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 language | English |
|---|---|
| Pages (from-to) | 211-224.e6 |
| Journal | Cancer Cell |
| Volume | 34 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 13 Aug 2018 |
Keywords
- alternative splicing
- cancer
- CPTAC
- exome
- GTEx
- immunoediting
- immunotherapy
- MS proteomics
- neoantigens
- RNA-seq
- splicing QTL
- TCGA
- TCGA Pan-Cancer Atlas
- tumor-specific splicing
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In: Cancer Cell, Vol. 34, No. 2, 13.08.2018, p. 211-224.e6.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients
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 - Looijenga, Leendert
AU - Timmers, Henri
AU - de Krijger, Ronald
N1 - Funding Information: Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc and a shareholder and advisory board member of Tempus. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae. Funding Information: Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals . Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck , Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD , NIH , and Astex Pharmaceuticals . Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc and a shareholder and advisory board member of Tempus. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma . Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae. Funding Information: We would like to thank the ICGC/PCAWG Transcriptome Working Group (in particular, Angela Brooks and Yuichi Shiraishi), Mitch Levesque, Mark Rubin, Ruedi Aebersold, Alessandra Curioni, Michal Bassani-Sternberg, George Coukos, and Nikolaus Schultz for fruitful discussions and feedback on project design, specific methods, and the manuscript. We also gratefully acknowledge the thorough review by the reviewers that has led to significant improvements of the manuscript. Data used in this publication were generated by the CPTAC (NCI/NIH). O.K. and T.S. acknowledge support from BMBF 031A535A . This work was funded by MSKCC core funding, ETH Zurich core funding to G.R., and SFA PHRT project grant PHRT #106 by the ETH Board to G.R. Publisher Copyright: © 2018 Elsevier Inc.
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
C2 - 30078747
AN - SCOPUS:85051096107
SN - 1535-6108
VL - 34
SP - 211-224.e6
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -