Systematic Analysis of Splice-Site-Creating Mutations in Cancer

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease.

Original languageEnglish
Pages (from-to)270-281.e3
JournalCell Reports
Volume23
Issue number1
DOIs
Publication statusPublished - 3 Apr 2018

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Tumors
Mutation
Neoplasms
Bioelectric potentials
Bioinformatics
Genes
RNA
DNA
Missense Mutation
Computational Biology
Glioma

Cite this

The Cancer Genome Atlas Research Network. / Systematic Analysis of Splice-Site-Creating Mutations in Cancer. In: Cell Reports. 2018 ; Vol. 23, No. 1. pp. 270-281.e3.
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abstract = "For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease.",
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The Cancer Genome Atlas Research Network 2018, 'Systematic Analysis of Splice-Site-Creating Mutations in Cancer' Cell Reports, vol. 23, no. 1, pp. 270-281.e3. https://doi.org/10.1016/j.celrep.2018.03.052

Systematic Analysis of Splice-Site-Creating Mutations in Cancer. / The Cancer Genome Atlas Research Network.

In: Cell Reports, Vol. 23, No. 1, 03.04.2018, p. 270-281.e3.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Systematic Analysis of Splice-Site-Creating Mutations in Cancer

AU - The Cancer Genome Atlas Research Network

AU - Jayasinghe, Reyka G.

AU - Cao, Song

AU - Gao, Qingsong

AU - Wendl, Michael C.

AU - Vo, Nam Sy

AU - Reynolds, Sheila M.

AU - Zhao, Yanyan

AU - Climente-González, Héctor

AU - Chai, Shengjie

AU - Wang, Fang

AU - Varghese, Rajees

AU - Huang, Mo

AU - Liang, Wen Wei

AU - Wyczalkowski, Matthew A.

AU - Sengupta, Sohini

AU - Li, Zhi

AU - Payne, Samuel H.

AU - Fenyö, David

AU - Miner, Jeffrey H.

AU - Walter, Matthew J.

AU - Caesar-Johnson, Samantha J.

AU - Demchok, John A.

AU - Felau, Ina

AU - Kasapi, Melpomeni

AU - Ferguson, Martin L.

AU - Hutter, Carolyn M.

AU - Sofia, Heidi J.

AU - Tarnuzzer, Roy

AU - Wang, Zhining

AU - Yang, Liming

AU - Zenklusen, Jean C.

AU - Zhang, Jiashan (Julia)

AU - Chudamani, Sudha

AU - Liu, Jia

AU - Lolla, Laxmi

AU - Naresh, Rashi

AU - Pihl, Todd

AU - Sun, Qiang

AU - Wan, Yunhu

AU - Wu, Ye

AU - Cho, Juok

AU - DeFreitas, Timothy

AU - Frazer, Scott

AU - Gehlenborg, Nils

AU - Getz, Gad

AU - Heiman, David I.

AU - Kim, Jaegil

AU - Lawrence, Michael S.

AU - Lin, Pei

AU - Meier, Sam

AU - Noble, Michael S.

AU - Saksena, Gordon

AU - Voet, Doug

AU - Zhang, Hailei

AU - Bernard, Brady

AU - Chambwe, Nyasha

AU - Dhankani, Varsha

AU - Knijnenburg, Theo

AU - Kramer, Roger

AU - Leinonen, Kalle

AU - Liu, Yuexin

AU - Miller, Michael

AU - Reynolds, Sheila

AU - Shmulevich, Ilya

AU - Thorsson, Vesteinn

AU - Zhang, Wei

AU - Akbani, Rehan

AU - Broom, Bradley M.

AU - Hegde, Apurva M.

AU - Ju, Zhenlin

AU - Kanchi, Rupa S.

AU - Korkut, Anil

AU - Li, Jun

AU - Liang, Han

AU - Ling, Shiyun

AU - Liu, Wenbin

AU - Lu, Yiling

AU - Mills, Gordon B.

AU - Ng, Kwok Shing

AU - Rao, Arvind

AU - Ryan, Michael

AU - Wang, Jing

AU - Weinstein, John N.

AU - Zhang, Jiexin

AU - Abeshouse, Adam

AU - Armenia, Joshua

AU - Chakravarty, Debyani

AU - Chatila, Walid K.

AU - de Bruijn, Ino

AU - Gao, Jianjiong

AU - Gross, Benjamin E.

AU - Heins, Zachary J.

AU - Kundra, Ritika

AU - La, Konnor

AU - Ladanyi, Marc

AU - Luna, Augustin

AU - Nissan, Moriah G.

AU - Ochoa, Angelica

AU - Phillips, Sarah M.

AU - Reznik, Ed

AU - Sanchez-Vega, Francisco

AU - Sander, Chris

AU - Schultz, Nikolaus

AU - Sheridan, Robert

AU - Sumer, S. Onur

AU - Sun, Yichao

AU - Taylor, Barry S.

AU - Wang, Jioajiao

AU - Zhang, Hongxin

AU - Anur, Pavana

AU - Peto, Myron

AU - Spellman, Paul

AU - Benz, Christopher

AU - Stuart, Joshua M.

AU - Wong, Christopher K.

AU - Yau, Christina

AU - Hayes, D. Neil

AU - Parker, Joel S.

AU - Wilkerson, Matthew D.

AU - Ally, Adrian

AU - Balasundaram, Miruna

AU - Bowlby, Reanne

AU - Brooks, Denise

AU - Carlsen, Rebecca

AU - Chuah, Eric

AU - Dhalla, Noreen

AU - Holt, Robert

AU - Jones, Steven J.M.

AU - Kasaian, Katayoon

AU - Lee, Darlene

AU - Ma, Yussanne

AU - Marra, Marco A.

AU - Mayo, Michael

AU - Moore, Richard A.

AU - Mungall, Andrew J.

AU - Mungall, Karen

AU - Robertson, A. Gordon

AU - Sadeghi, Sara

AU - Schein, Jacqueline E.

AU - Sipahimalani, Payal

AU - Tam, Angela

AU - Thiessen, Nina

AU - Tse, Kane

AU - Wong, Tina

AU - Berger, Ashton C.

AU - Beroukhim, Rameen

AU - Cherniack, Andrew D.

AU - Cibulskis, Carrie

AU - Gabriel, Stacey B.

AU - Gao, Galen F.

AU - Ha, Gavin

AU - Meyerson, Matthew

AU - Schumacher, Steven E.

AU - Shih, Juliann

AU - Kucherlapati, Melanie H.

AU - Kucherlapati, Raju S.

AU - Baylin, Stephen

AU - Cope, Leslie

AU - Danilova, Ludmila

AU - Bootwalla, Moiz S.

AU - Lai, Phillip H.

AU - Maglinte, Dennis T.

AU - Van Den Berg, David J.

AU - Weisenberger, Daniel J.

AU - Auman, J. Todd

AU - Balu, Saianand

AU - Bodenheimer, Tom

AU - Fan, Cheng

AU - Hoadley, Katherine A.

AU - Hoyle, Alan P.

AU - Jefferys, Stuart R.

AU - Jones, Corbin D.

AU - Meng, Shaowu

AU - Mieczkowski, Piotr A.

AU - Mose, Lisle E.

AU - Perou, Amy H.

AU - Perou, Charles M.

AU - Roach, Jeffrey

AU - Shi, Yan

AU - Simons, Janae V.

AU - Skelly, Tara

AU - Soloway, Matthew G.

AU - Tan, Donghui

AU - Veluvolu, Umadevi

AU - Fan, Huihui

AU - Hinoue, Toshinori

AU - Laird, Peter W.

AU - Shen, Hui

AU - Zhou, Wanding

AU - Bellair, Michelle

AU - Chang, Kyle

AU - Covington, Kyle

AU - Creighton, Chad J.

AU - Dinh, Huyen

AU - Doddapaneni, Harsha Vardhan

AU - Donehower, Lawrence A.

AU - Drummond, Jennifer

AU - Gibbs, Richard A.

AU - Glenn, Robert

AU - Hale, Walker

AU - Han, Yi

AU - Hu, Jianhong

AU - Korchina, Viktoriya

AU - Lee, Sandra

AU - Lewis, Lora

AU - Li, Wei

AU - Liu, Xiuping

AU - Morgan, Margaret

AU - Morton, Donna

AU - Muzny, Donna

AU - Santibanez, Jireh

AU - Sheth, Margi

AU - Shinbrot, Eve

AU - Wang, Linghua

AU - Wang, Min

AU - Wheeler, David A.

AU - Xi, Liu

AU - Zhao, Fengmei

AU - Hess, Julian

AU - Appelbaum, Elizabeth L.

AU - Bailey, Matthew

AU - Cordes, Matthew G.

AU - Ding, Li

AU - Fronick, Catrina C.

AU - Fulton, Lucinda A.

AU - Fulton, Robert S.

AU - Kandoth, Cyriac

AU - Mardis, Elaine R.

AU - McLellan, Michael D.

AU - Miller, Christopher A.

AU - Schmidt, Heather K.

AU - Wilson, Richard K.

AU - Crain, Daniel

AU - Curley, Erin

AU - Gardner, Johanna

AU - Lau, Kevin

AU - Mallery, David

AU - Morris, Scott

AU - Paulauskis, Joseph

AU - Penny, Robert

AU - Shelton, Candace

AU - Shelton, Troy

AU - Sherman, Mark

AU - Thompson, Eric

AU - Yena, Peggy

AU - Bowen, Jay

AU - Gastier-Foster, Julie M.

AU - Gerken, Mark

AU - Leraas, Kristen M.

AU - Creaney, Jenette

PY - 2018/4/3

Y1 - 2018/4/3

N2 - For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease.

AB - For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease.

KW - mutations of clinical relevance

KW - RNA

KW - splicing

UR - http://www.scopus.com/inward/record.url?scp=85044896624&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.03.052

DO - 10.1016/j.celrep.2018.03.052

M3 - Article

VL - 23

SP - 270-281.e3

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 1

ER -