.C. Zenklusen, J.(. Zhang, S. Chudamani, J. Liu, L. Lolla, R. Naresh, T. Pihl, Q. Sun, Y. Wan, W. Ye, J. Cho, T. Defreitas, S. Frazer, N. Gehlenborg, G. Getz, D.I. Heiman, J. Kim, M.S. Lawrence, P. Lin, S. Meier, M.S. Noble, G. Saksena, D. Voet, H. Zhang, B. Bernard, N. Chambwe, V. Dhankani, T. Knijnenburg, R. Kramer, K. Leinonen, Y. Liu, M. Miller, S. Reynolds, I. Shmulevich, V. Thorsson, W. Zhang, R. Akbani, B.M. Broom, A.M. Hegde, J. Zhenlin, R.S. Kanchi, A. Korkut, L. Jun, H. Liang, S. Ling, W. Liu, L. Yiling, G.B. Mills, N. Kwok-Shing, A. Rao, M. Ryan, J. Wang, J.N. Weinstein, J. Zhang, A. Abeshouse, J. Armenia, D. Chakravarty, W.K. Chatila, I. de Bruijn, J. Gao, B.E. Gross, Z.J. Heins, R. Kundra, L. Konnor, M. Ladanyi, A. Luna, M.G. Nissan, A. Ochoa, S.M. Phillips, E. Reznik, F. Sanchez-Vega, C. Sander, N. Schultz, R. Sheridan, S.O. Sumer, Y. Sun, B.S. Taylor, J. Wang, H. Zhang, P. Anur, M. Peto, P. Spellman, C. Benz, J.M. Stuart, C.K. Wong, C. Yau, D.N. Hayes, J.S. Parker, M.D. Wilkerson, A. Ally, M. Balasundaram, R. Bowlby, D. Brooks, R. Carlsen, E. Chuah, N. Dhalla, R. Holt, S.J.M. Jones, K. Kasaian, D. Lee, M. Yussanne, M.A. Marra, M. Mayo, R.A. Moore, A.J. Mungall, K. Mungall, A.G. Robertson, S. Sadeghi, J.E. Schein, P. Sipahimalani, A. Tam, N. Thiessen, K. Tse, T. Wong, A.C. Berger, R. Beroukhim, A.D. Cherniack, C. Cibulskis, S.B. Gabriel, G.F. Gao, H. Gavin, M. Meyerson, S.E. Schumacher, J. Shih, M.H. Kucherlapati, R.S. Kucherlapati, S. Baylin, L. Cope, L. Danilova, M.S. Bootwalla, P.H. Lai, D.T. Maglinte, D.J. Van Den Berg, D.J. Weisenberger, J.T. Auman, S. Balu, T. Bodenheimer, C. Fan, K.A. Hoadley, A.P. Hoyle, S.R. Jefferys, C.D. Jones, S. Meng, P.A. Mieczkowski, L.E. Mose, A.H. Perou, C.M. Perou, J. Roach, Y. Shi, J.V. Simons, T. Skelly, M.G. Soloway, D. Tan, U. Veluvolu, H. Fan, T. Hinoue, P.W. Laird, H. Shen, W. Zhou, M. Bellair, K. Chang, K. Covington, C.J. Creighton, H. Dinh, H. Doddapaneni, L.A. Donehower, J. Drummond, R.A. Gibbs, R. Glenn, W. Hale, Y. Han, H. Jianhong, V. Korchina, S. Lee, L. Lewis, L. Wei, X. Liu, M. Morgan, D. Morton, D. Muzny, J. Santibanez, M. Sheth, E. Shinbrot, L. Wang, M. Wang, D.A. Wheeler, X. Liu, F. Zhao, J. Hess, E.L. Appelbaum, M. Bailey, M.G. Cordes, L. Ding, C.C. Fronick, L.A. Fulton, R.S. Fulton, C. Kandoth, E.R. Mardis, M.D. Mclellan, C.A. Miller, H.K. Schmidt, R.K. Wilson, D. Crain, E. Curley, J. Gardner, K. Lau, D. Mallery, S. Morris, J. Paulauskis, R. Penny, C. Shelton, T. Shelton, M. Sherman, E. Thompson, P. Yena, J. Bowen, J.M. Gastier-Foster, M. Gerken, K.M. Leraas, T.M. Lichtenberg, N.C. Ramirez, L. Wise, E. Zmuda, N. Corcoran, T. Costello, C. Hovens, A.L. Carvalho, A.C. de Carvalho, J.H. Fregnani, A. Longatto-Filho, R.M. Reis, C. Scapulatempo-Neto, H.C.S. Silveira, D.O. Vidal, A. Burnette, J. Eschbacher, B. Hermes, A. Noss, R. Singh, M.L. Anderson, P.D. Castro, M. Ittmann, D. Huntsman, B. Kohl, L. Xuan, R. Thorp, C. Andry, E.R. Duffy, V. Lyadov, O. Paklina, G. Setdikova, A. Shabunin, M. Tavobilov, C. Mcpherson, R. Warnick, R. Berkowitz, D. Cramer, C. Feltmate, N. Horowitz, A. Kibel, M. Muto, C.P. Raut, A. Malykh, J.S. Barnholtz-Sloan, W. Barrett, K. Devine, J. Fulop, Q.T. Ostrom, K. Shimmel, Y. Wolinsky, A.E. Sloan, A. De Rose, F. Giuliante, M. Goodman, B.Y. Karlan, C.H. Hagedorn, J. Eckman, J. Harr, J. Myers, K. Tucker, L.A. Zach, B. Deyarmin, H. Hai, L. Kvecher, C. Larson, R.J. Mural, S. Somiari, A. Vicha, T. Zelinka, J. Bennett, M. Iacocca, B. Rabeno, P. Swanson, M. Latour, L. Lacombe, B. Têtu, A. Bergeron, M. Mcgraw, S.M. Staugaitis, J. Chabot, H. Hibshoosh, A. Sepulveda, S. Tao, T. Wang, O. Potapova, O. Voronina, L. Desjardins, O. Mariani, S. Roman-Roman, X. Sastre, M. Stern, F. Cheng, S. Signoretti, A. Berchuck, D. Bigner, E. Lipp, J. Marks, S. Mccall, R. Mclendon, A. Secord, A. Sharp, M. Behera, D.J. Brat, A. Chen, K. Delman, S. Force, F. Khuri, K. Magliocca, S. Maithel, J.J. Olson, T. Owonikoko, A. Pickens, S. Ramalingam, D.M. Shin, G. Sica, E.G. Van Meir, H. Zhang, W. Eijckenboom, A. Gillis, E. Korpershoek, L. Looijenga, W. Oosterhuis, H. Stoop, K.E. van Kessel, E.C. Zwarthoff, C. Calatozzolo, L. Cuppini, S. Cuzzubbo, F. Dimeco, G. Finocchiaro, L. Mattei, A. Perin, B. Pollo, C. Chen, J. Houck, P. Lohavanichbutr, A. Hartmann, C. Stoehr, R. Stoehr, H. Taubert, S. Wach, B. Wullich, W. Kycler, D. Murawa, M. Wiznerowicz, K. Chung, W.J. Edenfield, J. Martin, E. Baudin, G. Bubley, R. Bueno, A. De Rienzo, W.G. Richards, S. Kalkanis, T. Mikkelsen, H. Noushmehr, L. Scarpace, N. Girard, M. Aymerich, E. Campo, E. Giné, A.L. Guillermo, N. Van Bang, P.T. Hanh, B.D. Phu, Y. Tang, H. Colman, K. Evason, P.R. Dottino, J.A. Martignetti, H. Gabra, H. Juhl, T. Akeredolu, S. Stepa, D. Hoon, K. Ahn, K.J. Kang, F. Beuschlein, A. Breggia, M. Birrer, D. Bell, M. Borad, A.H. Bryce, E. Castle, V. Chandan, J. Cheville, J.A. Copland, M. Farnell, T. Flotte, N. Giama, H. Thai, M. Kendrick, J. Kocher, K. Kopp, C. Moser, D. Nagorney, D. O’Brien, B.P. O’Neill, T. Patel, G. Petersen, F. Que, M. Rivera, L. Roberts, R. Smallridge, T. Smyrk, M. Stanton, R.H. Thompson, M. Torbenson, J.D. Yang, L. Zhang, F. Brimo, J.A. Ajani, A.M.A. Gonzalez, C. Behrens, J. Bondaruk, R. Broaddus, B. Czerniak, B. Esmaeli, J. Fujimoto, J. Gershenwald, C. Guo, A.J. Lazar, C. Logothetis, F. Meric-Bernstam, C. Moran, L. Ramondetta, D. Rice, A. Sood, P. Tamboli, T. Thompson, P. Troncoso, A. Tsao, I. Wistuba, C. Carter, L. Haydu, P. Hersey, V. Jakrot, H. Kakavand, R. Kefford, K. Lee, G. Long, G. Mann, M. Quinn, R. Saw, R. Scolyer, K. Shannon, A. Spillane, J. Stretch, M. Synott, J. Thompson, J. Wilmott, H. Al-Ahmadie, T.A. Chan, R. Ghossein, A. Gopalan, D.A. Levine, V. Reuter, S. Singer, B. Singh, N.V. Tien, T. Broudy, C. Mirsaidi, P. Nair, P. Drwiega, J. Miller, J. Smith, H. Zaren, J. Park, N.P. Hung, E. Kebebew, W.M. Linehan, A.R. Metwalli, K. Pacak, P.A. Pinto, M. Schiffman, L.S. Schmidt, C.D. Vocke, N. Wentzensen, R. Worrell, H. Yang, M. Moncrieff, C. Goparaju, J. Melamed, H. Pass, N. Botnariuc, I. Caraman, M. Cernat, I. Chemencedji, A. Clipca, S. Doruc, G. Gorincioi, S. Mura, M. Pirtac, I. Stancul, D. Tcaciuc, M. Albert, I. Alexopoulou, A. Arnaout, J. Bartlett, J. Engel, S. Gilbert, J. Parfitt, H. Sekhon, G. Thomas, D.M. Rassl, R.C. Rintoul, C. Bifulco, R. Tamakawa, W. Urba, N. Hayward, H. Timmers, A. Antenucci, F. Facciolo, G. Grazi, M. Marino, R. Merola, R. de Krijger, A. Gimenez-Roqueplo, A. Piché, S. Chevalier, G. Mckercher, K. Birsoy, G. Barnett, C. Brewer, C. Farver, T. Naska, N.A. Pennell, D. Raymond, C. Schilero, K. Smolenski, F. Williams, C. Morrison, J.A. Borgia, M.J. Liptay, M. Pool, C.W. Seder, K. Junker, L. Omberg, M. Dinkin, G. Manikhas, D. Alvaro, M.C. Bragazzi, V. Cardinale, G. Carpino, E. Gaudio, D. Chesla, S. Cottingham, M. Dubina, F. Moiseenko, R. Dhanasekaran, K. Becker, K. Janssen, J. Slotta-Huspenina, M.H. Abdel-Rahman, D. Aziz, S. Bell, C.M. Cebulla, A. Davis, R. Duell, J.B. Elder, J. Hilty, B. Kumar, J. Lang, N.L. Lehman, R. Mandt, P. Nguyen, R. Pilarski, K. Rai, L. Schoenfield, K. Senecal, P. Wakely, P. Hansen, R. Lechan, J. Powers, A. Tischler, W.E. Grizzle, K.C. Sexton, A. Kastl, J. Henderson, S. Porten, J. Waldmann, M. Fassnacht, S.L. Asa, D. Schadendorf, M. Couce, M. Graefen, H. Huland, G. Sauter, T. Schlomm, R. Simon, P. Tennstedt, O. 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Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

Knijnenburg, Theo A.;Wang, Linghua;Zimmermann, Michael T.;Chambwe, Nyasha;Gao, Galen F.;Cherniack, Andrew D.;Fan, Huihui;Shen, Hui;Way, Gregory P.;Greene, Casey S.;Liu, Yuexin;Akbani, Rehan;Feng, Bin;Donehower, Lawrence A.;Miller, Chase;Shen, Yang;Karimi, Mostafa;Chen, Haoran;Kim, Pora;Jia, Peilin;Shinbrot, Eve;Zhang, Shaojun;Liu, Jianfang;Hu, Hai;Bailey, Matthew H.;Yau, Christina;Wolf, Denise;Zhao, Zhongming;Weinstein, John N.;Li, Lei;Ding, Li;Mills, Gordon B.;Laird, Peter W.;Wheeler, David A.;Shmulevich, Ilya;Monnat, Raymond J.;Xiao, Yonghong;Wang, Chen;Caesar-Johnson, Samantha J.;Demchok, John A.;Felau, Ina;Kasapi, Melpomeni;Ferguson, Martin L.;Hutter, Carolyn M.;Sofia, Heidi J.;Tarnuzzer, Roy;Wang, Zhining;Yang, Liming;Zenklusen, Jean C.;Zhang, Jiashan (Julia);Chudamani, Sudha;Liu, Jia;Lolla, Laxmi;Naresh, Rashi;Pihl, Todd;Sun, Qiang;Wan, Yunhu;Wu, Ye;Cho, Juok;DeFreitas, Timothy;Frazer, Scott;Gehlenborg, Nils;Getz, Gad;Heiman, David I.;Kim, Jaegil;Lawrence, Michael S.;Lin, Pei;Meier, Sam;Noble, Michael S.;Saksena, Gordon;Voet, Doug;Zhang, Hailei;Bernard, Brady;Chambwe, Nyasha;Dhankani, Varsha;Knijnenburg, Theo;Kramer, Roger;Leinonen, Kalle;Liu, Yuexin;Miller, Michael;Reynolds, Sheila;Shmulevich, Ilya;Thorsson, Vesteinn;Zhang, Wei;Akbani, Rehan;Broom, Bradley M.;Hegde, Apurva M.;Ju, Zhenlin;Kanchi, Rupa S.;Korkut, Anil;Li, Jun;Liang, Han;Ling, Shiyun;Liu, Wenbin;Lu, Yiling;Mills, Gordon B.;Ng, Kwok-Shing;Rao, Arvind;Ryan, Michael;Wang, Jing;Weinstein, John N.;Zhang, Jiexin;Abeshouse, Adam;Armenia, Joshua;Chakravarty, Debyani;Chatila, Walid K.;de Bruijn, Ino;Gao, Jianjiong;Gross, Benjamin E.;Heins, Zachary J.;Kundra, Ritika;La, Konnor;Ladanyi, Marc;Luna, Augustin;Nissan, Moriah G.;Ochoa, Angelica;Phillips, Sarah M.;Reznik, Ed;Sanchez-Vega, Francisco;Sander, Chris;Schultz, Nikolaus;Sheridan, Robert;Sumer, S. Onur;Sun, Yichao;Taylor, Barry S.;Wang, Jioajiao;Zhang, Hongxin;Anur, Pavana;Peto, Myron;Spellman, Paul;Benz, Christopher;Stuart, Joshua M.;Wong, Christopher K.;Yau, Christina;Hayes, D. Neil;Parker, Joel S.;Wilkerson, Matthew D.;Ally, Adrian;Balasundaram, Miruna;Bowlby, Reanne;Brooks, Denise;Carlsen, Rebecca;Chuah, Eric;Dhalla, Noreen;Holt, Robert;Jones, Steven J. M.;Kasaian, Katayoon;Lee, Darlene;Ma, Yussanne;Marra, Marco A.;Mayo, Michael;Moore, Richard A.;Mungall, Andrew J.;Mungall, Karen;Robertson, A. Gordon;Sadeghi, Sara;Schein, Jacqueline E.;Sipahimalani, Payal;Tam, Angela;Thiessen, Nina;Tse, Kane;Wong, Tina;Berger, Ashton C.;Beroukhim, Rameen;Cherniack, Andrew D.;Cibulskis, Carrie;Gabriel, Stacey B.;Gao, Galen F.;Ha, Gavin;Meyerson, Matthew;Schumacher, Steven E.;Shih, Juliann;Kucherlapati, Melanie H.;Kucherlapati, Raju S.;Baylin, Stephen;Cope, Leslie;Danilova, Ludmila;Bootwalla, Moiz S.;Lai, Phillip H.;Maglinte, Dennis T.;Van Den Berg, David J.;Weisenberger, Daniel J.;Auman, J. Todd;Balu, Saianand;Bodenheimer, Tom;Fan, Cheng;Hoadley, Katherine A.;Hoyle, Alan P.;Jefferys, Stuart R.;Jones, Corbin D.;Meng, Shaowu;Mieczkowski, Piotr A.;Mose, Lisle E.;Perou, Amy H.;Perou, Charles M.;Roach, Jeffrey;Shi, Yan;Simons, Janae V.;Skelly, Tara;Soloway, Matthew G.;Tan, Donghui;Veluvolu, Umadevi;Fan, Huihui;Hinoue, Toshinori;Laird, Peter W.;Shen, Hui;Zhou, Wanding;Bellair, Michelle;Chang, Kyle;Covington, Kyle;Creighton, Chad J.;Dinh, Huyen;Doddapaneni, HarshaVardhan;Donehower, Lawrence A.;Drummond, Jennifer;Gibbs, Richard A.;Glenn, Robert;Hale, Walker;Han, Yi;Hu, Jianhong;Korchina, Viktoriya;Lee, Sandra;Lewis, Lora;Li, Wei;Liu, Xiuping;Morgan, Margaret;Morton, Donna;Muzny, Donna;Santibanez, Jireh;Sheth, Margi;Shinbrot, Eve;Wang, Linghua;Wang, Min;Wheeler, David A.;Xi, Liu;Zhao, Fengmei;Hess, Julian;Appelbaum, Elizabeth L.;Bailey, Matthew;Cordes, Matthew G.;Ding, Li;Fronick, Catrina C.;Fulton, Lucinda A.;Fulton, Robert S.;Kandoth, Cyriac;Mardis, Elaine R.;McLellan, Michael D.;Miller, Christopher A.;Schmidt, Heather K.;Wilson, Richard K.;Crain, Daniel;Curley, Erin;Gardner, Johanna;Lau, Kevin;Mallery, David;Morris, Scott;Paulauskis, Joseph;Penny, Robert;Shelton, Candace;Shelton, Troy;Sherman, Mark;Thompson, Eric;Yena, Peggy;Bowen, Jay;Gastier-Foster, Julie M.;Gerken, Mark;Leraas, Kristen M.;Lichtenberg, Tara M.;Ramirez, Nilsa C.;Wise, Lisa;Zmuda, Erik;Corcoran, Niall;Costello, Tony;Hovens, Christopher;Carvalho, Andre L.;de Carvalho, Ana C.;Fregnani, José H.;Longatto-Filho, Adhemar;Reis, Rui M.;Scapulatempo-Neto, Cristovam;Silveira, Henrique C. S.;Vidal, Daniel O.;Burnette, Andrew;Eschbacher, Jennifer;Hermes, Beth;Noss, Ardene;Singh, Rosy;Anderson, Matthew L.;Castro, Patricia D.;Ittmann, Michael;Huntsman, David;Kohl, Bernard;Le, Xuan;Thorp, Richard;Andry, Chris;Duffy, Elizabeth R.;Lyadov, Vladimir;Paklina, Oxana;Setdikova, Galiya;Shabunin, Alexey;Tavobilov, Mikhail;McPherson, Christopher;Warnick, Ronald;Berkowitz, Ross;Cramer, Daniel;Feltmate, Colleen;Horowitz, Neil;Kibel, Adam;Muto, Michael;Raut, Chandrajit P.;Malykh, Andrei;Barnholtz-Sloan, Jill S.;Barrett, Wendi;Devine, Karen;Fulop, Jordonna;Ostrom, Quinn T.;Shimmel, Kristen;Wolinsky, Yingli;Sloan, Andrew E.;De Rose, Agostino;Giuliante, Felice;Goodman, Marc;Karlan, Beth Y.;Hagedorn, Curt H.;Eckman, John;Harr, Jodi;Myers, Jerome;Tucker, Kelinda;Zach, Leigh Anne;Deyarmin, Brenda;Hu, Hai;Kvecher, Leonid;Larson, Caroline;Mural, Richard J.;Somiari, Stella;Vicha, Ales;Zelinka, Tomas;Bennett, Joseph;Iacocca, Mary;Rabeno, Brenda;Swanson, Patricia;Latour, Mathieu;Lacombe, Louis;Têtu, Bernard;Bergeron, Alain;McGraw, Mary;Staugaitis, Susan M.;Chabot, John;Hibshoosh, Hanina;Sepulveda, Antonia;Su, Tao;Wang, Timothy;Potapova, Olga;Voronina, Olga;Desjardins, Laurence;Mariani, Odette;Roman-Roman, Sergio;Sastre, Xavier;Stern, Marc-Henri;Cheng, Feixiong;Signoretti, Sabina;Berchuck, Andrew;Bigner, Darell;Lipp, Eric;Marks, Jeffrey;McCall, Shannon;McLendon, Roger;Secord, Angeles;Sharp, Alexis;Behera, Madhusmita;Brat, Daniel J.;Chen, Amy;Delman, Keith;Force, Seth;Khuri, Fadlo;Magliocca, Kelly;Maithel, Shishir;Olson, Jeffrey J.;Owonikoko, Taofeek;Pickens, Alan;Ramalingam, Suresh;Shin, Dong M.;Sica, Gabriel;Van Meir, Erwin G.;Zhang, Hongzheng;Eijckenboom, Wil;Gillis, Ad;Korpershoek, Esther;Looijenga, Leendert;Oosterhuis, Wolter;Stoop, Hans;van Kessel, Kim E.;Zwarthoff, Ellen C.;Calatozzolo, Chiara;Cuppini, Lucia;Cuzzubbo, Stefania;F. Dimeco^{Membro del Collaboration Group};Finocchiaro, Gaetano;Mattei, Luca;Perin, Alessandro;Pollo, Bianca;Chen, Chu;Houck, John;Lohavanichbutr, Pawadee;Hartmann, Arndt;Stoehr, Christine;Stoehr, Robert;Taubert, Helge;Wach, Sven;Wullich, Bernd;Kycler, Witold;Murawa, Dawid;Wiznerowicz, Maciej;Chung, Ki;Edenfield, W. Jeffrey;Martin, Julie;Baudin, Eric;Bubley, Glenn;Bueno, Raphael;De Rienzo, Assunta;Richards, William G.;Kalkanis, Steven;Mikkelsen, Tom;Noushmehr, Houtan;Scarpace, Lisa;Girard, Nicolas;Aymerich, Marta;Campo, Elias;Giné, Eva;Guillermo, Armando López;Van Bang, Nguyen;Hanh, Phan Thi;Phu, Bui Duc;Tang, Yufang;Colman, Howard;Evason, Kimberley;Dottino, Peter R.;Martignetti, John A.;Gabra, Hani;Juhl, Hartmut;Akeredolu, Teniola;Stepa, Serghei;Hoon, Dave;Ahn, Keunsoo;Kang, Koo Jeong;Beuschlein, Felix;Breggia, Anne;Birrer, Michael;Bell, Debra;Borad, Mitesh;Bryce, Alan H.;Castle, Erik;Chandan, Vishal;Cheville, John;Copland, John A.;Farnell, Michael;Flotte, Thomas;Giama, Nasra;Ho, Thai;Kendrick, Michael;Kocher, Jean-Pierre;Kopp, Karla;Moser, Catherine;Nagorney, David;O’Brien, Daniel;O’Neill, Brian Patrick;Patel, Tushar;Petersen, Gloria;Que, Florencia;Rivera, Michael;Roberts, Lewis;Smallridge, Robert;Smyrk, Thomas;Stanton, Melissa;Thompson, R. Houston;Torbenson, Michael;Yang, Ju Dong;Zhang, Lizhi;Brimo, Fadi;Ajani, Jaffer A.;Gonzalez, Ana Maria Angulo;Behrens, Carmen;Bondaruk, Jolanta;Broaddus, Russell;Czerniak, Bogdan;Esmaeli, Bita;Fujimoto, Junya;Gershenwald, Jeffrey;Guo, Charles;Lazar, Alexander J.;Logothetis, Christopher;Meric-Bernstam, Funda;Moran, Cesar;Ramondetta, Lois;Rice, David;Sood, Anil;Tamboli, Pheroze;Thompson, Timothy;Troncoso, Patricia;Tsao, Anne;Wistuba, Ignacio;Carter, Candace;Haydu, Lauren;Hersey, Peter;Jakrot, Valerie;Kakavand, Hojabr;Kefford, Richard;Lee, Kenneth;Long, Georgina;Mann, Graham;Quinn, Michael;Saw, Robyn;Scolyer, Richard;Shannon, Kerwin;Spillane, Andrew;Stretch, Jonathan;Synott, Maria;Thompson, John;Wilmott, James;Al-Ahmadie, Hikmat;Chan, Timothy A.;Ghossein, Ronald;Gopalan, Anuradha;Levine, Douglas A.;Reuter, Victor;Singer, Samuel;Singh, Bhuvanesh;Tien, Nguyen Viet;Broudy, Thomas;Mirsaidi, Cyrus;Nair, Praveen;Drwiega, Paul;Miller, Judy;Smith, Jennifer;Zaren, Howard;Park, Joong-Won;Hung, Nguyen Phi;Kebebew, Electron;Linehan, W. Marston;Metwalli, Adam R.;Pacak, Karel;Pinto, Peter A.;Schiffman, Mark;Schmidt, Laura S.;Vocke, Cathy D.;Wentzensen, Nicolas;Worrell, Robert;Yang, Hannah;Moncrieff, Marc;Goparaju, Chandra;Melamed, Jonathan;Pass, Harvey;Botnariuc, Natalia;Caraman, Irina;Cernat, Mircea;Chemencedji, Inga;Clipca, Adrian;Doruc, Serghei;Gorincioi, Ghenadie;Mura, Sergiu;Pirtac, Maria;Stancul, Irina;Tcaciuc, Diana;Albert, Monique;Alexopoulou, Iakovina;Arnaout, Angel;Bartlett, John;Engel, Jay;Gilbert, Sebastien;Parfitt, Jeremy;Sekhon, Harman;Thomas, George;Rassl, Doris M.;Rintoul, Robert C.;Bifulco, Carlo;Tamakawa, Raina;Urba, Walter;Hayward, Nicholas;Timmers, Henri;Antenucci, Anna;Facciolo, Francesco;Grazi, Gianluca;Marino, Mirella;Merola, Roberta;de Krijger, Ronald;Gimenez-Roqueplo, Anne-Paule;Piché, Alain;Chevalier, Simone;McKercher, Ginette;Birsoy, Kivanc;Barnett, Gene;Brewer, Cathy;Farver, Carol;Naska, Theresa;Pennell, Nathan A.;Raymond, Daniel;Schilero, Cathy;Smolenski, Kathy;Williams, Felicia;Morrison, Carl;Borgia, Jeffrey A.;Liptay, Michael J.;Pool, Mark;Seder, Christopher W.;Junker, Kerstin;Omberg, Larsson;Dinkin, Mikhail;Manikhas, George;Alvaro, Domenico;Bragazzi, Maria Consiglia;Cardinale, Vincenzo;Carpino, Guido;Gaudio, Eugenio;Chesla, David;Cottingham, Sandra;Dubina, Michael;Moiseenko, Fedor;Dhanasekaran, Renumathy;Becker, Karl-Friedrich;Janssen, Klaus-Peter;Slotta-Huspenina, Julia;Abdel-Rahman, Mohamed H.;Aziz, Dina;Bell, Sue;Cebulla, Colleen M.;Davis, Amy;Duell, Rebecca;Elder, J. Bradley;Hilty, Joe;Kumar, Bahavna;Lang, James;Lehman, Norman L.;Mandt, Randy;Nguyen, Phuong;Pilarski, Robert;Rai, Karan;Schoenfield, Lynn;Senecal, Kelly;Wakely, Paul;Hansen, Paul;Lechan, Ronald;Powers, James;Tischler, Arthur;Grizzle, William E.;Sexton, Katherine C.;Kastl, Alison;Henderson, Joel;Porten, Sima;Waldmann, Jens;Fassnacht, Martin;Asa, Sylvia L.;Schadendorf, Dirk;Couce, Marta;Graefen, Markus;Huland, Hartwig;Sauter, Guido;Schlomm, Thorsten;Simon, Ronald;Tennstedt, Pierre;Olabode, Oluwole;Nelson, Mark;Bathe, Oliver;Carroll, Peter R.;Chan, June M.;Disaia, Philip;Glenn, Pat;Kelley, Robin K.;Landen, Charles N.;Phillips, Joanna;Prados, Michael;Simko, Jeffry;Smith-McCune, Karen;VandenBerg, Scott;Roggin, Kevin;Fehrenbach, Ashley;Kendler, Ady;Sifri, Suzanne;Steele, Ruth;Jimeno, Antonio;Carey, Francis;Forgie, Ian;Mannelli, Massimo;Carney, Michael;Hernandez, Brenda;Campos, Benito;Herold-Mende, Christel;Jungk, Christin;Unterberg, Andreas;von Deimling, Andreas;Bossler, Aaron;Galbraith, Joseph;Jacobus, Laura;Knudson, Michael;Knutson, Tina;Ma, Deqin;Milhem, Mohammed;Sigmund, Rita;Godwin, Andrew K.;Madan, Rashna;Rosenthal, Howard G.;Adebamowo, Clement;Adebamowo, Sally N.;Boussioutas, Alex;Beer, David;Giordano, Thomas;Mes-Masson, Anne-Marie;Saad, Fred;Bocklage, Therese;Landrum, Lisa;Mannel, Robert;Moore, Kathleen;Moxley, Katherine;Postier, Russel;Walker, Joan;Zuna, Rosemary;Feldman, Michael;Valdivieso, Federico;Dhir, Rajiv;Luketich, James;Pinero, Edna M. Mora;Quintero-Aguilo, Mario;Carlotti, Carlos Gilberto;Dos Santos, Jose Sebastião;Kemp, Rafael;Sankarankuty, Ajith;Tirapelli, Daniela;Catto, James;Agnew, Kathy;Swisher, Elizabeth;Creaney, Jenette;Robinson, Bruce;Shelley, Carl Simon;Godwin, Eryn M.;Kendall, Sara;Shipman, Cassaundra;Bradford, Carol;Carey, Thomas;Haddad, Andrea;Moyer, Jeffey;Peterson, Lisa;Prince, Mark;Rozek, Laura;Wolf, Gregory;Bowman, Rayleen;Fong, Kwun M.;Yang, Ian;Korst, Robert;Rathmell, W. Kimryn;Fantacone-Campbell, J. Leigh;Hooke, Jeffrey A.;Kovatich, Albert J.;Shriver, Craig D.;DiPersio, John;Drake, Bettina;Govindan, Ramaswamy;Heath, Sharon;Ley, Timothy;Van Tine, Brian;Westervelt, Peter;Rubin, Mark A.;Lee, Jung Il;Aredes, Natália D.;Mariamidze, Armaz

2018

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. Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores.

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Scheda completa

Scheda completa (DC)

	Parole chiave
	
			DNA damage footprints; DNA damage repair; epigenetic silencing; integrative statistical analysis; mutational signatures; protein structure analysis; somatic copy-number alterations; somatic mutations; The Cancer Genome Atlas PanCanAtlas project;
		
	Settori scientifico-disciplinari dell'articolo
	
			Settore MED/27 - Neurochirurgia
		
	Data di pubblicazione
	
			3-apr-2018
		
	Rivista in ANCE
	
			CELL REPORTS
		
	DOI
	
			https://dx.doi.org/10.1016/j.celrep.2018.03.076
		
	Tipologia
	
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			01 - Articolo su periodico

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