Multi-omic measurement of mutually exclusive loss-of-function enriches for candidate synthetic lethal gene pairs

BMC Genomics
Mark WappettJonathan R Dry

Abstract

Identification of synthetic lethal interactions in cancer cells could offer promising new therapeutic targets. Large-scale functional genomic screening presents an opportunity to test large numbers of cancer synthetic lethal hypotheses. Methods enriching for candidate synthetic lethal targets in molecularly defined cancer cell lines can steer effective design of screening efforts. Loss of one partner of a synthetic lethal gene pair creates a dependency on the other, thus synthetic lethal gene pairs should never show simultaneous loss-of-function. We have developed a computational approach to mine large multi-omic cancer data sets and identify gene pairs with mutually exclusive loss-of-function. Since loss-of-function may not always be genetic, we look for deleterious mutations, gene deletion and/or loss of mRNA expression by bimodality defined with a novel algorithm BiSEp. Applying this toolkit to both tumour cell line and patient data, we achieve statistically significant enrichment for experimentally validated tumour suppressor genes and synthetic lethal gene pairings. Notably non-reliance on genetic loss reveals a number of known synthetic lethal relationships otherwise missed, resulting in marked improvement over genetic-on...Continue Reading

References

Apr 25, 2003·International Journal of Cancer. Journal International Du Cancer·Koichi NagasakiNicolai Maass
Feb 7, 2004·The EMBO Journal·Slimane Ait-Si-AliAnnick Harel-Bellan
Oct 29, 2005·Science·Scott A TomlinsArul M Chinnaiyan
Dec 31, 2005·Nucleic Acids Research·Chris StarkMike Tyers
Feb 24, 2006·Nature Reviews. Molecular Cell Biology·Jean Paul Thiery, Jonathan P Sleeman
Jun 11, 2008·Molecular and Cellular Biology·Anwaar AhmadLaura J Niedernhofer
Oct 11, 2008·Reproduction : the Official Journal of the Society for the Study of Fertility·Luca Magnani, Ryan A Cabot
Jun 26, 2009·The New England Journal of Medicine·Peter C FongJohann S de Bono
Jan 23, 2010·Science·Michael CostanzoCharles Boone
Jan 26, 2010·Biostatistics·Matthew N McCallRafael A Irizarry
Mar 3, 2010·BMC Genomics·Marina BessarabovaTatiana Nikolskaya
Oct 12, 2010·Journal of the American Society of Nephrology : JASN·Guangdong SunRama Natarajan
Feb 9, 2011·BMC Genomics·Clinton C MasonClifton Bogardus
Jun 15, 2011·Biochimica Et Biophysica Acta·Masayo Morishita, Eric di Luccio
Sep 17, 2011·Transcription·Agda Karina Lucio-Eterovic, Phillip B Carpenter
Aug 17, 2012·Nature·Florian L MullerRonald A DePinho
Oct 16, 2012·Nucleic Acids Research·Min ZhaoZhongming Zhao
Jan 5, 2013·Science·Le CongFeng Zhang
May 17, 2013·Human Genomics·Bajinder S DhanoaJames S Friedman
Sep 28, 2013·Nature Genetics·UNKNOWN Cancer Genome Atlas Research NetworkJoshua M Stuart
Feb 13, 2014·Proceedings of the National Academy of Sciences of the United States of America·Gregory R HoffmanZainab Jagani
Aug 1, 2014·Nature·UNKNOWN Cancer Genome Atlas Research Network
Oct 31, 2014·Nucleic Acids Research·Simon A ForbesPeter J Campbell
May 2, 2015·PloS One·Xiaowen LuMartijn A Huynen
Nov 1, 2015·Nucleic Acids Research·Pora KimZhongming Zhao

❮ Previous
Next ❯

Citations

Jan 18, 2017·Pigment Cell & Melanoma Research·Nicola ThompsonMarco Ranzani
Jun 27, 2017·Nature Reviews. Genetics·Nigel J O'NeilPhilip Hieter
Feb 8, 2019·Leukemia·Brooks BenardDaniel Thomas
Oct 14, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Roz BrantDarren R Hodgson
Feb 28, 2021·Nature Communications·Nicola A ThompsonDavid J Adams

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE36133

Methods Mentioned

BETA
exome sequencing
exome
ubiquitination
in silico methods

Software Mentioned

ATARIS
Bioconductor package
COSMIC
FuRE
RSEM
BioGrid
BISEP
MEMU
R
BEEM

Related Concepts

Related Feeds

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.