Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Clinical Oncology, Assiut University Hospital, Faculty of Medicine, Assiut, Egypt.
Sci Rep. 2020 Dec 16;10(1):22087. doi: 10.1038/s41598-020-77939-6.
DNA repair gene aberrations (GAs) occur in several cancers, may be prognostic and are actionable. We investigated the frequency of DNA repair GAs in gallbladder cancer (GBC), association with tumor mutational burden (TMB), microsatellite instability (MSI), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) expression. Comprehensive genomic profiling (CGP) of 760 GBC was performed. We investigated GAs in 19 DNA repair genes including direct DNA repair genes (ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, and RAD50) and caretaker genes (BAP1, CDK12, MLL3, TP53, and BLM) and classified patients into 3 groups based on TMB level: low (< 5.5 mutations/Mb), intermediate (5.5-19.5 mutations/Mb), and high (≥ 19.5 mutations/Mb). We assessed MSI status and PD-1 & PD-L1 expression. 658 (86.6%) had at least 1 actionable GA. Direct DNA repair gene GAs were identified in 109 patients (14.2%), while 476 (62.6%) had GAs in caretaker genes. Both direct and caretaker DNA repair GAs were significantly associated with high TMB (P = 0.0005 and 0.0001, respectively). Tumor PD-L1 expression was positive in 119 (15.6%), with 17 (2.2%) being moderate or high. DNA repair GAs are relatively frequent in GBC and associated with coexisting actionable mutations and a high TMB.
DNA 修复基因异常（GAs）发生在几种癌症中，可能具有预后意义，并可采取治疗措施。我们研究了胆囊癌（GBC）中 DNA 修复 GAs 的频率、与肿瘤突变负担（TMB）、微卫星不稳定性（MSI）、程序性细胞死亡蛋白 1（PD-1）及其配体（PD-L1）表达的关系。对 760 例 GBC 进行了全面基因组分析（CGP）。我们研究了 19 个 DNA 修复基因中的 GAs，包括直接 DNA 修复基因（ATM、ATR、BRCA1、BRCA2、FANCA、FANCD2、MLH1、MSH2、MSH6、PALB2、POLD1、POLE、PRKDC 和 RAD50）和管家基因（BAP1、CDK12、MLL3、TP53 和 BLM），并根据 TMB 水平将患者分为 3 组：低（<5.5 个突变/Mb）、中（5.5-19.5 个突变/Mb）和高（≥19.5 个突变/Mb）。我们评估了 MSI 状态和 PD-1 和 PD-L1 表达。658 例（86.6%）至少有 1 种可采取治疗措施的 GA。109 例（14.2%）存在直接 DNA 修复基因 GAs，476 例（62.6%）存在管家基因 GAs。直接和管家 DNA 修复 GAs 与高 TMB 显著相关（P=0.0005 和 0.0001）。119 例（15.6%）肿瘤 PD-L1 表达阳性，其中 17 例（2.2%）为中或高表达。GBC 中 DNA 修复 GAs 较为常见，与共存的可治疗性突变和高 TMB 相关。
