Prognostic value of GRIM-19, NF-κB and IKK2 in patients with high-grade serous ovarian cancer

Felipe Ilelis; Nayra Soares do Amaral; Mariana Rezende Alves; Alexandre André Balieiro Anastácio da Costa; Vinícius Fernando Calsavara; Leonardo Lordello; Louise De Brot; Fernando Augusto Soares; Iara Sant'Ana Rodrigues; Rafael Malagoli Rocha

doi:10.1016/j.prp.2017.12.002

Prognostic value of GRIM-19, NF-κB and IKK2 in patients with high-grade serous ovarian cancer

Pathol Res Pract. 2018 Feb;214(2):187-194. doi: 10.1016/j.prp.2017.12.002. Epub 2017 Dec 6.

Affiliations

¹ Laboratory of Molecular Morphology, Department of Investigative Pathology,A.C.Camargo Cancer Center, Brazil. Electronic address: felipe.ilelis1@gmail.com.
² Laboratory of Molecular Morphology, Department of Investigative Pathology,A.C.Camargo Cancer Center, Brazil.
³ Department of Medical Oncology, A.C.Camargo Cancer Center, Brazil.
⁴ Department of Epidemiology and Statistics, A.C.Camargo Cancer Center, Brazil.
⁵ Department of Anatomic Pathology,A.C.Camargo Cancer Center, Brazil.
⁶ Laboratory of Molecular Gynaecology, Department of Gynaecology, Federal University of São Paulo, Brazil.

PMID: 29254797
DOI: 10.1016/j.prp.2017.12.002

Abstract

Aims: High grade serous carcinoma (HGSC) is an aggressive tumour, and most patients relapse after treatment, acquiring resistance to platinum-based chemotherapy. One of the resistance mechanisms proposed is apoptosis evasion triggered by drug-related cytotoxic effect in the cell. In this context, this study aims to evaluate the protein expression of GRIM-19, NF-κB and IKK2, their association with chemotherapy response and to determine their prognostic values in HGSC.

Methods: GRIM-19, NF-κB and IKK2 expression was evaluated by immunohistochemistry (IHC) in 71 patients with HGSC selected between 2003 and 2013, whose underwent primary debulking surgery with complete cytoreduction. Protein expression was analyzed in relation to platinum response groups, tumour progression, clinicopathological data and survival.

Results: Positive IKK2 expression was related to resistance (p = 0.011), shorter disease-free survival (p = 0.001) and overall survival (p = 0.026) and was also a risk factor for relapse (p = 0.002) and death (p = 0.032). The association between IKK2 and NF-κB positivity predicted a subgroup with shorter overall survival (p = 0.004), disease-free survival (p = 0.003) and resistance to platinum-based chemotherapy (p = 0.036). NF-κB positivity was associated with worse overall survival (p = 0.005) and disease-free survival (p = 0.027) and was a positive predictor for relapse (p = 0.032) and death (p = 0.008). Higher expression of GRIM-19 was associated with higher disease-free survival (p = 0.039) and was a negative predictor for relapse (p = 0.046).

Conclusions: GRIM-19 is a potential predictor of prognosis and disease recurrence in HGSC. IKK2 and NF-κB are related to poor prognosis and are potential predictors of response to platinum-based chemotherapy in HGSC. IHC analyses of GRIM19, IKK2 and NF-κB may be important in the attempt to provide prognostic values for relapse and response to treatment in patients with HGSC.

Keywords: Immunohistochemistry; Ovarian neoplasms; Platinum; Prognosis; Recurrence; Serous cystadenocarcinoma.

MeSH terms

Apoptosis Regulatory Proteins / metabolism*
Biomarkers, Tumor / analysis
Co-Repressor Proteins / metabolism*
Drug Resistance, Neoplasm / physiology
Female
Gene Expression Profiling / methods
Humans
I-kappa B Kinase / metabolism*
NADH, NADPH Oxidoreductases / metabolism*
Neoplasm Grading / methods
Neoplasms, Glandular and Epithelial / drug therapy
Neoplasms, Glandular and Epithelial / metabolism*
Nuclear Proteins / metabolism*
Ovarian Neoplasms / metabolism*
Tumor Microenvironment / physiology

Substances

Apoptosis Regulatory Proteins
Biomarkers, Tumor
Co-Repressor Proteins
NKAPL protein, human
Nuclear Proteins
NADH, NADPH Oxidoreductases
NDUFA13 protein, human
I-kappa B Kinase
IKBKB protein, human