EGAGenomicsIllumina HiSeq 2000, Illumina Genome Analyzer II, ILLUMINAOtherhttps://ega-archive.org/studies/EGAS00001002390EGAEGA study EGAS00001002390ENOC WGS for the study Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypesGCT WGS for the study Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypesCCOC WGS for the study Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypesHGSC WGS for the study Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypesrestrictedEGAOvary Cancer, Cancer of the Ovary, atypia, Cancer of Ovary, aberrant, ovarian neoplasm, Neoplasms, Ovarian Cancer, Ovary, ovarian epithelial cancer, Ovary Neoplasm., OC, Ovary Neoplasms, defective, Cancers, Ovary Cancers, primary ovarian cancer, ovary neoplasm, malignant tumour of ovary, ovarian cancer, Ovarian Neoplasm, epithelial, Ovarian, tumor of the Ovary, malignant Ovarian tumor, DNA Damage Response, Neoplasm, atypical, Ovarian Cancers, CancerBiological Markers, Viral Marker, Materials, Surrogate Endpoints, Laboratory, Period Prevalence, Ass-1, neoplasia, adult stage, QC, Biochemical, Endpoint, Tumor, Serum, clefted, granular cell tumour NOS (morphologic abnormality), Mutation Frequency, Mutations, malignant tumour of ovary, Laboratory Markers, ovarian cancer, Point Prevalence, Biological, AA408052, Point Prevalences, fold, Mutation Frequencies, adult, imprinted and ancient gene protein, treatment, Man (Taxonomy), Gene Expressions, enzymes, Genomes, Prevalences, cell process disease, tumor disease, neoplasm (disease), apoB mRNA editing enzyme complex, Clear Cells, primary ovarian cancer, high grade, ASS, set, Immune, Markers, Viral Markers, disease management, Therapies, Ovarian Cancers, tumor, Frequency, Tumors, Diagnostic Findings, Therapy, SIGNS SYMPTOMS, Prevalence, Cancer of Ovary, anatomical protrusion, Viral, subdivided, Surrogate Endpoint, aberrant, DESC, Modern, frequency, Ovary Neoplasm., neoplastic disease, Biochemical Markers, Biologic Marker, tumours, epithelial, Frequencies, Marker, malignant Ovarian tumor, RENBP, Genetic Materials, Adults, neoplasm of granular cell, granular cell tumor NOS (morphologic abnormality), Genetic Material, forked, Ovary Neoplasm, grade 3/4, divided, End Points, Ovary Neoplasms, INSDC_feature:gene, whole genome, Immunologic, Laboratory Marker, septate, surveillance, morbidity, Treatments, human, ovary neoplasm, AGE, Patient, spine, Material, Biochemical Marker, Cells, Biocatalyst, Cistron, other neoplasm, E430016J11Rik, GCT, Clinical Finding, Gruppe, Ovary Cancer, atypia, human being, localised, Clinical Markers, Biocatalysts, Clinical Marker, Neoplasms, Gene, Period Prevalences, APOBEC, Ximpact, Symptoms and Signs, NEOPL, protrusion, Human, Surrogate End Points, Surrogate Markers, Rate, Homo sapiens, Ovarian, granulosa cell of ovary, Core Genome, DNA Damage Response, atypical, Finding, neoplasm, Man, Biomarker, localized, Genetic, Clinical, occurrence, Biological Marker, Accessory Genome, Ovarian Cancer, prevalence, tumour, Granulosa, Expressions, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS), Enzyme, Immunologic Markers, grupos, Clients, Expression, Immunologic Marker, Neoplastic Growth, incidence, Biologic, Cancer, Granulosa Cell, grupo, ovarian neoplasm, RnBP, Serum Markers, Ovary, Point Mutations, GlcNAc 2-epimerase, End Point, enzyme activity, defective, Ovary Cancers, Cistrons, Pangenome, Client, impact-a, Cell, group, Immune Marker, Signs and Symptoms, neoplastic growth, N-acetyl-D-glucosamine 2-epimerase, Period, Surrogate End Point, Mutation Rates, Neoplasm, imprinted and ancient gene protein homolog, IMPACT, Mutation, outbreaks, Biologic Markers, Cancer of the Ovary, Rates, sQC, Serum Marker, distinct, ensemble, Surrogate, Endpoints, Rest, ovarian epithelial cancer, OC, Cancers, disease of cellular proliferation, endemics, Surrogate Marker, Pan-genome, Ovarian Neoplasm, Therapeutic, tumor of the Ovary, Point, Modern Man, ovarian granulosa cell, renin-binding protein, epidemics, Treatment, groupe, NEOPLASMS BENIGN, Neoplasia, RWDD5, Immune MarkersfalseGenomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypesAberrant DNA repair processes are a hallmark of human tumours. How these deficiencies variously impact the genomes of ovarian cancer between and within histotypes remains unknown. We studied the whole genome pointmutation and structural variation patterns of 133 tumours (59 high grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell tumours (GCT)) as a substrate for class discovery in ovarian cancer. Ab-initio clustering of integrated point mutation and structural variation signatures revealed seven novel subgroups, comprising between and within histotype stratification. Prevalence of fold-back inversions (FBI) co-localised with high level amplification events divided HGSC into two prognostically significant subgroups. This finding was recapitulated in two additional independent cohorts (total n=576 cases), and transcended gene based mutation status and gene expression as prognostically relevant features of HGSC. CCOC were divided into one group harbouring a signature reflective of active genome editing via APOBEC enzymes (26%) and a complementary group with an age-relatedmutational signature. ENOC were divided intomicrosatellite instable (MSI) cases (28%) with a distinctmismatch repairmutation signature and an outlying mutation rate, with the remainder of cases distributed amongst the remaining six groups. We suggest the FBI, MSI, and APOBEC groups represent biologic strata that could direct treatment strategies. Taken together, our work establishes the efficacy of the somatic genome as a biomarker to stratify ovarian cancers, simultaneously identifying patients that may benefit from emerging therapeutics and distinct subgroups within classic ovarian cancer histotypes.2022-11-22 12:10:03EGAS000010023909606EGAD00001003266EGAD00001003267EGAD00001003268EGAD00001003265EGAC00000000011