13
IRUS Total
Downloads

Systematic analysis of splice-site-creating mutations in cancer

File Description SizeFormat 
1-s2.0-S2211124718303978-main.pdfPublished version10.26 MBAdobe PDFView/Open
Title: Systematic analysis of splice-site-creating mutations in cancer
Authors: Jayasinghe, RG
Cao, S
Gao, Q
Wendl, MC
Vo, NS
Reynolds, SM
Zhao, Y
Climente-Gonzalez, H
Chai, S
Wang, F
Varghese, R
Huang, M
Liang, W-W
Wyczalkowski, MA
Sengupta, S
Li, Z
Payne, SH
Fenyo, D
Miner, JH
Walter, MJ
Vincent, B
Eyras, E
Chen, K
Shmulevich, I
Chen, F
Ding, L
Item Type: Journal Article
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.
Issue Date: 3-Apr-2018
Date of Acceptance: 13-Mar-2018
URI: http://hdl.handle.net/10044/1/71240
DOI: https://doi.org/10.1016/j.celrep.2018.03.052
ISSN: 2211-1247
Publisher: Elsevier
Start Page: 270
End Page: 281.e3
Journal / Book Title: Cell Reports
Volume: 23
Issue: 1
Copyright Statement: © 2018 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: SAIC-F-Frederick, Inc
Leidos Biomedical Research, Inc.
Funder's Grant Number: TCGA Pilot Program
15Y011ST
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
MESSENGER-RNA
SYNONYMOUS MUTATIONS
UNCLASSIFIED VARIANTS
REPORTER MINIGENE
GENETIC-VARIANTS
BREAST-CANCER
ABERRANT
RETINOBLASTOMA
TRANSCRIPTOME
INACTIVATION
RNA
mutations of clinical relevance
splicing
Cancer Genome Atlas Research Network
Science & Technology
Life Sciences & Biomedicine
Cell Biology
MESSENGER-RNA
SYNONYMOUS MUTATIONS
UNCLASSIFIED VARIANTS
REPORTER MINIGENE
GENETIC-VARIANTS
BREAST-CANCER
ABERRANT
RETINOBLASTOMA
TRANSCRIPTOME
INACTIVATION
Publication Status: Published
Online Publication Date: 2018-04-05
Appears in Collections:Department of Surgery and Cancer