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Comparative Assessment of Diagnostic Homologous Recombination Deficiency-Associated Mutational Signatures in Ovarian Cancer.
Sztupinszki, Zsofia; Diossy, Miklos; Borcsok, Judit; Prosz, Aurel; Cornelius, Nanna; Kjeldsen, Maj K; Mirza, Mansoor R; Szallasi, Zoltan.
Afiliación
  • Sztupinszki Z; Danish Cancer Society Research Center, Copenhagen, Denmark.
  • Diossy M; Computational Health Informatics Program (CHIP), Boston Children's Hospital, Harvard Medical School Teaching Hospital, Boston, Massachusetts.
  • Borcsok J; Danish Cancer Society Research Center, Copenhagen, Denmark.
  • Prosz A; Danish Cancer Society Research Center, Copenhagen, Denmark.
  • Cornelius N; Danish Cancer Society Research Center, Copenhagen, Denmark.
  • Kjeldsen MK; OvaCure Foundation, Copenhagen, Denmark.
  • Mirza MR; Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark.
  • Szallasi Z; Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark.
Clin Cancer Res ; 27(20): 5681-5687, 2021 10 15.
Article en En | MEDLINE | ID: mdl-34380641
PURPOSE: Homologous recombination (HR) deficiency (HRD) is one of the key determinants of PARP inhibitor response in ovarian cancer, and its accurate detection in tumor biopsies is expected to improve the efficacy of this therapy. Because HRD induces a wide array of genomic aberrations, mutational signatures may serve as a companion diagnostic to identify PARP inhibitor-responsive cases. EXPERIMENTAL DESIGN: From the The Cancer Genome Atlas (TCGA) whole-exome sequencing (WES) data, we extracted different types of mutational signature-based HRD measures, such as the HRD score, genome-wide LOH, and HRDetect trained on ovarian and breast cancer-specific sequencing data. We compared their performance to identify BRCA1/2-deficient cases in the TCGA ovarian cancer cohort and predict survival benefit in platinum-treated, BRCA1/2 wild-type ovarian cancer. RESULTS: We found that the HRD score, which is based on large chromosomal alterations alone, performed similarly well to an ovarian cancer-specific HRDetect, which incorporates mutations on a finer scale as well (AUC = 0.823 vs. AUC = 0.837). In an independent cohort these two methods were equally accurate predicting long-term survival after platinum treatment (AUC = 0.787 vs. AUC = 0.823). We also found that HRDetect trained on ovarian cancer was more accurate than HRDetect trained on breast cancer data (AUC = 0.837 vs. AUC = 0.795; P = 0.0072). CONCLUSIONS: When WES data are available, methods that quantify only large chromosomal alterations such as the HRD score and HRDetect that captures a wider array of HRD-induced genomic aberrations are equally efficient identifying HRD ovarian cancer cases.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Recombinación Homóloga / Mutación Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Female / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2021 Tipo del documento: Article País de afiliación: Dinamarca

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Recombinación Homóloga / Mutación Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Female / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2021 Tipo del documento: Article País de afiliación: Dinamarca