Chatrath Ajay, Ratan Aakrosh, Dutta Anindya
Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, 1240 Pinn Hall, Charlottesville, VA 22908, USA.
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
iScience. 2021 Mar 4;24(3):102248. doi: 10.1016/j.isci.2021.102248. eCollection 2021 Mar 19.
High tumor mutational burden (TMB) is associated with response to checkpoint blockade in several cancers. We identify pathogenic germline variants associated with increased TMB (GVITMB). GVITMB were found in 7 genes using a pan-cancer approach (, , , , , and ) and 38 gene sets (e.g., those involved in DNA repair and programmed cell death). GVITMB were also associated with mutational signatures related to the dysfunction of the gene carrying the variant, somatic mutations that further affect the gene or pathway with the variant, or transcriptomic changes concordant with the expected effect of the variant. In a validation cohort of 140 patients with cutaneous melanoma, we found that patients with GVITMB had prolonged progression-free survival (p = 0.0349, hazard ratio = 0.688) and responded favorably (p = 0.0341, odds = 1.842) when treated with immune checkpoint inhibitors. Our results suggest that germline variants can influence the molecular phenotypes of tumors and predict the response to immune checkpoint inhibitors.
高肿瘤突变负荷（TMB）与多种癌症中对检查点阻断的反应相关。我们鉴定出与TMB升高相关的致病性种系变异（GVITMB）。使用泛癌方法在7个基因（、、、、、和）以及38个基因集中发现了GVITMB（例如，那些参与DNA修复和程序性细胞死亡的基因集）。GVITMB还与与携带变异的基因功能障碍相关的突变特征、进一步影响该变异基因或途径的体细胞突变，或与该变异预期效应一致的转录组变化有关。在一个由140例皮肤黑色素瘤患者组成的验证队列中，我们发现携带GVITMB的患者在接受免疫检查点抑制剂治疗时无进展生存期延长（p = 0.0349，风险比 = 0.688）且反应良好（p = 0.0341，优势比 = 1.842）。我们的结果表明，种系变异可影响肿瘤的分子表型并预测对免疫检查点抑制剂的反应。
