State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China.
Breast Medical Oncology, School of Medicine, Yale University, Connecticut, New Haven, USA.
Cancer Med. 2023 Apr;12(8):10077-10090. doi: 10.1002/cam4.5663. Epub 2023 Jan 27.
Defects in DNA damage repair (DDR) pathways lead to genomic instability and oncogenesis. DDR deficiency is prevalent in esophageal squamous cell carcinoma (ESCC), but the effects of DDR alterations on mutational processes and tumor immune microenvironment in ECSS remain unclear.
Whole-exome and transcriptome sequencing data of 45 ESCC samples from Taizhou, China, were used to identify genomic variations, gene expression modulation in DDR pathways, and the abundance of tumor-infiltrating immune cells. Ninety-six ESCC cases from The Cancer Genome Atlas (TCGA) project were used for validation.
A total of 57.8% (26/45) of the cases in the Taizhou data and 70.8% (68/96) of the cases in the TCGA data carried at least one functional impact DDR mutation. Mutations in the DDR pathways were associated with a high tumor mutation burden. Several DDR deficiency-related mutational signatures were discovered and were associated with immune cell infiltration, including T cells, monocytes, dendritic cells, and mast cells. The expression levels of two DDR genes, HFM1 and NEIL1, were downregulated in ESCC tumor tissues and had an independent effect on the infiltration of mast cells. In the Taizhou data, increased expression of HFM1 was associated with a poor prognosis, and the increased expression of NEIL1 was associated with a good outcome, but no reproducible correlation was observed in the TCGA data.
This research demonstrated that DDR alterations could impact mutational processes and immune cell infiltration in ESCC. The suppression of HFM1 and NEIL1 could play a crucial role in ESCC progression and may also serve as prognostic markers.
DNA 损伤修复 (DDR) 途径的缺陷导致基因组不稳定和肿瘤发生。DDR 缺陷在食管鳞状细胞癌 (ESCC) 中很常见，但 DDR 改变对 ECSS 突变过程和肿瘤免疫微环境的影响尚不清楚。
使用来自中国台州的 45 个 ESCC 样本的全外显子组和转录组测序数据，鉴定基因组变异、DDR 途径中的基因表达调控以及肿瘤浸润免疫细胞的丰度。来自癌症基因组图谱 (TCGA) 项目的 96 个 ESCC 病例用于验证。
台州数据中共有 57.8%（26/45）的病例和 TCGA 数据中 70.8%（68/96）的病例携带至少一种具有功能影响的 DDR 突变。DDR 途径中的突变与高肿瘤突变负担相关。发现了几个与 DDR 缺陷相关的突变特征，与免疫细胞浸润有关，包括 T 细胞、单核细胞、树突状细胞和肥大细胞。两种 DDR 基因 HFM1 和 NEIL1 的表达水平在 ESCC 肿瘤组织中下调，并且对肥大细胞的浸润有独立影响。在台州数据中，HFM1 的高表达与预后不良相关，而 NEIL1 的高表达与良好的预后相关，但在 TCGA 数据中未观察到可重复的相关性。
本研究表明，DDR 改变可能影响 ESCC 的突变过程和免疫细胞浸润。HFM1 和 NEIL1 的抑制可能在 ESCC 进展中发挥关键作用，并且也可以作为预后标志物。
