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

Guillaume Beinse, Pierre Alexandre Just, Marie Aude Le Frere Belda, Pierre Laurent-Puig, Sebastien Jacques, Meriem Koual, Simon Garinet, Karen Leroy, Nicolas Delanoy, Helene Blons, Claire Gervais, Catherine Durdux, Charles Chapron, François Goldwasser, Benoit Terris, Cecile Badoual, Valerie Taly, Anne Sophie Bats, Bruno Borghese, Jérôme Alexandre

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

5 Citations (Scopus)

Résumé

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.

langue originaleAnglais
Pages (de - à)1123-1132
Nombre de pages10
journalBritish Journal of Cancer
Volume127
Numéro de publication6
Les DOIs
étatPublié - 5 oct. 2022
Modification externeOui

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