Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

被引：12

作者：

Planas-Paz, Lara ^{[1
]}

Pliego-Mendieta, Alicia ^{[1
]}

Hagedorn, Catherine ^{[1
]}

Aguilera-Garcia, Domingo ^{[2
]}

Haberecker, Martina ^{[1
]}

Arnold, Fabian ^{[2
]}

Herzog, Marius ^{[1
]}

Bankel, Lorenz ^{[3
]}

Guggenberger, Roman ^{[4
]}

Steiner, Sabrina ^{[1
]}

Chen, Yanjiang ^{[1
]}

Kahraman, Abdullah ^{[2
,5
]}

Zoche, Martin ^{[2
]}

Rubin, Mark A. ^{[6
]}

Moch, Holger ^{[1
]}

Britschgi, Christian ^{[3
]}

Pauli, Chantal ^{[1
,7
]}

机构：

[1] Univ Hosp Zurich, Dept Pathol & Mol Pathol, Lab Syst Pathol & Funct Tumor Pathol, Zurich, Switzerland

[2] Univ Hosp Zurich, Dept Pathol & Mol Pathol, Mol Tumor Profiling Lab, Zurich, Switzerland

[3] Univ Hosp Zurich, Dept Med Oncol & Haematol, Zurich, Switzerland

[4] Univ Hosp Zurich, Diagnost & Intervent Radiol, Zurich, Switzerland

[5] Swiss Inst Bioinformat, Lausanne, Switzerland

[6] Bern Ctr Precis Med, Dept Biomed Res, Precis Oncol Lab, Bern, Switzerland

[7] Univ Zurich, Med Fac, Zurich, Switzerland

来源：

EMBO MOLECULAR MEDICINE | 2023年 / 15卷 / 04期

关键词：

genomic instability; HRDness; HRD score; sarcoma; DNA-DAMAGE; GENOMIC INSTABILITY; MOLECULAR SIGNATURES; MUTATIONAL PROCESSES; OVARIAN-CARCINOMA; SENSITIVITY; TUMORS; GRADE; CELLS; CLASSIFICATION;

D O I：

10.15252/emmm.202216863

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient-derived sarcoma cells. Concomitantly, HRDhigh sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.

引用

页数：21

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