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Genetics and Genomics

Discovery and validation of a transcriptional signature identifying homologous recombination-deficient breast, endometrial and ovarian cancers

Abstract

Background

Molecular alterations leading to homologous recombination deficiency (HRD) are heterogeneous. We aimed to identify a transcriptional profile shared by endometrial (UCEC), breast (BRCA) and ovarian (OV) cancers with HRD.

Methods

Genes differentially expressed with HRD genomic score (continuous gHRD score) in UCEC/BRCA/OV were identified using edgeR, and used to train a RNAseq score (ridge-regression model) predictive of the gHRD score (PanCanAtlas, N = 1684 samples). The RNAseq score was applied in independent gynaecological datasets (CARPEM/CPTAC/SCAN/TCGA, N = 4038 samples). Validations used ROC curves, linear regressions and Pearson correlations. Overall survival (OS) analyses used Kaplan–Meier curves and Cox models.

Results

In total, 656 genes were commonly up/downregulated with gHRD score in UCEC/BRCA/OV. Upregulated genes were enriched for nuclear/chromatin/DNA-repair processes, while downregulated genes for cytoskeleton (gene ontologies). The RNAseq score correlated with gHRD score in independent gynaecological cancers (R² = 0.4–0.7, Pearson correlation = 0.64–0.86, all P < 10−11), and was predictive of gHRD score >42 (RNAseq HRD profile; AUC = 0.95/0.92/0.78 in UCEC/BRCA/OV). RNAseq HRD profile was associated (i) with better OS in platinum-treated advanced TP53-mutated-UCEC (P < 0.001) and OV (P = 0.013), and (ii) with poorer OS (P < 0.001) and higher benefit of adjuvant chemotherapy in Stage I–III BRCA (interaction test, P < 0.001).

Conclusions

UCEC/BRCA/OV with HRD-associated genomic scars share a common transcriptional profile. RNAseq signatures might be relevant for identifying HRD-gynaecological cancers, for prognostication and for therapeutic decision.

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Fig. 1: Analytical workflow.
Fig. 2: Homologous recombination deficiency-associated transcriptional programme.
Fig. 3: RNAseq signature associated with HRD: RNAseq HRD profile.
Fig. 4: Validation of the RNAseq HRD profile in gynaecological cancers (independent samples).
Fig. 5: Translational applicability of the RNAseq HRD profile in gynaecological cancers.

Data availability

Materials, data, and protocols described in the manuscript will be made available upon reasonable request at the corresponding author. Full details on data generation and data quality have been reported elsewhere [27]. The R objects to be used for the prediction on external data are provided as Supplementary Data 2.

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Acknowledgements

The work was conducted in a research team supported by the Ligue Nationale Contre le Cancer (LNCC, Program “Equipe labelisée LIGUE”; no. EL2016.LNCC). FFPE sections were provided by the Biological Resources Centers and Tumour Bank Platforms of Cochin Hospital (BB-0033-00023 certification) and HEGP (BB-0033-00063 certification). RNA sequencing was performed at the sequencing platform of the Institut du Cerveau et de la Moelle Institute (Mr. Yannick Marie, Mme Mundwiller, CNRS UMR 7225—Inserm U 1127—Sorbonne Université UM75, Paris, France). Targeted sequencing and OncoScan microarray analyses have been performed at the GENOM’IC sequencing platform (Institut Cochin, U1016, Paris, France) and at the Department of Biochemistry and Molecular Oncology, Hopital Européen Georges Pompidou (APHP.Centre, Paris, France). Bioinformatical analyses used the French Institute of Bioinformatic clusters and local R studio on R v4. The authors would like to thank Mme De Jesus (Department of Gynaecological Surgery, Cochin Hospital), Mme Lannoy (Department of Medical Oncology, Cochin Hospital), Mme Philibert (Department of Gynecological Surgery, HEGP), Mme Hermary, Mme Le Lay (Tumour Bank Platform, Cochin Hospital), Mme Geromin, Mme Largeau, Dr. Védie, Mme Carron, Mme Le Dannois, Mme Valognes, Mme Moussy, Mme Bruneau, Mr. Maisonneuve, Mme Chabert (Tumour bank platform & pathology department, HEGP), Mme Leger, Mme Urban, Mme Goyer, Mme Auribault (Department of biochemistry/molecular oncology, HEGP), Mme Mulot, Mme Didelot, Mme Chaba, Mme Agueff, Mme Bourreau, Mme Mazoyer (Centre de Recherche des Cordeliers, Paris, France), Mr. Ladeiro and Mme Lusson (CARPEM) for their technical and administrative support. Data used in this publication were generated by the (i) National Cancer Institute Clinical Proteomic Tumour Analysis Consortium (CPTAC), (ii) the Cancer Genome Atlas, (iii) the Sweden Cancerome Analysis Network and (iv) the CARPEM institute.

Funding

This work was supported by ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé/ National Alliance for Life Sciences & Health) within the framework of the Cancer Plan and by GHU-Assistance Publique-Hopitaux de Paris Centre (translational research program). The work was conducted within the SIRIC CARPEM translational research platform.

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Contributions

Conceptualisation: GB, BB and JA. Data curation: GB, P-AJ, M-ALFB, MK, SG and KL. Formal analysis: GB. Funding acquisition: GB and JA. Investigation: GB, PAJ, MALFB, MK, SG, PL-P, A-SB, BB, JA. Patient accrual and data collection: GB, MK, ND, CG, CD, CC, FG, A-SB, BB, JA. Methodology: GB, P-AJ, MALFB, PL-P, A-SB, BB, JA. Project administration: GB and JA. Resources: GB, PAJ, MALFB, MK, HB, SJ, BT, CB, PL-P, A-SB, BB and JA. Supervision: PL-P, BB and JA. Writing—original draft: GB and JA. Writing—review & editing: all authors.

Corresponding author

Correspondence to Jérôme Alexandre.

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Competing interests

GB: institutional funding from ITMO Cancer AVIESAN (French National Cancer Institute); JA: research funding from MSD; advisory board: GSK, MSD, AstraZeneca, Clovis, Eisaï. No external entities had any role in the design and conduction of the study, the collection, management, analysis, and interpretation of the data, the preparation, review and approval of the manuscript or the decision to submit the manuscript for publication. The remaining authors declare no competing interests.

Ethics approval and consent to participate

Patients treated for Stage I–IV UCEC in two University Hospitals in Paris [2010–2017] were post hoc included and referred as to the CAncer Research for Personalised Medicine Institute upon written consent or non-opposition (CARPEM) cohort (ethical approvals from National Ethical Committee CPP Ile-de-France I II & IV, DC-2020/144; DC-2019-3677; DC-2009-950, Data Protection Committee approval ID APHP2020-1109121347).

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Beinse, G., Just, PA., Le Frere Belda, MA. et al. Discovery and validation of a transcriptional signature identifying homologous recombination-deficient breast, endometrial and ovarian cancers. Br J Cancer 127, 1123–1132 (2022). https://doi.org/10.1038/s41416-022-01900-9

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