He Junjun, Ouyang Wei, Zhao Wugan, Shao Lin, Li Bing, Liu Bihao, Wang Dejuan, Han-Zhang Han, Zhang Zhou, Shao Liang, Li Wencai
Key Laboratory of Pancreatic Disease Research of Zhejiang Province, First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Department of Oncology, Zhuzhou Central Hospital, Xiangya School of Medicine, Central South University, Zhuzhou, China.
Ann Transl Med. 2021 Jan;9(2):129. doi: 10.21037/atm-20-7553.
Mutations in proofreading domain can cause deficiencies in DNA repair, conferring ultramutated cancer phenotypes. Preliminary clinical studies have revealed an association between mutations and beneficial clinical outcomes to immune checkpoint inhibitor (ICI) therapy This study aims to investigate the genomic characteristics of mutant tumors and the prognostic value of mutation for ICI treatment.
Genomic data of 21,074 patients with 23 cancer types were retrieved from Burning Rock variant database (BR VarDB). The prevalence and spectra of and mutations were assessed and compared with that in The Cancer Genome Atlas (TCGA) samples. The correlations of mutation with tumor mutational burden (TMB) and microsatellite instability (MSI) were investigated. The prognostic value of mutations was also explored in 2,487 ICI-treated patients from published studies.
BR VarDB samples displayed a similar mutational prevalence of (3.2% 3.2%) and (1.4% 1.6%, P=0.248) versusTCGA samples, but a slightly lower frequency of and co-mutations (0.21% 0.43%, P<0.001). -mutant tumors harbored increased TCT→TAT and TCG→TTG transversions, and genomic signatures associated with DNA mismatch repair (MMR) deficiency and ultra-hypermuation. Furthermore, tumors with proofreading mutation showed a significantly higher TMB than tumors with non-proofreading mutations (P<0.01), although both possessed a higher TMB than wild-type (WT) tumors (P<0.0001 and P<0.0001, respectively). MSI was commonly observed in tumors harboring dominant clone of mutation (10.2%), but occurred rarely in WT tumors (0.5%) and tumors with accumulating sub-cloned mutation (0%). Survival analysis revealed that mutation was not independently correlated with longer survival after adjusting for TMB and other factors (HR =0.86, P=0.372). However, patients harboring mutation demonstrated a higher response rate than patients with WT tumors (35.2% 19.6%, P=0.0165).
We delineated distinctive genomic characteristics in -mutant tumors, suggesting the potential predictive role of mutations, especially those in the proofreading domain, for beneficial outcomes of immunotherapy. Our results also suggest that MSI caused by a loss-of-function mutation in the MMR pathway tends to result from proofreading deficiency in mutant tumors with MSI.
校对结构域中的突变可导致DNA修复缺陷，赋予超突变癌症表型。初步临床研究揭示了这些突变与免疫检查点抑制剂（ICI）治疗的有益临床结果之间的关联。本研究旨在调查突变肿瘤的基因组特征以及这些突变对ICI治疗的预后价值。
从燃石变异数据库（BR VarDB）中检索了21,074例患有23种癌症类型患者的基因组数据。评估了这些突变的患病率和谱，并与癌症基因组图谱（TCGA）样本中的进行比较。研究了这些突变与肿瘤突变负荷（TMB）和微卫星不稳定性（MSI）的相关性。还在已发表研究中的2,487例接受ICI治疗的患者中探索了这些突变的预后价值。
与TCGA样本相比，BR VarDB样本显示出相似的这些突变患病率（分别为3.2%和3.2%）以及这些突变患病率（分别为1.4%和1.6%，P = 0.248），但这些和这些共突变的频率略低（分别为0.21%和0.43%，P < 0.001）。这些突变肿瘤存在TCT→TAT和TCG→TTG颠换增加，以及与DNA错配修复（MMR）缺陷和超超突变相关的基因组特征。此外，具有校对突变的肿瘤显示出比无校对突变的肿瘤显著更高的TMB（P < 0.01），尽管两者的TMB均高于野生型（WT）肿瘤（分别为P < 0.0001和P < 0.0001）。MSI在具有这些突变优势克隆的肿瘤中常见（10.2%），但在这些WT肿瘤（0.5%）和具有累积亚克隆这些突变的肿瘤（0%）中很少发生。生存分析显示，在校正TMB和其他因素后，这些突变与更长生存期无独立相关性（HR = 0.86，P = 0.372）。然而，具有这些突变的患者表现出比这些WT肿瘤患者更高的缓解率（分别为35.2%和19.6%，P = 0.0165）。
我们描绘了这些突变肿瘤独特的基因组特征，表明这些突变，尤其是校对结构域中的突变，对免疫治疗的有益结果具有潜在预测作用。我们的结果还表明，MMR途径功能丧失突变导致的MSI往往源于具有MSI的突变肿瘤中的这些校对缺陷。
