TY - JOUR
T1 - ARID1A mutation may define an immunologically active subgroup in patients with microsatellite stable colorectal cancer
AU - Sarshekeh, Amir Mehrvarz
AU - Alshenaifi, Jumanah
AU - Roszik, Jason
AU - Manyam, Ganiraju C.
AU - Advani, Shailesh M.
AU - Katkhuda, Riham
AU - Verma, Anuj
AU - Lam, Michael
AU - Willis, Jason
AU - Shen, John Paul
AU - Morris, Jeffrey
AU - Davis, Jennifer S.
AU - Loree, Jonathan M.
AU - Lee, Hey Min
AU - Ajani, Jaffer A.
AU - Maru, Dipen M.
AU - Overman, Michael J.
AU - Kopetz, Scott
N1 - Funding Information:
This study is supported by the UT MD Anderson Cancer Center Moon Shot Program, Support Grant No. P30CA016672 and NIH Grant No. R01CA184843 (to S. Kopetz). The results presented here are in part based upon data generated by TCGA Research Network (http://cancergenome.nih.gov/).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/3
Y1 - 2021/3
N2 - Purpose: AT-rich interactive domain 1A (ARID1A) is commonly mutated in colorectal cancer, frequently resulting in truncation and loss of protein expression. ARID1A recruits MSH2 for mismatch repair during DNA replication. ARID1A deficiency promotes hypermutability and immune activation in preclinical models, but its role in patients with colorectal cancer is being explored. Experimental Design: The DNA sequencing and gene expression profiling of patients with colorectal cancer were extracted from The Cancer Genome Atlas and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. IHC for T-cell markers was performed on a separate cohort of patients. Results: Twenty-eight of 417 patients with microsatellite stable (MSS) colorectal cancer (6.7%) had ARID1A mutation. Among 58 genes most commonly mutated in colorectal cancer, ARID1A mutation had the highest increase with frameshift mutation rates in MSS cases (8-fold, P < 0.001). In MSS, ARID1A mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFNg expression (Dz score þ1.91, P < 0.001). Compared with ARID1A wild-type, statistically significant higher expression for key checkpoint genes (e.g., PD-L1, CTLA4, and PDCD1) and gene sets (e.g., antigen presentation, cytotoxic T-cell function, and immune checkpoints) was observed in mutant cases. This was validated by unsupervised differential expression of genes related to immune response and further confirmed by higher infiltration of T cells in IHC of tumors with ARID1A mutation (P ¼ 0.01). Conclusions: The immunogenicity of ARID1A-mutant cases is likely due to an increased level of neoantigens resulting from increased tumor mutational burden and frameshift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should be recognized as a unique molecular subgroup in future immune therapy trials.
AB - Purpose: AT-rich interactive domain 1A (ARID1A) is commonly mutated in colorectal cancer, frequently resulting in truncation and loss of protein expression. ARID1A recruits MSH2 for mismatch repair during DNA replication. ARID1A deficiency promotes hypermutability and immune activation in preclinical models, but its role in patients with colorectal cancer is being explored. Experimental Design: The DNA sequencing and gene expression profiling of patients with colorectal cancer were extracted from The Cancer Genome Atlas and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. IHC for T-cell markers was performed on a separate cohort of patients. Results: Twenty-eight of 417 patients with microsatellite stable (MSS) colorectal cancer (6.7%) had ARID1A mutation. Among 58 genes most commonly mutated in colorectal cancer, ARID1A mutation had the highest increase with frameshift mutation rates in MSS cases (8-fold, P < 0.001). In MSS, ARID1A mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFNg expression (Dz score þ1.91, P < 0.001). Compared with ARID1A wild-type, statistically significant higher expression for key checkpoint genes (e.g., PD-L1, CTLA4, and PDCD1) and gene sets (e.g., antigen presentation, cytotoxic T-cell function, and immune checkpoints) was observed in mutant cases. This was validated by unsupervised differential expression of genes related to immune response and further confirmed by higher infiltration of T cells in IHC of tumors with ARID1A mutation (P ¼ 0.01). Conclusions: The immunogenicity of ARID1A-mutant cases is likely due to an increased level of neoantigens resulting from increased tumor mutational burden and frameshift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should be recognized as a unique molecular subgroup in future immune therapy trials.
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U2 - 10.1158/1078-0432.CCR-20-2404
DO - 10.1158/1078-0432.CCR-20-2404
M3 - Article
C2 - 33414133
AN - SCOPUS:85101831153
SN - 1078-0432
VL - 27
SP - 1663
EP - 1670
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -