The impact of ARID1A mutation on molecular characteristics in colorectal cancer

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.

Keywords: ARID1A; Colorectal cancer; Immune profile; Molecular profile; Mutation; Right-sided location; SWI/SNF complex.

Figure 1.

CONSORT diagram. Flow chart showing the inclusion/exclusion criteria in this study. Abbreviations: CCLE, cancer cell line encyclopedia; CRC, colorectal cancer; NGS, next-generation sequencing; RNA-seq, RNA sequencing.

Figure 2.

The impact of ARID1A mutation on tumor characteristics in the discovery cohort. A: The function of ARID1A as a SWI/SNF complex subunit for chromatin remodeling. B: Mutation location and type of ARID1A. C: Frequency of gene mutations in right-sided and left-sided CRC. D: The characteristics of immune profile and tumor location in all samples, comparing POLE mutant, MSI-H, ARID1A mutant and ARID1A wild-type subtypes. E: The characteristics of immune profile and tumor location in ARID1A mutant without MSI-H status. F: X-axis indicates co-occurring mutations (right, positive log ratio) and mutually exclusive mutations (left, negative log ratio), and Y-axis indicates the significance. Log ratio is Log2 based ratio of samples with mutation in ARID1A mutation group/samples with mutation in ARID1A wild-type group. Abbreviations: CRC, colorectal cancer; Mb, megabase; MSI, microsatellite instability; MSI-H, MSI-high; MSI-L, MSI-low; MSS, microsatellite stable; PD-L1, programmed death ligand 1; POLE, polymerase ε; TMB, tumor mutational burden.

Figure 3.

The impact of ARID1A mutation on tumor microenvironment in the TCGA cohort. A: The characteristics of tumor microenvironment in ARID1A mutant samples, comparing POLE mutant, MSI-H, and ARID1A wild-type subtypes. B: The characteristics of tumor microenvironment in ARID1A mutant samples without MSI-H status. C: CMS classifier in ARID1A mutant samples, comparing ARID1A wild-type samples. D: CMS classifier in ARID1A mutant samples without MSI-H status. Abbreviations: MSI, microsatellite instability; MSI-H, MSI-high; MSI-L, MSI-low; MSS, microsatellite stable; PD-L1, programmed death ligand 1; POLE, polymerase ε.

Figure 4.

The impact of ARID1A mutation on tumor characteristics in the validation cohorts. A: OncoPrint representation of gene mutations in the validation cohorts within each sample for the 50 top mutated genes and for the tumor location and MSI status (indicated in orange and red on the bottom annotation heatmap). Top and side bar plots indicate the number of mutations per sample and the number of each gene mutation across all the samples, respectively. B: X-axis indicates co-occurring mutations (right, positive log ratio) and mutually exclusive mutations (left, negative log ratio), and Y-axis indicates the significance. Log ratio is Log2 based ratio of samples with mutation in ARID1A mutation group/samples with mutation in ARID1A wild-type group. C: Gene set enrichment analysis with hallmarks gene sets in the TCGA and CSE59857 cohort (ARID1A mutant vs. ARID1A wild-type samples). Abbreviations: MSI, microsatellite instability; MSI-H, MSI-high; MSI-L, MSI-low; MSS, microsatellite stable.