Clinical importance of FANCD2, BRIP1, BRCA1, BRCA2 and FANCF expression in ovarian carcinomas

Cancer Biol Ther. 2019;20(6):843-854. doi: 10.1080/15384047.2019.1579955. Epub 2019 Mar 1.

Abstract

Objective: DNA repair pathways are potential targets of molecular therapy in cancer patients. The FANCD2, BRIP1, BRCA1/2, and FANCF genes are involved in homologous recombination DNA repair, which implicates their possible role in cell response to DNA-damaging agents. We evaluated a clinical significance of pre-treatment expression of these genes at mRNA level in 99 primary, advanced-stage ovarian carcinomas from patients, who later received taxane-platinum (TP) or platinum-cyclophosphamide (PC) treatment.

Methods: Gene expression was determined with the use of Real-Time PCR. The BRCA2 and BRIP1 gene sequence was investigated with the use of SSCP, dHPLC, and PCR-sequencing.

Results: Increased FANCD2 expression occurred to be a negative prognostic factor for all patients (PC+TP:HR 3.85, p = 0.0003 for the risk of recurrence; HR 1.96, p = 0.02 for the risk of death), and this association was even stronger in the TP-treated group (HR 6.7, p = 0.0002 and HR 2.33, p = 0.01, respectively). Elevated BRIP1 expression was the only unfavorable molecular factor in the PC-treated patients (HR 8.37, p = 0.02 for the risk of recurrence). Additionally, an increased FANCD2 and BRCA1/2 expression levels were associated with poor ovarian cancer outcome in either TP53-positive or -negative subgroups of the TP-treated patients, however these groups were small. Sequence analysis identified one protein truncating variant (1/99) in BRCA2 and no mutations (0/56) in BRIP1.

Conclusions: Our study shows for the first time that FANCD2 overexpression is a strong negative prognostic factor in ovarian cancer, particularly in patients treated with TP regimen. Moreover, increased mRNA level of the BRIP1 is a negative prognostic factor in the PC-treated patients. Next, changes in the BRCA2 and BRIP1 genes are rare and together with other analyzed FA genes considered as homologous recombination deficiency may not affect the expression level of analyzed genes.

Keywords: BRCA1; BRCA2; BRIP1; DNA repair; FANCD2; FANCF; FANCJ; TP53; gene expression; ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • Biomarkers, Tumor
  • Fanconi Anemia Complementation Group D2 Protein / genetics*
  • Fanconi Anemia Complementation Group F Protein / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Middle Aged
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / mortality
  • Ovarian Neoplasms / pathology*
  • Ovarian Neoplasms / therapy
  • Prognosis
  • Proportional Hazards Models
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Biomarkers, Tumor
  • FANCD2 protein, human
  • FANCF protein, human
  • Fanconi Anemia Complementation Group D2 Protein
  • Fanconi Anemia Complementation Group F Protein
  • Tumor Suppressor Protein p53

Grants and funding

This study was supported by the Polish Ministry of Science and Higher Education [NN301 462038].