Systematic Analysis of Splice-Site-Creating Mutations in Cancer

Jayasinghe, R.G.; Cao, S.; Gao, Q.; Wendl, M.C.; Nam Sy, V.; Reynolds, S.M.; Zhao, Y.; Climente-González, H.; Chai, S.; Wang, F.; Varghese, R.; Huang, M.; Liang, W.; Wyczalkowski, M.A.; Sengupta, S.; Zhi, L.; Payne, S.H.; Fenyö, D.; Miner, J.H.; Walter, M.J.; 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.; Vincent, B.; Eyras, E.; Chen, K.; Shmulevich, I.; Chen, F.; Ding, L.

doi:10.1016/j.celrep.2018.03.052

For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease.

Systematic Analysis of Splice-Site-Creating Mutations in Cancer / R.G. Jayasinghe, S. Cao, Q. Gao, M.C. Wendl, V. Nam Sy, S.M. Reynolds, Y. Zhao, H. Climente-González, S. Chai, F. Wang, R. Varghese, M. Huang, W. Liang, M.A. Wyczalkowski, S. Sengupta, L. Zhi, S.H. Payne, D. Fenyö, J.H. Miner, M.J. Walter, 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. 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Systematic Analysis of Splice-Site-Creating Mutations in Cancer

Jayasinghe, Reyka G.;Cao, Song;Gao, Qingsong;Wendl, Michael C.;Vo, Nam Sy;Reynolds, Sheila M.;Zhao, Yanyan;Climente-González, Héctor;Chai, Shengjie;Wang, Fang;Varghese, Rajees;Huang, Mo;Liang, Wen-Wei;Wyczalkowski, Matthew A.;Sengupta, Sohini;Li, Zhi;Payne, Samuel H.;Fenyö, David;Miner, Jeffrey H.;Walter, Matthew J.;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;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;Vincent, Benjamin;Eyras, Eduardo;Chen, Ken;Shmulevich, Ilya;Chen, Feng;Ding, Li

2018

Abstract

For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease.

Scheda breve

Scheda completa

Scheda completa (DC)

	Parole chiave
	
			mutations of clinical relevance; RNA; splicing; Biochemistry, Genetics and Molecular Biology (all)
		
	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.2018.03.052
		
	Tipologia
	
			Article (author)
		
	Appare nelle tipologie:
	
			01 - Articolo su periodico

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