Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA; Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Caris Life Sciences, Phoenix, USA.
Eur J Cancer. 2020 Nov;140:119-129. doi: 10.1016/j.ejca.2020.09.006. Epub 2020 Oct 17.
ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC.
We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry.
ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell-inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples.
Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.
ARID1A 是 SWItch/Sucrose Non-Fermentable（SWI/SNF）复合物的关键亚基，该复合物调节核小体的动态重定位以修复 DNA 损伤。只有少数小型试点研究评估了 ARID1A 突变在结直肠癌（CRC）中的作用。本研究旨在探讨 ARID1A 突变对 CRC 临床病理和分子特征的潜在影响。
我们使用了 7978 例 CRC 病例的综合数据集（一个数据集来自临床实验室改进修正案 [CLIA] 认证实验室，三个独立的已发表数据集）。使用下一代测序、RNA 测序和免疫组织化学分析 ARID1A 突变与分子特征（包括免疫谱[微卫星不稳定性 [MSI]、肿瘤突变负担 [TMB]、程序性死亡配体 1 [PD-L1] 和估计浸润免疫细胞]、临床病理特征和相关途径的关联。
在发现和验证队列中，ARID1A 突变样本具有更多基因组不稳定的肿瘤特征（MSI-高和 TMB-高），并且表现出更多的 T 细胞浸润的微环境特征（PD-L1 表达和高估计浸润细胞毒性 T 淋巴细胞 [CTLs]），与 ARID1A 野生型样本相比。即使 ARID1A 突变样本没有 MSI-高状态，它们也是 TMB-高，PD-L1 表达水平高，估计浸润 CTL 水平高。ARID1A 突变更常见于右侧原发性和早期阶段的肿瘤。ARID1A 突变肿瘤主要存在与染色质修饰、DNA 修复、WNT 信号和表皮生长因子受体抑制剂耐药途径相关的共同发生基因突变，并且 ARID1A 突变强烈调节 DNA 修复途径。化疗/放疗敏感性的关键基因在 ARID1A 突变样本中受到抑制。
我们的发现可能为基于 ARID1A 突变状态为 CRC 开发个体化治疗方法提供新的见解。
