Pathogenic Germline Variants in 10,389 Adult Cancers

著者: Kuan‐lin Huang, R. Jay Mashl, Yige Wu, Deborah Ritter, Jiayin Wang, Clara Oh, Marta Paczkowska, Sheila M. Reynolds, Matthew A. Wyczalkowski, Ninad Oak, Adam Scott, Michał Krassowski, Andrew D. Cherniack, Kathleen E. Houlahan, Reyka G. Jayasinghe, Liang-Bo Wang, Daniel Cui Zhou, Di Liu, Song Cao, Young Won Kim, Amanda Koire, Joshua F. McMichael, Vishwanathan Hucthagowder, Tae‐Beom Kim, Abigail Hahn, Chen Wang, Michael D. McLellan, Fahd Al‐Mulla, Kimberly Johnson, Rory Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy Defreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael B. Miller, Sheila M. Reynolds, Ilya Shmulevich, Vésteinn Thórsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Galen F. Gao, Benjamin E. Gross, Zachary Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah Phillips, Ed Reznik, Francisco Sánchez-Vega, Chris Sander, Nikolaus Schultz, Robert P. Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul T. Spellman, Christopher C. Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert A. Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju Kucherlapati, Stephen B. Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle R. Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Hai Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna M. Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian M. Hess, Elizabeth L. Appelbaum, Matthew H. Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark E. Sherman, Eric M. Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier‐Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall M. Corcoran, Tony Costello, Christopher M. Hovens, André Lopes Carvalho, Ana Carolina de Carvalho, José Humberto Tavares Guerreiro Fregnani, Adhemar Longatto‐Filho, Rui Manuel Reis, Cristovam Scapulatempo‐Neto, Henrique C.S. Silveira, Daniel Onofre Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David G. Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Shabunin Av, Mikhail Tavobilov, Christopher McPherson, Ronald E. Warnick, Ross S. Berkowitz, Daniel Cramer, Colleen M. Feltmate, Neil S. Horowitz, Adam S. Kibel, Michael G. Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz‐Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino Maria De Rose, Felice Giuliante, Marc T. Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome K. Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard Mural, Stella Somiari, Aleš Vícha, Tomáš Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John A. Chabot, Hanina Hibshoosh, Antonia R. Sepulveda, Tao Su, Timothy C. Wang, Olga Potapova, Olga L. Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman‐Roman, Xavier Sastre, Marc‐Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell D. Bigner, Eric Lipp, Jeffrey S. Marks, Shannon J. McCall, Roger E. McLendon, Angeles Alvarez Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith A. Delman, Seth Force, Fadlo R. Khuri, Kelly R. Magliocca, Shishir K. Maithel, Jeffrey J. Olson, Taofeek K. Owonikoko, Alan Pickens, Suresh S. Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert H. J. Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, J. C. Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Robert Stoehr, Robert Stoehr, Helge Täubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Wung Chung, W. Jeffrey Edenfield, Julie Martin, Éric Baudin, Glenn J. Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven N. Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elı́as Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bùi Đức Phú, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave S.�B. Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael J. Birrer, Debra Bell, Mitesh J. Borad, Alan H. Bryce, Erik P. Castle, Vishal S. Chandan, John C. Cheville, John A. Copland, Michael B. Farnell, Thomas J. Flotte, Nasra H. Giama, Thai H. Ho, Michael L. Kendrick, Jean‐Pierre Kocher, Karla Kopp, Catherine D. Moser, David M. Nagorney, Daniel R. O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria M. Petersen, Florencia G. Que, Michael Rivera, Lewis R. Roberts, Robert C. Smallridge, Thomas C. Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell R. Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher J. Logothetis, Funda Meric‐Bernstam, César A. Moran, Lois M. Ramondetta, David C. Rice, Anil K. Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne S. Tsao, Ignacio Wistuba, Candace Carter, Lauren E. Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina V. Long, Graham J. Mann, Michael Quinn, Robyn P.M. Saw, Richard A. Scolyer, Kerwin F. Shannon, Andrew J. Spillane, Jonathan R. Stretch, Maria Synott, John F. Thompson, James S. Wilmott, Hikmat Al‐Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer R. Smith, Howard Zaren, Joong-Won Park, Nguyễn Phi Hùng, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacák, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey I. Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John G. Bartlett, Jay Engel, Sébastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter J. Urba, Nicholas K. Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gian Luca Grazi, Mirella Marino, Roberta Merola, Ronald R. de Krijger, Anne‐Paule Gimenez‐Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kıvanç Birsoy, Gene H. Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Quaid Morris, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl‐Friedrich Becker, Klaus‐Peter Janssen, Julia Slotta‐Huspenina, Mohamed H. Abdel‐Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James C. Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul E. Wakely, Paul Hansen, Ronald M. Lechan, James F. Powers, Arthur S. Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima P. Porten, Jens Waldmann, Martin Faßnacht, L. Sylvia, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark A. Nelson, Oliver F. Bathe, Peter R. Carroll, June M. Chan, Philip J. DiSaia, Pat Glenn, Robin Kate Kelley, Charles N. Landen, Joanna Phillips, Michael D. Prados, Jeffry Simko, Karen Smith‐McCune, Scott Vandenberg, Kevin K. Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis A. Carey, Ian Forgie, Massimo Mannelli, Michael E. Carney, Brenda Hernandez, Benito Campos, Christel Herold‐Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David G. Beer, Thomas J. Giordano, Anne‐Marie Mes‐Masson, Fred Saad, Thèrése Bocklage, Lisa M. Landrum, Robert S. Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan L. Walker, Rosemary E. Zuna, Michael D. Feldman, Federico Valdivieso, Rajiv Dhir, James D. Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, José Sebastião dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Pretti da Cunha Tirapelli, James W.F. Catto, Kathy Agnew, Elizabeth M. Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol R. Bradford, Thomas E. Carey, Andrea Haddad, Jeffey Moyer, Lisa A. Peterson, Mark E. Prince, Laura S. Rozek, Gregory T. Wolf, Rayleen Bowman, Kwun M. Fong, Ian A. Yang, Robert J. Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John F. DiPersio, Bettina F. Drake, Ramaswamy Govindan, Sharon E. Heath, Timothy J. Ley, Brian A. Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, Armaz Mariamidze, Olivier Lichtarge, Paul C. Boutros, Benjamin J. Raphael, Alexander J. Lazar, Wei Zhang, Michael C. Wendl, Ramaswamy Govindan, Sanjay Jain, David A. Wheeler, Shashikant Kulkarni, John F. DiPersio, Jüri Reimand, Funda Meric‐Bernstam, Ken Chen, Ilya Shmulevich, Sharon E. Plon, Feng Chen, Li Ding - Cell 2018 被引用: 903

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.