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

doi:10.1038/s41416-022-01900-9

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

Br J Cancer. 2022 Oct;127(6):1123-1132. doi: 10.1038/s41416-022-01900-9. Epub 2022 Jun 25.

Authors

Guillaume Beinse^{1

2}, Pierre-Alexandre Just^#^{3

4}, Marie-Aude Le Frere Belda^#⁵, Pierre Laurent-Puig^{1

4

6

7}, Sebastien Jacques⁸, Meriem Koual^{4

9}, Simon Garinet^{1

4

6}, Karen Leroy^{4

6}, Nicolas Delanoy¹⁰, Helene Blons^{4

6}, Claire Gervais^{4

10}, Catherine Durdux^{4

11}, Charles Chapron^{4

12}, François Goldwasser^{2

4}, Benoit Terris^{3

4}, Cecile Badoual^{4

5}, Valerie Taly¹, Anne-Sophie Bats^#^{1

4

9}, Bruno Borghese^#^{1

4

12}, Jérôme Alexandre^#^{13

14

15}

Affiliations

¹ Centre de Recherche des Cordeliers, « Equipe labélisée Ligue Contre le Cancer », CNRS SNC 5096, Sorbonne Université, Université de Paris Cité, INSERM, Paris, France.
² Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Medical Oncology, Hopital Cochin, Paris, France.
³ Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Pathology, Hopital Cochin, Paris, France.
⁴ Université de Paris Cité, Paris, France.
⁵ Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Pathology, Hopital Européen Georges Pompidou, Paris, France.
⁶ Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Biology, Hopital Européen Georges Pompidou, Paris, France.
⁷ Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Paris, France.
⁸ GENOM'IC platform, Institut Cochin, Paris, France.
⁹ Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Gynecological Surgery, Hopital Européen Georges Pompidou, Paris, France.
¹⁰ Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Medical Oncology, Hopital Européen Georges Pompidou, Paris, France.
¹¹ Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Radiotherapy, Hopital Européen Georges Pompidou, Paris, France.
¹² Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Gynecological Surgery, Hopital Cochin, Paris, France.
¹³ Centre de Recherche des Cordeliers, « Equipe labélisée Ligue Contre le Cancer », CNRS SNC 5096, Sorbonne Université, Université de Paris Cité, INSERM, Paris, France. [email protected].
¹⁴ Institut du Cancer Paris CARPEM, AP-HP, APHP.Centre, Department of Medical Oncology, Hopital Cochin, Paris, France. [email protected].
¹⁵ Université de Paris Cité, Paris, France. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

BRCA1 Protein / genetics
BRCA2 Protein* / genetics
DNA Repair
Female
Homologous Recombination / genetics
Humans
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / genetics

Substances

BRCA1 Protein
BRCA2 Protein