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Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2023

Open Access 01-12-2023 | Ovarian Cancer | Research

High EVI1 and PARP1 expression as favourable prognostic markers in high-grade serous ovarian carcinoma

Authors: Paul Jank, Jonas Leichsenring, Svenja Kolb, Inga Hoffmann, Philip Bischoff, Catarina Alisa Kunze, Mihnea P. Dragomir, Moritz Gleitsmann, Moritz Jesinghaus, Wolfgang D. Schmitt, Hagen Kulbe, Christine Sers, Albrecht Stenzinger, Jalid Sehouli, Ioana Elena Braicu, Christina Westhoff, David Horst, Carsten Denkert, Stefan Gröschel, Eliane T. Taube

Published in: Journal of Ovarian Research | Issue 1/2023

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Abstract

Background

Mechanisms of development and progression of high-grade serous ovarian cancer (HGSOC) are poorly understood. EVI1 and PARP1, part of TGF-ß pathway, are upregulated in cancers with DNA repair deficiencies with DNA repair deficiencies and may influce disease progression and survival. Therefore we questioned the prognostic significance of protein expression of EVI1 alone and in combination with PARP1 and analyzed them in a cohort of patients with HGSOC.

Methods

For 562 HGSOC patients, we evaluated EVI1 and PARP1 expression by immunohistochemical staining on tissue microarrays with QuPath digital semi-automatic positive cell detection.

Results

High EVI1 expressing (> 30% positive tumor cells) HGSOC were associated with improved progression-free survival (PFS) (HR = 0.66, 95% CI: 0.504–0.852, p = 0.002) and overall survival (OS) (HR = 0.45, 95% CI: 0.352–0.563, p < 0.001), including multivariate analysis. Most interestingly, mutual high expression of both proteins identifies a group with particularly good prognosis. Our findings were proven technically and clinically using bioinformatical data sets for single-cell sequencing, copy number variation and gene as well as protein expression.

Conclusions

EVI1 and PARP1 are robust prognostic biomarkers for favorable prognosis in HGSOC and imply further research with respect to their reciprocity.
Appendix
Available only for authorised users
Literature
1.
Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.PubMedCrossRef
2.
3.
Kurman R, et al. WHO classification of tumours of female reproductive organs. Int Agency Res Cancer. 2014;6:22–4.
4.
Jorge S, et al. Simultaneous germline and somatic sequencing in ovarian carcinoma: mutation rate and impact on clinical decision-making. Gynecol Oncol. 2020;156(3):517–22.PubMedCrossRef
5.
Cancer Genome Atlas Research, N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15.CrossRef
6.
Witjes VM, et al. Probability of detecting germline BRCA1/2 pathogenic variants in histological subtypes of ovarian carcinoma A meta-analysis. Gynecol Oncol. 2022;164(1):221–30.PubMedCrossRef
7.
Herzog TJ, et al. Testing for homologous recombination repair or homologous recombination deficiency for poly (ADP-ribose) polymerase inhibitors: a current perspective. Eur J Cancer. 2023;179:136–46.PubMedCrossRef
8.
9.
Revythis A, et al. Recent insights into PARP and immuno-checkpoint inhibitors in epithelial ovarian cancer. Int J Environ Res Public Health. 2022;19(14):8577.PubMedPubMedCentralCrossRef
10.
Miller RE, et al. ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer. Ann Oncol. 2020;31(12):1606–22.PubMedCrossRef
11.
Mekonnen N, Yang H, Shin YK. Homologous recombination deficiency in ovarian, breast, colorectal, pancreatic, non-small cell lung and prostate cancers, and the mechanisms of resistance to PARP inhibitors. Front Oncol. 2022;12:880643.PubMedPubMedCentralCrossRef
12.
Morishita K, et al. Retroviral activation of a novel gene encoding a zinc finger protein in IL-3-dependent myeloid leukemia cell lines. Cell. 1988;54(6):831–40.PubMedCrossRef
13.
Tonnies H, et al. Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor. Blood. 2003;101(10):3872–4.PubMedCrossRef
14.
15.
Bard-Chapeau EA, et al. Ecotopic viral integration site 1 (EVI1) regulates multiple cellular processes important for cancer and is a synergistic partner for FOS protein in invasive tumors. Proc Natl Acad Sci U S A. 2012;109(6):2168–73.PubMedPubMedCentralCrossRef
16.
Wieser R. The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Gene. 2007;396(2):346–57.PubMedCrossRef
17.
Liu Y, et al. Evi1 is a survival factor which conveys resistance to both TGFbeta- and taxol-mediated cell death via PI3K/AKT. Oncogene. 2006;25(25):3565–75.PubMedCrossRef
18.
Kurokawa M, et al. The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3. Nature. 1998;394(6688):92–6.PubMedCrossRef
19.
Bard-Chapeau EA, et al. EVI1 oncoprotein interacts with a large and complex network of proteins and integrates signals through protein phosphorylation. Proc Natl Acad Sci U S A. 2013;110(31):E2885–94.PubMedPubMedCentralCrossRef
20.
21.
Rockfield S, Kee Y, Nanjundan M. Chronic iron exposure and c-Myc/H-ras-mediated transformation in fallopian tube cells alter the expression of EVI1, amplified at 3q26.2 in ovarian cancer. Oncogenesis. 2019;8(9):46.PubMedPubMedCentralCrossRef
22.
23.
Groschel S, et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell. 2014;157(2):369–81.PubMedCrossRef
24.
Groschel S, et al. High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. J Clin Oncol. 2010;28(12):2101–7.PubMedCrossRef
25.
Groschel S, et al. Deregulated expression of EVI1 defines a poor prognostic subset of MLL-rearranged acute myeloid leukemias: a study of the German-Austrian acute myeloid leukemia study group and the Dutch-Belgian-Swiss HOVON/SAKK cooperative group. J Clin Oncol. 2013;31(1):95–103.PubMedCrossRef
26.
Kiehlmeier S, et al. Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia. Leukemia. 2021;35(11):3127–38.PubMedPubMedCentralCrossRef
27.
Meyer S, et al. Amplification and translocation of 3q26 with overexpression of EVI1 in Fanconi anemia-derived childhood acute myeloid leukemia with biallelic FANCD1/BRCA2 disruption. Genes Chromosomes Cancer. 2007;46(4):359–72.PubMedCrossRef
28.
Budczies J, et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE. 2012;7(12): e51862.PubMedPubMedCentralCrossRef
29.
Gyorffy B, Lanczky A, Szallasi Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 2012;19(2):197–208.PubMedCrossRef
30.
da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.PubMedCrossRef
31.
Olbrecht S, et al. High-grade serous tubo-ovarian cancer refined with single-cell RNA sequencing: specific cell subtypes influence survival and determine molecular subtype classification. Genome Med. 2021;13(1):111.PubMedPubMedCentralCrossRef
32.
Olalekan S, et al. Characterizing the tumor microenvironment of metastatic ovarian cancer by single-cell transcriptomics. Cell Rep. 2021;35(8): 109165.PubMedCrossRef
33.
34.
Li Q, et al. Jetset: selecting the optimal microarray probe set to represent a gene. BMC Bioinform. 2011;12:474.CrossRef
35.
36.
Nanjundan M, et al. Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer. Cancer Res. 2007;67(7):3074–84.PubMedCrossRef
37.
38.
Gan A, et al. Poly(adenosine diphosphate-ribose) polymerase expression in BRCA-proficient ovarian high-grade serous carcinoma; association with patient survival. Hum Pathol. 2013;44(8):1638–47.PubMedCrossRef
39.
Hjortkjaer M, et al. The prognostic value of BRCA1 and PARP expression in epithelial ovarian carcinoma: immunohistochemical detection. Int J Gynecol Pathol. 2017;36(2):180–9.PubMedCrossRef
40.
Moore K, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495–505.PubMedCrossRef
41.
Wiggans AJ, et al. Poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev. 2015;5:CD007929.
42.
Veskimae K, et al. Assessment of PARP protein expression in epithelial ovarian cancer by ELISA pharmacodynamic assay and immunohistochemistry. Tumour Biol. 2016;37(9):11991–9.PubMedCrossRef
43.
Molnar S, et al. The prognostic relevance of poly (ADP-Ribose) polymerase expression in ovarian cancer tissue of wild type and BRCA-mutation carrier patients. Diagnostics (Basel). 2021;11(1):144.PubMedCrossRef
Metadata
Title
High EVI1 and PARP1 expression as favourable prognostic markers in high-grade serous ovarian carcinoma
Authors
Paul Jank
Jonas Leichsenring
Svenja Kolb
Inga Hoffmann
Philip Bischoff
Catarina Alisa Kunze
Mihnea P. Dragomir
Moritz Gleitsmann
Moritz Jesinghaus
Wolfgang D. Schmitt
Hagen Kulbe
Christine Sers
Albrecht Stenzinger
Jalid Sehouli
Ioana Elena Braicu
Christina Westhoff
David Horst
Carsten Denkert
Stefan Gröschel
Eliane T. Taube
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2023
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/s13048-023-01239-6

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