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- Title
Discovery and validation of a transcriptional signature identifying homologous recombination-deficient breast, endometrial and ovarian cancers.
- Authors
Beinse, Guillaume; Just, Pierre-Alexandre; Le Frere Belda, Marie-Aude; Laurent-Puig, Pierre; Jacques, Sebastien; Koual, Meriem; Garinet, Simon; Leroy, Karen; Delanoy, Nicolas; Blons, Helene; Gervais, Claire; Durdux, Catherine; Chapron, Charles; Goldwasser, François; Terris, Benoit; Badoual, Cecile; Taly, Valerie; Bats, Anne-Sophie; Borghese, Bruno; Alexandre, Jérôme
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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).<bold>Conclusions: </bold>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.
- Subjects
PROTEINS; OVARIAN tumors; GENETICS; DNA
- Publication
British Journal of Cancer, 2022, Vol 127, Issue 6, p1123
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-022-01900-9