Predictive biomarkers of platinum and taxane resistance using the transcriptomic data of 1816 ovarian cancer patients

Gynecol Oncol. 2020 Mar;156(3):654-661. doi: 10.1016/j.ygyno.2020.01.006. Epub 2020 Jan 20.

Abstract

Objective: The first-line chemotherapy for ovarian cancer is based on a combination of platinum and taxane. To date, no reliable predictive biomarker has been recognized that is capable of identifying patients with pre-existing resistance to these agents. Here, we have established an integrated database and identified the most significant biomarker candidates for chemotherapy resistance in serous ovarian cancer.

Methods: Gene arrays were collected from the GEO and TCGA repositories. Treatment response was defined based on pathological response or duration of relapse-free survival. The responder and nonresponder cohorts were compared using the Mann-Whitney and receiver operating characteristic tests. An independent validation set was established to investigate the correlation between chemotherapy response for the top 8 genes. Statistical significance was set at p < 0.05.

Results: The entire database included 1816 tumor samples from 12 independent datasets. From analyzing all the genes for platinum + taxane response, we identified the eight strongest genes correlated to chemotherapy resistance: AKIP1 (p = 1.60E-08, AUC = 0.728), MARVELD1 (p = 2.70E-07, AUC = 0.712), AKIRIN2 (p = 2.60E-07, AUC = 0.704), CFL1 (p = 8.10E-08, AUC = 0.694), SERBP1 (p = 8.10E-07, AUC = 0.684), PDXK (p = 1.30E-04, AUC = 0.634), TFE3 (p = 7.90E-05, AUC = 0.631) and NCOR2 (p = 1.90E-03, AUC = 0.611). Of these, the independent validation confirmed TFE3 (p = 0.012, AUC = 0.718), NCOR2 (p = 0.048, AUC = 0.671), PDXK (p = 0.019, AUC = 0.702), AKIP1 (p = 0.002, AUC = 0.773), MARVELD1 (p = 0.044, AUC = 0.675) and AKIRIN2 (p = 0.042, AUC = 0.676). An online interface was set up to enable future validation and ranking of new biomarker candidates in an automated manner (www.rocplot.org/ovar).

Conclusions: We compiled a large integrated database with available treatment and response information and used this to uncover new biomarkers of chemotherapy response in serous ovarian cancer.

Keywords: AKIP1; AKIRIN2; Chemotherapy; MARVELD1; NCOR2; PDXK; ROC; TFE3; Treatment resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Ovarian Epithelial / drug therapy*
  • Carcinoma, Ovarian Epithelial / genetics*
  • Cohort Studies
  • DNA-Binding Proteins / genetics
  • Databases, Genetic
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Organoplatinum Compounds / pharmacology*
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics*
  • Predictive Value of Tests
  • RNA, Neoplasm / genetics
  • Real-Time Polymerase Chain Reaction
  • Taxoids / pharmacology*
  • Transcription Factors / genetics

Substances

  • AKIP1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • NCOR2 protein, human
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 2
  • Organoplatinum Compounds
  • RNA, Neoplasm
  • Taxoids
  • Transcription Factors
  • ZBTB7A protein, human