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Genomic analyses of germline and somatic variation in high-grade serous ovarian cancer.
Adamson, A W; Ding, Y C; Steele, L; Leong, L A; Morgan, R; Wakabayashi, M T; Han, E S; Dellinger, T H; Lin, P S; Hakim, A A; Wilczynski, S; Warden, C D; Tao, S; Bedell, V; Cristea, M C; Neuhausen, S L.
Affiliation
  • Adamson AW; Department of Population Sciences, Beckman Research Institute of City of Hope, CA, Duarte, USA.
  • Ding YC; Department of Population Sciences, Beckman Research Institute of City of Hope, CA, Duarte, USA.
  • Steele L; Department of Population Sciences, Beckman Research Institute of City of Hope, CA, Duarte, USA.
  • Leong LA; Formerly, Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
  • Morgan R; Formerly, Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
  • Wakabayashi MT; Currently at Regeneron Pharmaceuticals Inc, Formerly City of Hope National Medical Center, Duarte, CA, USA.
  • Han ES; Formerly, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.
  • Dellinger TH; Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.
  • Lin PS; Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.
  • Hakim AA; Formerly, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.
  • Wilczynski S; Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA.
  • Warden CD; Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
  • Tao S; Integrative Genomics Core, Beckman Research Institute of City of Hope, Duarte, CA, USA.
  • Bedell V; Integrative Genomics Core, Beckman Research Institute of City of Hope, Duarte, CA, USA.
  • Cristea MC; Cytogenetics Core, City of Hope National Medical Center, Duarte, CA, USA.
  • Neuhausen SL; Formerly, Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
J Ovarian Res ; 16(1): 141, 2023 Jul 17.
Article in En | MEDLINE | ID: mdl-37460928
ABSTRACT

BACKGROUND:

High-grade serous ovarian cancers (HGSCs) display a high degree of complex genetic alterations. In this study, we identified germline and somatic genetic alterations in HGSC and their association with relapse-free and overall survival. Using a targeted capture of 557 genes involved in DNA damage response and PI3K/AKT/mTOR pathways, we conducted next-generation sequencing of DNA from matched blood and tumor tissue from 71 HGSC participants. In addition, we performed the OncoScan assay on tumor DNA from 61 participants to examine somatic copy number alterations (SCNA).

RESULTS:

Approximately one-third of tumors had loss-of-function (LOF) germline (18/71, 25.4%) or somatic (7/71, 9.9%) variants in the DNA homologous recombination repair pathway genes BRCA1, BRCA2, CHEK2, MRE11A, BLM, and PALB2. LOF germline variants also were identified in other Fanconi anemia genes and in MAPK and PI3K/AKT/mTOR pathway genes. Most tumors harbored somatic TP53 variants (65/71, 91.5%). Using the OncoScan assay on tumor DNA from 61 participants, we identified focal homozygous deletions in BRCA1, BRCA2, MAP2K4, PTEN, RB1, SLX4, STK11, CREBBP, and NF1. In total, 38% (27/71) of HGSC patients harbored pathogenic variants in DNA homologous recombination repair genes. For patients with multiple tissues from the primary debulking or from multiple surgeries, the somatic mutations were maintained with few newly acquired point mutations suggesting that tumor evolution was not through somatic mutations. There was a significant association of LOF variants in homologous recombination repair pathway genes and high-amplitude somatic copy number alterations. Using GISTIC analysis, we identified NOTCH3, ZNF536, and PIK3R2 in these regions that were significantly associated with an increase in cancer recurrence and a reduction in overall survival.

CONCLUSIONS:

From 71 patients with HGCS, we performed targeted germline and tumor sequencing and provided a comprehensive analysis of these 557 genes. We identified germline and somatic genetic alterations including somatic copy number alterations and analyzed their associations with relapse-free and overall survival. This single-site long-term follow-up study provides additional information on genetic alterations related to occurrence and outcome of HGSC. Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Female / Humans Language: En Journal: J Ovarian Res Year: 2023 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms Type of study: Observational_studies / Prognostic_studies / Risk_factors_studies Limits: Female / Humans Language: En Journal: J Ovarian Res Year: 2023 Document type: Article