Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types / M. Seiler, S. Peng, A.A. Agrawal, J. Palacino, T. Teng, P. Zhu, P.G. Smith, S. Buonamici, Y. Lihua, 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. Angulo 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. Olabode, M. Nelson, O. Bathe, P.R. Carroll, J.M. Chan, P. Disaia, P. Glenn, R.K. Kelley, C.N. Landen, J. Phillips, M. Prados, J. Simko, K. Smith-McCune, S. Vandenberg, K. Roggin, A. Fehrenbach, A. Kendler, S. Sifri, R. Steele, A. Jimeno, F. Carey, I. Forgie, M. Mannelli, M. Carney, B. Hernandez, B. Campos, C. Herold-Mende, C. Jungk, A. Unterberg, A. von Deimling, A. Bossler, J. Galbraith, L. Jacobus, M. Knudson, T. Knutson, M. Deqin, M. Milhem, R. Sigmund, A.K. Godwin, R. Madan, H.G. Rosenthal, C. Adebamowo, S.N. Adebamowo, A. Boussioutas, D. Beer, T. Giordano, A. Mes-Masson, F. Saad, T. Bocklage, L. Landrum, R. Mannel, K. Moore, K. Moxley, R. Postier, J. Walker, R. Zuna, M. Feldman, F. Valdivieso, R. Dhir, J. Luketich, E.M. Mora Pinero, M. Quintero-Aguilo, C.G. Carlotti, J.S. Dos Santos, R. Kemp, A. Sankarankuty, D. Tirapelli, J. Catto, K. Agnew, E. Swisher, J. Creaney, B. Robinson, C.S. Shelley, E.M. Godwin, S. Kendall, C. Shipman, C. Bradford, T. Carey, A. Haddad, J. Moyer, L. Peterson, M. Prince, L. Rozek, G. Wolf, R. Bowman, K.M. Fong, I. Yang, R. Korst, W.K. Rathmell, J.L. Fantacone-Campbell, J.A. Hooke, A.J. Kovatich, C.D. Shriver, J. Dipersio, B. Drake, R. Govindan, S. Heath, T. Ley, B. Van Tine, P. Westervelt, M.A. Rubin, J.I. Lee, N.D. Aredes, A. Mariamidze. - In: CELL REPORTS. - ISSN 2211-1247. - 23:1(2018 Apr 03), pp. 282-296.e4.

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

F. Dimeco;
2018

Abstract

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.
Settore MED/27 - Neurochirurgia
Article (author)
File in questo prodotto:
File Dimensione Formato  
PIIS2211124718301529.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 9.91 MB
Formato Adobe PDF
9.91 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/586848
Citazioni
  • ???jsp.display-item.citation.pmc??? 130
  • Scopus 202
  • ???jsp.display-item.citation.isi??? 205
social impact