Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas
HUMAN COLON
MICROSATELLITE INSTABILITY
Medical Physiology
Loss of Heterozygosity
Cancer Genome Atlas Research Network
REPLICATION FORK STABILITY
Grade Gliomas
Machine Learning
PREDICTS RESPONSE
Neoplasms
2.1 Biological and endogenous factors
DNA damage repair
protein structure analysis
DNA damage footprints
DNA damage footprints; DNA damage repair; epigenetic silencing; integrative statistical analysis; mutational signatures; protein structure analysis; somatic copy-number alterations; somatic mutations; The Cancer Genome Atlas PanCanAtlas project;
Biology (General)
Cancer
0303 health sciences
Tumor
Genome
Therapeutic Opportunities
DNA damage footprints; DNA damage repair; The Cancer Genome Atlas PanCanAtlas project; epigenetic silencing; integrative statistical analysis; mutational signatures; protein structure analysis; somatic copy-number alterations; somatic mutations
Biological Sciences
epigenetic silencing
Replication Fork Stability
Ovarian Cancer
3. Good health
Microsatellite Instability
INACTIVATION
somatic copy-number alterations
Life Sciences & Biomedicine
Human
STRUCTURAL BASIS
QH301-705.5
POLYMERASE-EPSILON
Bioinformatics and Computational Biology
610
mutational signatures
Article
Cell Line
03 medical and health sciences
Endometrial Cancers
Cancer Genomics
Rare Diseases
Cell Line, Tumor
Genetics
Humans
Gene Silencing
integrative statistical analysis
Science & Technology
MUTANT-CELLS
MUTATIONS
Genome, Human
Predicts Response
Tumor Suppressor Proteins
Human Genome
Recombinational DNA Repair
Cell Biology
Polymerase-Epsilon
Structural Basis
Promoter Hypermethylation
Orphan Drug
PROMOTER HYPERMETHYLATION
Fanconi-Anemia
Mutation
Women's Health
somatic mutations
Biochemistry and Cell Biology
The Cancer Genome Atlas PanCanAtlas project
DNA Damage
DOI:
10.1016/j.celrep.2018.03.076
Publication Date:
2018-04-05T14:55:36Z
AUTHORS (763)
ABSTRACT
DNA 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.
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CITATIONS (874)
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