Expression Profiling in Ovarian Cancer Reveals Coordinated Regulation of and Homologous Recombination Genes

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2022 Feb 25

PMID 35203410

Authors

Noelia Custodio

Rosina Savisaar

Celia Carvalho

Pedro Bak-Gordon

Maria I Ribeiro

Joana Tavares

Paula B Nunes

Ana Peixoto

Carla Pinto

Carla Escudeiro

Manuel R Teixeira

Maria Carmo-Fonseca

Affiliations

Soon will be listed here.

Abstract

Predictive biomarkers are crucial in clarifying the best strategy to use poly(ADP-ribose) polymerase inhibitors (PARPi) for the greatest benefit to ovarian cancer patients. PARPi are specifically lethal to cancer cells that cannot repair DNA damage by homologous recombination (HR), and HR deficiency is frequently associated with mutations. Genetic tests for mutations are currently used in the clinic, but results can be inconclusive due to the high prevalence of rare DNA sequence variants of unknown significance. Most tests also fail to detect epigenetic modifications and mutations located deep within introns that may alter the mRNA. The aim of this study was to investigate whether quantitation of mRNAs in ovarian cancer can provide information beyond the DNA tests. Using the nCounter assay from NanoString Technologies, we analyzed RNA isolated from 38 ovarian cancer specimens and 11 normal fallopian tube samples. We found that expression was highly variable among tumors. We further observed that tumors with lower levels of mRNA showed downregulated expression of 12 additional HR genes. Analysis of 299 ovarian cancer samples from The Cancer Genome Atlas (TCGA) confirmed the coordinated expression of and HR genes. To facilitate the routine analysis of mRNA in the clinical setting, we developed a targeted droplet digital PCR approach that can be used with FFPE samples. In conclusion, this study underscores the potential clinical benefit of measuring mRNA levels in tumors when DNA tests are negative or inconclusive.

Citing Articles

Alterations in the expression of homologous recombination repair (HRR) genes in breast cancer tissues considering germline BRCA1/2 mutation status.

Laczmanska I, Matkowski R, Supplitt S, Karpinski P, Abrahamowska M, Laczmanski L Breast Cancer Res Treat. 2024; 208(3):501-510.

PMID: 39080120 PMC: 11522089. DOI: 10.1007/s10549-024-07441-4.

The Associations and Causal Relationships of Ovarian Cancer - Construction of a Prediction Model.

Liu J, Hu T, Guan Y, Zhai J Int J Womens Health. 2024; 16:1127-1135.

PMID: 38912202 PMC: 11193432. DOI: 10.2147/IJWH.S462883.

Cannabis and cancer: unveiling the potential of a green ally in breast, colorectal, and prostate cancer.

Alsalamat H, Abuarab S, Salamah H, Ishqair A, Dwikat M, Nourelden A J Cannabis Res. 2024; 6(1):24.

PMID: 38755733 PMC: 11097556. DOI: 10.1186/s42238-024-00233-z.

An artificial intelligence prediction model based on extracellular matrix proteins for the prognostic prediction and immunotherapeutic evaluation of ovarian serous adenocarcinoma.

Geng T, Zheng M, Wang Y, Reseland J, Samara A Front Mol Biosci. 2023; 10:1200354.

PMID: 37388244 PMC: 10301747. DOI: 10.3389/fmolb.2023.1200354.

Possible Association of Hysterectomy Accompanied with Opportunistic Salpingectomy with Early Menopause: A Retrospective Cohort Study.

Chen P, Li P, Ding D Int J Environ Res Public Health. 2022; 19(19).

PMID: 36231169 PMC: 9565814. DOI: 10.3390/ijerph191911871.

References

Lindeboom R, Supek F, Lehner B . The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat Genet. 2016; 48(10):1112-8. PMC: 5045715. DOI: 10.1038/ng.3664. View

Tsibulak I, Wieser V, Degasper C, Shivalingaiah G, Wenzel S, Sprung S . BRCA1 and BRCA2 mRNA-expression prove to be of clinical impact in ovarian cancer. Br J Cancer. 2018; 119(6):683-692. PMC: 6173779. DOI: 10.1038/s41416-018-0217-4. View

Meehan K, Clynick B, Mirzai B, Maslen P, Harvey J, Erber W . HER2 mRNA transcript quantitation in breast cancer. Clin Transl Oncol. 2016; 19(5):606-615. DOI: 10.1007/s12094-016-1573-2. View

Caputo S, Leone M, Damiola F, Ehlen A, Carreira A, Gaidrat P . Full in-frame exon 3 skipping of confers high risk of breast and/or ovarian cancer. Oncotarget. 2018; 9(25):17334-17348. PMC: 5915120. DOI: 10.18632/oncotarget.24671. View

Huang Y, Wu P, Liu B, Du J . Successful personalized chemotherapy for metastatic gastric cancer based on quantitative BRCA1 mRNA expression level: A case report. Oncol Lett. 2016; 11(6):4183-4186. PMC: 4888084. DOI: 10.3892/ol.2016.4546. View

Wang L, Wei J, Qian X, Yin H, Zhao Y, Yu L . ERCC1 and BRCA1 mRNA expression levels in metastatic malignant effusions is associated with chemosensitivity to cisplatin and/or docetaxel. BMC Cancer. 2008; 8:97. PMC: 2394535. DOI: 10.1186/1471-2407-8-97. View

Carser J, Quinn J, Michie C, OBrien E, McCluggage W, Maxwell P . BRCA1 is both a prognostic and predictive biomarker of response to chemotherapy in sporadic epithelial ovarian cancer. Gynecol Oncol. 2011; 123(3):492-8. DOI: 10.1016/j.ygyno.2011.08.017. View

Wright W, Shah S, Heyer W . Homologous recombination and the repair of DNA double-strand breaks. J Biol Chem. 2018; 293(27):10524-10535. PMC: 6036207. DOI: 10.1074/jbc.TM118.000372. View

Vaz-Drago R, Custodio N, Carmo-Fonseca M . Deep intronic mutations and human disease. Hum Genet. 2017; 136(9):1093-1111. DOI: 10.1007/s00439-017-1809-4. View

10.

Roy R, Chun J, Powell S . BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2011; 12(1):68-78. PMC: 4972490. DOI: 10.1038/nrc3181. View

11.

Intidhar Labidi-Galy S, Papp E, Hallberg D, Niknafs N, Adleff V, Noe M . High grade serous ovarian carcinomas originate in the fallopian tube. Nat Commun. 2017; 8(1):1093. PMC: 5653668. DOI: 10.1038/s41467-017-00962-1. View

12.

North B, Curtis D, Sham P . A note on calculation of empirical P values from Monte Carlo procedure. Am J Hum Genet. 2003; 72(2):498-9. PMC: 379244. DOI: 10.1086/346173. View

13.

Esteller M, Silva J, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E . Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000; 92(7):564-9. DOI: 10.1093/jnci/92.7.564. View

14.

Moskwa P, Buffa F, Pan Y, Panchakshari R, Gottipati P, Muschel R . miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 2011; 41(2):210-20. PMC: 3249932. DOI: 10.1016/j.molcel.2010.12.005. View

15.

Gao Y, Zhu J, Zhang X, Wu Q, Jiang S, Liu Y . BRCA1 mRNA expression as a predictive and prognostic marker in advanced esophageal squamous cell carcinoma treated with cisplatin- or docetaxel-based chemotherapy/chemoradiotherapy. PLoS One. 2013; 8(1):e52589. PMC: 3541365. DOI: 10.1371/journal.pone.0052589. View

16.

Rajan J, Marquis S, Gardner H, Chodosh L . Developmental expression of Brca2 colocalizes with Brca1 and is associated with proliferation and differentiation in multiple tissues. Dev Biol. 1997; 184(2):385-401. DOI: 10.1006/dbio.1997.8526. View

17.

Hu Z, Yau C, Ahmed A . A pan-cancer genome-wide analysis reveals tumour dependencies by induction of nonsense-mediated decay. Nat Commun. 2017; 8:15943. PMC: 5490262. DOI: 10.1038/ncomms15943. View

18.

. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474(7353):609-15. PMC: 3163504. DOI: 10.1038/nature10166. View

19.

Lheureux S, Gourley C, Vergote I, Oza A . Epithelial ovarian cancer. Lancet. 2019; 393(10177):1240-1253. DOI: 10.1016/S0140-6736(18)32552-2. View

20.

Farmer H, McCabe N, Lord C, Tutt A, Johnson D, Richardson T . Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434(7035):917-21. DOI: 10.1038/nature03445. View