Landscape and function of multiple mutations within individual oncogenes

被引：88

作者：

Saito, Yuki ^{[1
,2
]}

Koya, Junji ^{[1
]}

Araki, Mitsugu ^{[3
]}

Kogure, Yasunori ^{[1
]}

Shingaki, Sumito ^{[1
]}

Tabata, Mariko ^{[1
,4
]}

McClure, Marni B. ^{[1
]}

Yoshifuji, Kota ^{[1
,5
]}

Matsumoto, Shigeyuki ^{[6
]}

Isaka, Yuta ^{[7
]}

Tanaka, Hiroko ^{[8
]}

Kanai, Takanori ^{[2
]}

Miyano, Satoru ^{[8
]}

Shiraishi, Yuichi ^{[9
]}

Okuno, Yasushi ^{[3
]}

Kataoka, Keisuke ^{[1
]}

机构：

[1] Natl Canc Ctr, Div Mol Oncol, Tokyo, Japan

[2] Keio Univ, Dept Gastroenterol, Sch Med, Tokyo, Japan

[3] Kyoto Univ, Grad Sch Med, Dept Clin Syst Oncoinformat, Kyoto, Japan

[4] Univ Tokyo, Grad Sch Med, Dept Urol, Tokyo, Japan

[5] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Hematol, Tokyo, Japan

[6] RIKEN, Med Sci Innovat Hub Program, Cluster Sci Technol & Innovat Hub, Yokohama, Kanagawa, Japan

[7] Fdn Biomed Res & Innovat, Ctr Cluster Dev & Coordinat, Res & Dev Grp Silico Drug Discovery, Kobe, Hyogo, Japan

[8] Univ Tokyo, Human Genome Ctr, Inst Med Sci, Lab Sequence Anal, Tokyo, Japan

[9] Natl Canc Ctr, Ctr Canc Genom & Adv Therapeut, Tokyo, Japan

来源：

NATURE | 2020年 / 582卷 / 7810期

基金：

日本学术振兴会;

关键词：

CANCER GENOME; PRECISION MEDICINE; SOMATIC MUTATIONS; CELL; RESISTANCE; DISCOVERY; PROGNOSIS; JAK2;

D O I：

10.1038/s41586-020-2175-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene(1,2). However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations.

引用

页码：95 / +

页数：29

共 45 条

[1] AACR Project GENIE: Powering Precision Medicine through an International Consortium [J].

Andre, Fabrice ;

Arnedos, Monica ;

Baras, Alexander S. ;

Baselga, Jose ;

Bedard, Philippe L. ;

Berger, Michael F. ;

Bierkens, Mariska ;

Calvo, Fabien ;

Cerami, Ethan ;

Chakravarty, Debyani ;

Dang, Kristen K. ;

Davidson, Nancy E. ;

Del Vecchio, Fitz Catherine ;

Dogan, Semih ;

DuBois, Raymond N. ;

Ducar, Matthew D. ;

Futreal, P. Andrew ;

Gao Jianjiong ;

Garcia, Francisco ;

Gardos, Stu ;

Gocke, Christopher D. ;

Gross, Benjamin E. ;

Guinney, Justin ;

Heins, Zachary J. ;

Hintzen, Stephanie ;

Horlings, Hugo ;

Hudecek, Jan ;

Hyman, David M. ;

Kamel-Reid, Suzanne ;

Kandoth, Cyriac ;

Kinyua, Walter ;

Kumari, Priti ;

Kundra, Ritika ;

Ladanyi, Marc ;

Lefebvre, Celine ;

LeNoue-Newton, Michele L. ;

Lepisto, Eva M. ;

Levy, Mia A. ;

Lindeman, Neal, I ;

Lindsay, James ;

Liu, David ;

Lu Zhibin ;

MacConaill, Laura E. ;

Ian, Maurer ;

Maxwell, David S. ;

Meijer, Gerrit A. ;

Meric-Bernstam, Funda ;

Micheel, Christine M. ;

Miller, Clinton ;

Mills, Gordon .

CANCER DISCOVERY, 2017, 7 (08) :818-831

[2]

Bailey MH, 2018, CELL, V173, P371, DOI [10.1016/j.cell.2018.02.060, 10.1016/j.cell.2018.07.034]

[3] Widespread Selection for Oncogenic Mutant Allele Imbalance in Cancer [J].

Bielski, Craig M. ;

Donoghue, Mark T. A. ;

Gadiya, Mayur ;

Hanrahan, Aphrothiti J. ;

Won, Helen H. ;

Chang, Matthew T. ;

Jonsson, Philip ;

Penson, Alexander, V ;

Gorelick, Alexander ;

Harris, Christopher ;

Schram, Alison M. ;

Syed, Aijazuddin ;

Zehir, Ahmet ;

Chapman, Paul B. ;

Hyman, David M. ;

Solit, David B. ;

Shannon, Kevin ;

Chandarlapaty, Sarat ;

Berger, Michael F. ;

Taylor, Barry S. .

CANCER CELL, 2018, 34 (05) :852-+

[4] Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features [J].

Buisson, Remi ;

Langenbucher, Adam ;

Bowen, Danae ;

Kwan, Eugene E. ;

Benes, Cyril H. ;

Zou, Lee ;

Lawrence, Michael S. .

SCIENCE, 2019, 364 (6447) :1251-+

[5] Comprehensive Analysis of Hypermutation in Human Cancer [J].

Campbell, Brittany B. ;

Light, Nicholas ;

Fabrizio, David ;

Zatzman, Matthew ;

Fuligni, Fabio ;

de Borja, Richard ;

Davidson, Scott ;

Edwards, Melissa ;

Elvin, Julia A. ;

Hodel, Karl P. ;

Zahurancik, Walter J. ;

Suo, Zucai ;

Lipman, Tatiana ;

Wimmer, Katharina ;

Kratz, Christian P. ;

Bowers, Daniel C. ;

Laetsch, Theodore W. ;

Dunn, Gavin P. ;

Johanns, Tanner M. ;

Grimmer, Matthew R. ;

Smirnov, Ivan V. ;

Larouche, Valerie ;

Samuel, David ;

Bronsema, Annika ;

Osborn, Michael ;

Stearns, Duncan ;

Raman, Pichai ;

Cole, Kristina A. ;

Storm, Phillip B. ;

Yalon, Michal ;

Opocher, Enrico ;

Mason, Gary ;

Thomas, Gregory A. ;

Sabel, Magnus ;

George, Ben ;

Ziegler, David S. ;

Lindhorst, Scott ;

Issai, Vanan Magimairajan ;

Constantini, Shlomi ;

Toledano, Helen ;

Elhasid, Ronit ;

Farah, Roula ;

Dvir, Rina ;

Dirks, Peter ;

Huang, Annie ;

Galati, Melissa A. ;

Chung, Jiil ;

Ramaswamy, Vijay ;

Irwin, Meredith S. ;

Aronson, Melyssa .

CELL, 2017, 171 (05) :1042-+

[6]

Chakravarty Debyani, 2017, JCO Precis Oncol, V2017, DOI 10.1200/PO.17.00011

[7] Accelerating Discovery of Functional Mutant Alleles in Cancer [J].

Chang, Matthew T. ;

Bhattarai, Tripti Shrestha ;

Schram, Alison M. ;

Bielski, Craig M. ;

Donoghue, Mark T. A. ;

Jonsson, Philip ;

Chakravarty, Debyani ;

Phillips, Sarah ;

Kandoth, Cyriac ;

Penson, Alexander ;

Gorelick, Alexander ;

Shamu, Tambudzai ;

Patel, Swati ;

Harris, Christopher ;

Gao, JianJiong ;

Sumer, Selcuk Onur ;

Kundra, Ritika ;

Razavi, Pedram ;

Li, Bob T. ;

Reales, Dalicia N. ;

Socci, Nicholas D. ;

Jayakumaran, Gowtham ;

Zehir, Ahmet ;

Benayed, Ryma ;

Arcila, Maria E. ;

Chandarlapaty, Sarat ;

Ladanyi, Marc ;

Schultz, Nikolaus ;

Baselga, Jose ;

Berger, Michael F. ;

Rosen, Neal ;

Solit, David B. ;

Hyman, David M. ;

Taylor, Barry S. .

CANCER DISCOVERY, 2018, 8 (02) :174-183

[8] Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity [J].

Chang, Matthew T. ;

Asthana, Saurabh ;

Gao, Sizhi Paul ;

Lee, Byron H. ;

Chapman, Jocelyn S. ;

Kandoth, Cyriac ;

Gao, JianJiong ;

Socci, Nicholas D. ;

Solit, David B. ;

Olshen, Adam B. ;

Schultz, Nikolaus ;

Taylor, Barry S. .

NATURE BIOTECHNOLOGY, 2016, 34 (02) :155-+

[9] Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes [J].

Chapuy, Bjoern ;

Stewart, Chip ;

Dunford, Andrew J. ;

Kim, Jaegil ;

Kamburov, Atanas ;

Redd, Robert A. ;

Lawrence, Mike S. ;

Roemer, Margaretha G. M. ;

Li, Amy J. ;

Ziepert, Marita ;

Staiger, Annette M. ;

Wala, Jeremiah A. ;

Ducar, Matthew D. ;

Leshchiner, Ignaty ;

Rheinbay, Ester ;

Taylor-Weiner, Amaro ;

Coughlin, Caroline A. ;

Hess, Julian M. ;

Pedamallu, Chandra S. ;

Livitz, Dimitri ;

Rosebrock, Daniel ;

Rosenberg, Mara ;

Tracy, Adam A. ;

Horn, Heike ;

van Hummelen, Paul ;

Feldman, Andrew L. ;

Link, Brian K. ;

Novak, Anne J. ;

Cerhan, James R. ;

Habermann, Thomas M. ;

Siebert, Reiner ;

Rosenwald, Andreas ;

Thorner, Aaron R. ;

Meyerson, Matthew L. ;

Golub, Todd R. ;

Beroukhim, Rameen ;

Wulf, Gerald G. ;

Ott, German ;

Rodig, Scott J. ;

Monti, Stefano ;

Neuberg, Donna S. ;

Loeffler, Markus ;

Pfreundschuh, Michael ;

Truemper, Lorenz ;

Getz, Gad ;

Shipp, Margaret A. .

NATURE MEDICINE, 2018, 24 (05) :679-+

[10] Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics [J].

Ding, Li ;

Bailey, Matthew H. ;

Porta-Pardo, Eduard ;

Thorsson, Vesteinn ;

Colaprico, Antonio ;

Bertrand, Denis ;

Gibbs, David L. ;

Weerasinghe, Amila ;

Huang, Kuan-lin ;

Tokheim, Collin ;

Cortes-Ciriano, Isidro ;

Jayasinghe, Reyka ;

Chen, Feng ;

Yu, Lihua ;

Sun, Sam ;

Olsen, Catharina ;

Kim, Jaegil ;

Taylor, Alison M. ;

Cherniack, Andrew D. ;

Akbani, Rehan ;

Suphavilai, Chayaporn ;

Nagarajan, Niranjan ;

Stuart, Joshua M. ;

Mills, Gordon B. ;

Wyczalkowski, Matthew A. ;

Vincent, Benjamin G. ;

Hutter, Carolyn M. ;

Zenklusen, Jean Claude ;

Hoadley, Katherine A. ;

Wendl, Michael C. ;

Shmulevich, Llya ;

Lazar, Alexander J. ;

Wheeler, David A. ;

Getz, Gad .

CELL, 2018, 173 (02) :305-+

← 1 2 3 4 5 →