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

被引：6

作者：

Beinse, Guillaume ^{[1
,2
]}

Just, Pierre-Alexandre ^{[3
,4
]}

Le Frere Belda, Marie-Aude ^{[5
]}

Laurent-Puig, Pierre ^{[1
,4
,6
,7
]}

Jacques, Sebastien ^{[8
]}

Koual, Meriem ^{[4
,9
]}

Garinet, Simon ^{[1
,4
,6
]}

Leroy, Karen ^{[4
,6
]}

Delanoy, Nicolas

Blons, Helene ^{[4
,6
]}

Gervais, Claire ^{[4
,10
]}

Durdux, Catherine ^{[4
,11
]}

Chapron, Charles ^{[4
]}

Goldwasser, Francois ^{[2
,4
]}

Terris, Benoit ^{[3
,4
]}

Badoual, Cecile ^{[4
,5
]}

Taly, Valerie ^{[1
]}

Bats, Anne-Sophie ^{[1
,4
,9
]}

Borghese, Bruno ^{[4
,12
]}

Alexandre, Jerome ^{[1
,2
,4
]}

机构：

[1] Univ Paris Cite, Sorbonne Univ, CNRS SNC 5096, Ctr Rech Cordeliers, Paris, France

[2] Inst Canc Paris CARPEM, Dept Med Oncol, APHP Ctr, AP HP, Paris, France

[3] Inst Canc Paris CARPEM, Dept Pathol, APHP Ctr, AP HP, Paris, France

[4] Univ Paris Cite, Paris, France

[5] Inst Canc Paris CARPEM, Dept Pathol, APHP Ctr, AP HP, Paris, France

[6] Hop Europeen Georges Pompidou, Dept Biol, APHP Ctr, AP HP,Inst Canc Paris CARPEM, Paris, France

[7] Inst Canc Paris CARPEM, APHP Ctr, AP HP, Paris, France

[8] Inst Cochin, GENOMIC platform, Paris, France

[9] Hop Europeen Georges Pompidou, Dept Gynecol Surg, APHP Ctr, AP HP,Inst Canc Paris CARPEM, Paris, France

[10] Hop Europeen Georges Pompidou, Dept Med Oncol, APHP Ctr, AP HP,Inst Canc Paris CARPEM, Paris, France

[11] Hop Europeen Georges Pompidou, Dept Radiotherapy, APHP Ctr, AP HP,Inst Canc Paris CARPEM, Paris, France

[12] Hop Cochin, Dept Gynecol Surg, APHP Ctr, AP HP,Inst Canc Paris CARPEM, Paris, France

来源：

BRITISH JOURNAL OF CANCER | 2022年 / 127卷 / 06期

关键词：

GENE; OLAPARIB; BRCA1; RECOMMENDATIONS; CHEMOTHERAPY; MAINTENANCE; MUTATIONS; CARCINOMA;

D O I：

10.1038/s41416-022-01900-9

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (R-2 = 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.

引用

页码：1123 / 1132

页数：10