ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression3, which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.
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Wilson, B. G. & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 11, 481–492 (2011).
Wu, J. N. & Roberts, C. W. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov. 3, 35–43 (2013).
Wu, R. C., Wang, T. L. & Shih, Ie. M. The emerging roles of ARID1A in tumor suppression. Cancer Biol. Ther. 15, 655–664 (2014).
Wang, X. et al. Expression of p270 (ARID1A), a component of human SWI/SNF complexes, in human tumors. Int. J. Cancer 112, 636 (2004).
Wang, X. et al. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Biochem. J. 383, 319–325 (2004).
Nagel, Z. D. et al. Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis. Proc. Natl. Acad. Sci. USA 111, E1823–E1832 (2014).
Mathur, R. et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat. Genet. 49, 296–302 (2017).
Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013).
Hause, R. J., Pritchard, C. C., Shendure, J. & Salipante, S. J. Classification and characterization of microsatellite instability across 18 cancer types. Nat. Med. 22, 1342–1350 (2016).
Kane, M. F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811 (1997).
Zhao, H. et al. Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks. eLife 3, e02725 (2014).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Llosa, N. J. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43–51 (2015).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
Tscharke, D. C., Croft, N. P., Doherty, P. C. & La Gruta, N. L. Sizing up the key determinants of the CD8(+) T cell response. Nat. Rev. Immunol. 15, 705–716 (2015).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Angelova, M. et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol. 16, 64 (2015).
Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013).
West, N. R. et al. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. BCR 13, R126 (2011).
Allo, G. et al. ARID1A loss correlates with mismatch repair deficiency and intact p53 expression in high-grade endometrial carcinomas. Mod. Pathol. 27, 255–261 (2014).
Chou, A. et al. Loss of ARID1A expression in colorectal carcinoma is strongly associated with mismatch repair deficiency. Hum. Pathol. 45, 1697–1703 (2014).
Kim, M. S., Je, E. M., Yoo, N. J. & Lee, S. H. Loss of ARID1A expression is uncommon in gastric, colorectal, and prostate cancers. APMIS 120, 1020–1022 (2012).
Wang, K. et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat. Genet. 43, 1219–1223 (2011).
Koster, B. D., de Gruijl, T. D. & van den Eertwegh, A. J. Recent developments and future challenges in immune checkpoint inhibitory cancer treatment. Curr. Opin. Oncol. 27, 482–488 (2015).
Khalil, D. N., Smith, E. L., Brentjens, R. J. & Wolchok, J. D. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat. Rev. Clin. Oncol. 13, 273–290 (2016).
Pan, D. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770–775 (2018).
Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).
Romano, P. et al. Cell Line Data Base: structure and recent improvements towards molecular authentication of human cell lines. Nucleic Acids Res. 37, D925–D932 (2009).
Li, F. et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 153, 590–600 (2013).
Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).
Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
Van der Auwera, G. A. et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinformatics 43, 1–33 (2013).
Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6, 80–92 (2012).
This research was supported by NCI Cancer Center Support Grant CA016672 to The University of Texas MD Anderson Cancer Center, Department of Defense grant OC140431, NIH R01 grant CA181663 to G.P., Cancer Prevention and Research Institute of Texas grant RP160242 to X.S. and G.P., NIH R01 grant GM093104 to X.S, and NIH P01 grant CA092584 to Z.D.N.
Supplementary Figures 1–14
ARID1A mutation rate across cancer types
MS peptides in Vector- and ARID1A-expressing 293T cells
Ingenuity pathway analysis of ARID1A-interacting proteins
Mutation load in tumors with wild-type or mutant ARID1A, BRG1
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