Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Cancer Sci. 2022 Mar;113(3):1018-1027. doi: 10.1111/cas.15251. Epub 2022 Jan 10.
We undertook genomic analyses of Japanese patients with stage I esophageal squamous cell carcinoma (ESCC) to investigate the frequency of genomic alterations and the association with survival outcomes. Biomarker analysis was carried out for patients with clinical stage T1bN0M0 ESCC enrolled in JCOG0502 (UMIN000000551). Whole-exome sequencing (WES) was performed using DNA extracted from formalin-fixed, paraffin-embedded tissue of ESCC and normal tissue or blood sample. Single nucleotide variants (SNVs), insertions/deletions (indels), and copy number alterations (CNAs) were identified. We then evaluated the associations between each gene alteration with a frequency of 10% or more and progression-free survival (PFS) using a Cox regression model. We controlled for family-wise errors at 0.05 using the Bonferroni method. Among the 379 patients who were enrolled in JCOG0502, 127 patients were successfully analyzed using WES. The median patient age was 63 years (interquartile range, 57-67 years), and 78.0% of the patients ultimately underwent surgery. The 3-year PFS probability was 76.3%. We detected 20 genes with SNVs, indels, or amplifications with a frequency of 10% or more. Genomic alterations in FGF19 showed the strongest association with PFS with a borderline level of statistical significance of P = .00252 (Bonferroni-adjusted significance level is .0025). Genomic alterations in FGF4, MYEOV, CTTN, and ORAOV1 showed a marginal association with PFS (P < .05). These genomic alterations were all CNAs at chromosome 11q13.3. We have identified new genomic alterations associated with the poor efficacy of ESCC (T1bN0M0). These findings open avenues for the development of new potential treatments for patients with ESCC.
我们对日本 I 期食管鳞状细胞癌（ESCC）患者进行了基因组分析，以研究基因组改变的频率及其与生存结果的关系。对入组 JCOG0502（UMIN000000551）的临床分期 T1bN0M0 ESCC 患者进行了生物标志物分析。采用从 ESCC 及正常组织或血液样本的福尔马林固定、石蜡包埋组织中提取的 DNA 进行全外显子组测序（WES）。鉴定单核苷酸变异（SNV）、插入/缺失（indel）和拷贝数改变（CNA）。然后，我们使用 Cox 回归模型评估每个基因改变与无进展生存期（PFS）之间的关联，该基因改变的频率为 10%或更高。我们使用 Bonferroni 方法将总体错误率控制在 0.05。在入组 JCOG0502 的 379 名患者中，有 127 名患者成功进行了 WES 分析。患者中位年龄为 63 岁（四分位距为 57-67 岁），78.0%的患者最终接受了手术。3 年 PFS 概率为 76.3%。我们检测到 20 个基因的 SNV、indel 或扩增频率为 10%或更高。FGF19 基因的改变与 PFS 相关性最强，具有统计学意义的边界水平为 P=0.00252（Bonferroni 校正后显著性水平为 0.0025）。FGF4、MYEOV、CTTN 和 ORAOV1 基因的改变与 PFS 呈边缘相关性（P<0.05）。这些基因改变均为染色体 11q13.3 的 CNA。我们已经确定了与 ESCC（T1bN0M0）疗效不佳相关的新的基因组改变。这些发现为 ESCC 患者新的潜在治疗方法的开发开辟了道路。
