Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal samples; on average, we identified ≈930 exon-exon junctions (“neojunctions”) in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor samples, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor sample that are also predicted major histocompatibility complex-I binders (“putative neoantigens”). A pan-cancer analysis by Kahles et al. shows increased alternative splicing events in tumors versus normal tissue and identifies trans-acting variants associated with alternative splicing events. Tumors contain neojunction-derived peptides absent in normal samples, including predicted MHC-I binders that are putative neoantigens.

Original languageEnglish
Pages (from-to)211-224.e6
JournalCancer Cell
Volume34
Issue number2
DOIs
Publication statusPublished - 13 Aug 2018

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Alternative Splicing
Neoplasms
Exons
Exome
Peptides
Atlases
Major Histocompatibility Complex
Proteomics
Nucleotides
Genome
RNA
Breast Neoplasms

Cite this

The Cancer Genome Atlas Research Network. / Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients. In: Cancer Cell. 2018 ; Vol. 34, No. 2. pp. 211-224.e6.
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Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients. / The Cancer Genome Atlas Research Network.

In: Cancer Cell, Vol. 34, No. 2, 13.08.2018, p. 211-224.e6.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients

AU - The Cancer Genome Atlas Research Network

AU - Kahles, André

AU - Lehmann, Kjong Van

AU - Toussaint, Nora C.

AU - Hüser, Matthias

AU - Stark, Stefan G.

AU - Sachsenberg, Timo

AU - Stegle, Oliver

AU - Kohlbacher, Oliver

AU - Sander, Chris

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 - Lichtenberg, Tara M.

AU - Ramirez, Nilsa C.

AU - Wise, Lisa

AU - Zmuda, Erik

AU - Corcoran, Niall

AU - Costello, Tony

AU - Hovens, Christopher

AU - Carvalho, Andre L.

AU - de Carvalho, Ana C.

AU - Fregnani, José H.

AU - Longatto-Filho, Adhemar

AU - Creaney, Jenette

PY - 2018/8/13

Y1 - 2018/8/13

N2 - Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal samples; on average, we identified ≈930 exon-exon junctions (“neojunctions”) in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor samples, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor sample that are also predicted major histocompatibility complex-I binders (“putative neoantigens”). A pan-cancer analysis by Kahles et al. shows increased alternative splicing events in tumors versus normal tissue and identifies trans-acting variants associated with alternative splicing events. Tumors contain neojunction-derived peptides absent in normal samples, including predicted MHC-I binders that are putative neoantigens.

AB - Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal samples. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal samples; on average, we identified ≈930 exon-exon junctions (“neojunctions”) in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor samples, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor sample that are also predicted major histocompatibility complex-I binders (“putative neoantigens”). A pan-cancer analysis by Kahles et al. shows increased alternative splicing events in tumors versus normal tissue and identifies trans-acting variants associated with alternative splicing events. Tumors contain neojunction-derived peptides absent in normal samples, including predicted MHC-I binders that are putative neoantigens.

KW - alternative splicing

KW - cancer

KW - CPTAC

KW - exome

KW - GTEx

KW - immunoediting

KW - immunotherapy

KW - MS proteomics

KW - neoantigens

KW - RNA-seq

KW - splicing QTL

KW - TCGA

KW - TCGA Pan-Cancer Atlas

KW - tumor-specific splicing

UR - http://www.scopus.com/inward/record.url?scp=85051096107&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.07.001

DO - 10.1016/j.ccell.2018.07.001

M3 - Article

VL - 34

SP - 211-224.e6

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 2

ER -