SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair.

Oncogene
N KanuC Swanton

Abstract

Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away fro...Continue Reading

References

Sep 19, 1996·The New England Journal of Medicine·R J MotzerD M Nanus
Dec 28, 1999·Trends in Cell Biology·D P CahillC Lengauer
Feb 19, 2004·Journal of the National Cancer Institute·Asad UmarSudhir Srivastava
Oct 23, 2004·Science·UNKNOWN ENCODE Project Consortium
Nov 30, 2005·Proceedings of the National Academy of Sciences of the United States of America·Ming LiPei Zhou
Dec 22, 2007·Science·Anja GrothGeneviève Almouzni
Feb 12, 2008·Current Protocols in Molecular Biology·Ken Zaret
Mar 8, 2008·Science·Thanos D HalazonetisJiri Bartek
Dec 9, 2008·Cancer Cell·Beth A Weaver, Don W Cleveland
May 20, 2009·Bioinformatics·Heng Li, Richard Durbin
May 12, 2010·Bioinformatics·Aaron L StathamMark D Robinson
Sep 3, 2010·Oncology Reports·Giuseppe AltavillaLuciano Giacomelli
Sep 15, 2010·Proceedings of the National Academy of Sciences of the United States of America·Peter Van LooVessela N Kristensen
Oct 15, 2010·Nature Biotechnology·Bradley E BernsteinJames A Thomson
Apr 29, 2011·PLoS Biology·UNKNOWN ENCODE Project Consortium
Jun 3, 2011·Science Translational Medicine·Natsuko SuwakiGeorge V Thomas
Jul 26, 2011·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Rebecca RoylanceCharles Swanton
Jul 28, 2011·Nature Structural & Molecular Biology·Sérgio Fernandes de AlmeidaMaria Carmo-Fonseca
Jan 18, 2012·Nature Reviews. Urology·James LarkinCharles Swanton
Mar 9, 2012·The New England Journal of Medicine·Marco GerlingerCharles Swanton
Jun 23, 2012·Genome Research·Simon AndersWolfgang Huber
Jul 10, 2012·Nature Structural & Molecular Biology·Mads DaugaardMarja Jäättelä
Jul 20, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
Sep 18, 2012·Cell·Ramaswamy GovindanRichard K Wilson
Jan 16, 2013·Cell Reports·Ludmil B AlexandrovMichael R Stratton
Jan 18, 2013·Nucleic Acids Research·Sílvia CarvalhoSérgio Fernandes de Almeida
Mar 30, 2013·Cancer Discovery·Lynn BjerkeChris Jones
May 30, 2013·The Journal of Pathology·Pierre MartinezCharles Swanton
Jun 25, 2013·Nature·UNKNOWN Cancer Genome Atlas Research Network
Aug 16, 2013·Nature·Ludmil B AlexandrovMichael R Stratton

❮ Previous
Next ❯

Citations

Jan 20, 2016·Science·Ludmil B Alexandrov
Nov 26, 2015·Cancer Cell·Sophia X PfisterTimothy C Humphrey
Apr 2, 2015·Biochimica Et Biophysica Acta·Samra TurajlicCharles Swanton
May 22, 2016·Carcinogenesis·Mia Petljak, Ludmil B Alexandrov
Apr 14, 2016·Genes, Chromosomes & Cancer·Lu WangMeera Hameed
Aug 23, 2016·Future Medicinal Chemistry·David S RogawskiTomasz Cierpicki
Sep 17, 2016·Genome Biology·Nnennaya KanuCharles Swanton
Jun 19, 2016·Journal of Medical Genetics·Camille TlemsaniLydie Burglen
Jan 29, 2017·Biochimica Et Biophysica Acta. Molecular Cell Research·Xin YiJiang Chang
Mar 10, 2017·Nature Reviews. Disease Primers·James J HsiehVincenzo Ficarra
Nov 26, 2016·Radiation Protection Dosimetry·E Forssell-Aronsson, R A Quinlan
Feb 6, 2017·Cold Spring Harbor Perspectives in Medicine·Catherine C Fahey, Ian J Davis
Nov 29, 2016·Nature Communications·Swaminathan VenkateshJerry L Workman
Apr 8, 2017·Cellular and Molecular Life Sciences : CMLS·Stephen L McDaniel, Brian D Strahl
Apr 1, 2018·European Journal of Clinical Investigation·Christiana DemetriouPaolo Vineis
Oct 30, 2018·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·James J HsiehEmily H Cheng
Mar 18, 2015·Nature Reviews. Urology·Louise Stone
May 31, 2019·Cellular and Molecular Life Sciences : CMLS·Jie LiGang Greg Wang
Oct 18, 2015·EMBO Reports·Tianyi ZhangNeil Brockdorff
Jan 5, 2016·Nature Structural & Molecular Biology·Alex M JaegerDennis J Thiele
Jan 30, 2020·Journal of Cellular Physiology·Ling MaYinghui Huang
Dec 10, 2015·Oncotarget·Rochelle L TiedemannKeith D Robertson
Jun 6, 2020·International Journal of Molecular Sciences·Margherita MartelliSimona Soverini
Mar 5, 2020·Wiley Interdisciplinary Reviews. RNA·Michael TellierShona Murphy
Mar 23, 2019·Cancers·Mafalda Ramos de MatosSérgio Fernandes de Almeida
Apr 11, 2019·Proceedings of the National Academy of Sciences of the United States of America·Krupa S JaniTom W Muir
May 22, 2019·Nature Reviews. Urology·Ronan FlippotGabriel G Malouf
Jul 22, 2018·Nature Reviews. Urology·Aguirre A de Cubas, W Kimryn Rathmell
Dec 21, 2016·Molecular Cancer·Klaudia K BrodaczewskaAnna M Czarnecka
Aug 14, 2018·Current Pharmacology Reports·Yi Ching Esther WanKui Ming Chan
Apr 24, 2018·American Journal of Medical Genetics. Part a·Maartje C van RijMartine J van Belzen

❮ Previous
Next ❯

Datasets Mentioned

BETA
GSE19465
GSM621634
GSM773000
GSM621638
GSM7733000
GSM621424
GSM772733

Methods Mentioned

BETA
ChIP-Seq
chromosomal aberrations
biopsies
RNA-Seq
PCR
transfections
immunoprecipitation

Software Mentioned

ChromaBlocks
Repitools
MutSig
DEXSeq
bwa
Picard MarkDuplicates
TumourBoost
Ensembl
aroma R package
ASCAT

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.

CREs: Gene & Cell Therapy

Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.

Adenocarcinoma, Clear Cell

Clear Cell Adenocarcinoma is a tumor that arises in the female genital tract and is characterized by cells that appear clear under the microscope. Discover the latest research here.