Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Classification and characterization of microsatellite instability across 18 cancer types. Mutational landscape and significance across 12 major cancer types.
ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Expression of p270 (ARID1A), a component of human SWI/SNF complexes, in human tumors. The emerging roles of ARID1A in tumor suppression. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov. SWI/SNF nucleosome remodellers and cancer. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy. 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. 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. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression 3, which makes ARID1A a poor therapeutic target. ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer 1, 2.
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