PBRM1突变可能使胆道癌的亚型对针对DNA损伤修复系统的药物敏感,npj Precision Oncology

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PBRM1突变可能使胆道癌的亚型对针对DNA损伤修复系统的药物敏感
npj Precision Oncology ( IF 6.8 ) Pub Date : 2023-07-03 , DOI: 10.1038/s41698-023-00409-5
Kai Zimmer ₁ , Florian Kocher ₁ , Gerold Untergasser _{1,

2} , Brigitte Kircher _{1,

2} , Arno Amann ₁ , Yasmine Baca ₃ , Joanne Xiu ₃ , W Micheal Korn ₃ , Martin D Berger ₄ , Heinz-Josef Lenz ₅ , Alberto Puccini ₆ , Elisa Fontana ₇ , Anthony F Shields ₈ , John L Marshall ₉ , Michael Hall ₁₀ , Wafik S El-Deiry ₁₁ , David Hsiehchen ₁₂ , Teresa Macarulla ₁₃ , Josep Tabernero ₁₃ , Renate Pichler ₁₄ , Moh'd Khushman ₁₅ , Upender Manne ₁₅ , Emil Lou ₁₆ , Dominik Wolf ₁ , Viktorija Sokolova ₁₇ , Simon Schnaiter ₁₈ , Alain G Zeimet ₁₉ , Pat Gulhati ₂₀ , Gerlig Widmann ₂₁ , Andreas Seeber ₁

Affiliation

Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria.
Tyrolean Cancer Research Institute, Innsbruck, Austria.
Caris Life Sciences, Phoenix, AZ, USA.
Department of Medical Oncology, Inselspital, University of Bern, Bern, Switzerland.
Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Medical Oncology Unit 1, Ospedale Policlinico San Martino, Genoa, Italy.
Drug Development Unit, Sarah Cannon Research Institute UK, Marylebone, London, UK.
Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Department of Hematology and Oncology, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, Cancer Center at Brown University, Providence, RI, USA.
Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Medical Oncology Department, Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain.
Department of Urology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
O'Neal Comprehensive Cancer Center, the University of Alabama at Birmingham, Birmingham, Al, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Department of Nuclear Medicine, Provincial Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of the Paracelsus Medical Private University, Bolzano-Bozen, Italy.
Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Department of Obstetrics and Gynaecology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
Department of Radiology, Medical University of Innsbruck, Innsbruck, Austria.

Polybromo-1 ( PBRM1 ) 功能丧失突变存在于部分胆道癌 (BTC) 中。PBRM1是 PBAF 染色质重塑复合物的一个亚基，参与 DNA 损伤修复。在此，我们的目的是破译PBRM1突变 (mut) BTC的分子景观并定义潜在的翻译方面。使用下一代 DNA 测序和免疫组织化学（Caris Life Sciences，菲尼克斯，亚利桑那州）总共分析了 1848 个 BTC 样本。在 BTC 细胞系 EGI1 中进行siRNA 介导的PBRM1敲低，以评估 ATR 和 PARP 抑制剂的体外治疗脆弱性。8.1% 的人发现了PBRM1突变（ n = 150) 的 BTC，并且与胆囊癌 (6.0%) 或肝外 BTC (4.5%) 相比，在肝内 BTC (9.9%) 中更为常见。PBRM1突变(mut) 与PBRM1相比，染色质重塑基因 (例如ARID1A 31% vs. 16%) 和 DNA 损伤修复基因 (例如ATRX 4.4% vs. 0.3%)的共突变率更高-野生型（wt）BTC。PBRM1 -mut 和PBRM1 -wt 患者之间未观察到实际总生存率存在差异（HR 1.043，95% CI 0.821–1.325，p = 0.731）。体外实验表明 PARP ± ATR 抑制剂可诱导 PBRM1 的合成致死作用击倒 BTC 模型。我们的研究结果为在经过大量预处理的PBRM1- mut BTC 患者中抑制 PARP 提供了科学依据，从而诱导了疾病控制。这项研究代表了PBRM1- mut BTC最大、最广泛的分子分析研究，该 BTC 在体外对 DNA 损伤修复抑制化合物敏感。我们的研究结果可能为未来在PBRM1- mut BTC中测试 PARP/ATR 抑制剂提供依据。

"点击查看英文标题和摘要"

PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system

Polybromo-1 (PBRM1) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). PBRM1, a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of PBRM1 mutated (mut) BTCs and to define potential translational aspects. Totally, 1848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of PBRM1 was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. PBRM1 mutations were identified in 8.1% (n = 150) of BTCs and were more prevalent in intrahepatic BTCs (9.9%) compared to gallbladder cancers (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., ARID1A 31% vs. 16%) and DNA damage repair genes (e.g., ATRX 4.4% vs. 0.3%) were detected in PBRM1-mutated (mut) vs. PBRM1-wildtype (wt) BTCs. No difference in real-world overall survival was observed between PBRM1-mut and PBRM1-wt patients (HR 1.043, 95% CI 0.821–1.325, p = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the PBRM1 knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated PBRM1-mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of PBRM1-mut BTCs, which in vitro sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as a rationale for future testing of PARP/ATR inhibitors in PBRM1-mut BTCs.

更新日期：2023-07-03

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