Pierre-Alexandre Just1,2, Marie-Aude Le Frere Belda3, Anne-Sophie Bats4,2,5, Bruno Borghese4,2,6, Jérôme Alexandre7,8,9, Guillaume Beinse4,10, Pierre Laurent-Puig4,2,11,12, Sebastien Jacques13, Meriem Koual2,5, Simon Garinet4,2,11, Karen Leroy2,11, Nicolas Delanoy14, Helene Blons2,11, Claire Gervais2,14, Catherine Durdux2,15, Charles Chapron2,6, François Goldwasser10,2, Benoit Terris1,2, Cecile Badoual2,3, Valerie Taly4. 1. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Pathology, Hopital Cochin, Paris, France. 2. Université de Paris Cité, Paris, France. 3. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Pathology, Hopital Européen Georges Pompidou, Paris, France. 4. Centre de Recherche des Cordeliers, « Equipe labélisée Ligue Contre le Cancer », CNRS SNC 5096, Sorbonne Université, Université de Paris Cité, INSERM, Paris, France. 5. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Gynecological Surgery, Hopital Européen Georges Pompidou, Paris, France. 6. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Gynecological Surgery, Hopital Cochin, Paris, France. 7. Centre de Recherche des Cordeliers, « Equipe labélisée Ligue Contre le Cancer », CNRS SNC 5096, Sorbonne Université, Université de Paris Cité, INSERM, Paris, France. jerome.alexandre@aphp.fr. 8. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Medical Oncology, Hopital Cochin, Paris, France. jerome.alexandre@aphp.fr. 9. Université de Paris Cité, Paris, France. jerome.alexandre@aphp.fr. 10. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Medical Oncology, Hopital Cochin, Paris, France. 11. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Biology, Hopital Européen Georges Pompidou, Paris, France. 12. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Paris, France. 13. GENOM'IC platform, Institut Cochin, Paris, France. 14. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Medical Oncology, Hopital Européen Georges Pompidou, Paris, France. 15. Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Radiotherapy, Hopital Européen Georges Pompidou, Paris, France.
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.
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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