Pathogenic Germline Variants in 10,389 Adult Cancers Journal Articles uri icon

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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.

authors

  • Huang, Kuan-lin
  • Mashl, R Jay
  • Wu, Yige
  • Ritter, Deborah I
  • Wang, Jiayin
  • Oh, Clara
  • Paczkowska, Marta
  • Reynolds, Sheila
  • Wyczalkowski, Matthew A
  • Oak, Ninad
  • Scott, Adam D
  • Krassowski, Michal
  • Cherniack, Andrew D
  • Houlahan, Katie
  • Jayasinghe, Reyka
  • Wang, Liang-Bo
  • Zhou, Daniel Cui
  • Liu, Di
  • Cao, Song
  • Kim, Young Won
  • Koire, Amanda
  • McMichael, Joshua F
  • Hucthagowder, Vishwanathan
  • Kim, Tae-Beom
  • Hahn, Abigail
  • Wang, Chen
  • McLellan, Michael D
  • Al-Mulla, Fahd
  • Johnson, Kimberly J
  • Lichtarge, Olivier
  • Boutros, Paul C
  • Raphael, Benjamin
  • Lazar, Alexander J
  • Zhang, Wei
  • Wendl, Michael C
  • Govindan, Ramaswamy
  • Jain, Sanjay
  • Wheeler, David
  • Kulkarni, Shashikant
  • Dipersio, John F
  • Reimand, Jüri
  • Meric-Bernstam, Funda
  • Chen, Ken
  • Shmulevich, Ilya
  • Plon, Sharon E
  • Chen, Feng
  • Ding, Li
  • 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 JM
  • 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 CS
  • 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
  • DiMeco, Francesco
  • 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

publication date

  • April 2018

has subject area

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