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Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.

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dc.contributor.authorKnijnenburg, Theo A
dc.contributor.authorWang, Linghua
dc.contributor.authorZimmermann, Michael T
dc.contributor.authorChambwe, Nyasha
dc.contributor.authorGao, Galen F
dc.contributor.authorCherniack, Andrew D
dc.contributor.authorFan, Huihui
dc.contributor.authorShen, Hui
dc.contributor.authorWay, Gregory P
dc.contributor.authorGreene, Casey S
dc.contributor.authorLiu, Yuexin
dc.contributor.authorAkbani, Rehan
dc.contributor.authorFeng, Bin
dc.contributor.authorDonehower, Lawrence A
dc.contributor.authorMiller, Chase
dc.contributor.authorShen, Yang
dc.contributor.authorKarimi, Mostafa
dc.contributor.authorChen, Haoran
dc.contributor.authorKim, Pora
dc.contributor.authorJia, Peilin
dc.contributor.authorShinbrot, Eve
dc.contributor.authorZhang, Shaojun
dc.contributor.authorLiu, Jianfang
dc.contributor.authorHu, Hai
dc.contributor.authorBailey, Matthew H
dc.contributor.authorYau, Christina
dc.contributor.authorWolf, Denise
dc.contributor.authorZhao, Zhongming
dc.contributor.authorWeinstein, John N
dc.contributor.authorLi, Lei
dc.contributor.authorDing, Li
dc.contributor.authorMills, Gordon B
dc.contributor.authorLaird, Peter W
dc.contributor.authorWheeler, David A
dc.contributor.authorShmulevich, Ilya
dc.contributor.authorCancer Genome Atlas Research Network
dc.contributor.authorMonnat, Raymond J
dc.contributor.authorXiao, Yonghong
dc.contributor.authorWang, Chen
dc.date.accessioned2018-09-20T12:03:58Z
dc.date.available2018-09-20T12:03:58Z
dc.date.issued2018-04-03
dc.description.abstractDNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.
dc.format.mediumPrint
dc.identifier.doi10.17863/CAM.27829
dc.identifier.eissn2211-1247
dc.identifier.issn2211-1247
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280458
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.celrep.2018.03.076
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectDNA damage footprints
dc.subjectDNA damage repair
dc.subjectThe Cancer Genome Atlas PanCanAtlas project
dc.subjectepigenetic silencing
dc.subjectintegrative statistical analysis
dc.subjectmutational signatures
dc.subjectprotein structure analysis
dc.subjectsomatic copy-number alterations
dc.subjectsomatic mutations
dc.subjectCell Line, Tumor
dc.subjectDNA Damage
dc.subjectGene Silencing
dc.subjectGenome, Human
dc.subjectHumans
dc.subjectLoss of Heterozygosity
dc.subjectMachine Learning
dc.subjectMutation
dc.subjectNeoplasms
dc.subjectRecombinational DNA Repair
dc.subjectTumor Suppressor Proteins
dc.titleGenomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.
dc.typeArticle
dcterms.dateAccepted2018-03-19
prism.endingPage254.e6
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameCell Rep
prism.startingPage239
prism.volume23
pubs.declined2018-06-07T09:17:43.425+0100
rioxxterms.licenseref.startdate2018-04
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.celrep.2018.03.076

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