We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer. A pan-cancer analysis identifies hundreds of predisposing germline variants.

Pathogenic Germline Variants in 10,389 Adult Cancers / K. Huang, R.J. Mashl, W. Yige, D.I. Ritter, J. Wang, O. Clara, M. Paczkowska, S. Reynolds, M.A. Wyczalkowski, N. Oak, A.D. Scott, M. Krassowski, A.D. Cherniack, K.E. Houlahan, R. Jayasinghe, L. Wang, D.C. Zhou, D. Liu, S. Cao, Y.W. Kim, A. Koire, J.F. Mcmichael, V. Hucthagowder, T. Kim, A. Hahn, C. Wang, M.D. Mclellan, F. Al-Mulla, K.J. Johnson, O. Lichtarge, P.C. Boutros, B. Raphael, A.J. Lazar, W. Zhang, M.C. Wendl, R. Govindan, S. Jain, D. Wheeler, S. Kulkarni, J.F. Dipersio, J. Reimand, F. Meric-Bernstam, K. Chen, I. Shmulevich, S.E. Plon, F. Chen, L. Ding, 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. 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.M. 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. - ISSN 0092-8674. - 173:2(2018 Apr 05), pp. 355-370.e14. [10.1016/j.cell.2018.03.039]

Pathogenic Germline Variants in 10,389 Adult Cancers

F. Dimeco;
2018

Abstract

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer. A pan-cancer analysis identifies hundreds of predisposing germline variants.
cancer predisposition; germline and somatic genomes; LOH; variant pathogenicity
Settore MED/27 - Neurochirurgia
5-apr-2018
Article (author)
File in questo prodotto:
File Dimensione Formato  
PIIS0092867418303635.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 6.31 MB
Formato Adobe PDF
6.31 MB Adobe PDF Visualizza/Apri
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/2434/586845
Citazioni
  • ???jsp.display-item.citation.pmc??? 217
  • Scopus 487
  • ???jsp.display-item.citation.isi??? 475
social impact