Prevalence of ARID1A Mutations in Cell-Free Circulating Tumor DNA in a Cohort of 71,301 Patients and Association with Driver Co-Alterations

SIMPLE SUMMARY: ARID1A abnormalities disturb gene coding processes and correlate with immunotherapy responsiveness. We report the first blood sample-based genomic sequencing of ARID1A in DNA shed from tumors into the circulation (known as cell-free DNA (cfDNA) from liquid biopsy). Altogether, of 62,851 cancer patients with ≥1 cfDNA alteration in the blood, 3137 (5%) had ≥1 deleterious ARID1A alteration (a frequency similar to the ~6% generally reported in tissue sequencing), suggesting this non-invasive test’s value in detecting ARID1A. ARID1A alterations were most frequent in endometrial (21.3% of patients) and bladder cancer (12.9% of patients). As compared to blood samples without ARID1A aberrations, those with a functional (deleterious) ARID1A abnormality had more DNA alterations/sample (median, 6 versus 4; p < 0.0001) and more frequent co-alterations in one or more genes in key pathways promoting cancer development/progression, which may inform therapeutic strategies. ABSTRACT: ARID1A abnormalities disturb transcriptional processes regulated by chromatin remodeling and correlate with immunotherapy responsiveness. We report the first blood-based cell-free DNA (cfDNA) next-generation sequencing (NGS) ARID1A analysis. From November 2016 through August 2019, 71,301 patients with advanced solid tumors underwent clinical blood-derived cfDNA testing. Of these patients, 62,851 (88%) had ≥1 cfDNA alteration, and 3137 (of the 62,851) (5%) had ≥1 deleterious ARID1A alteration (a frequency similar to the ~6% generally reported in tissue NGS), suggesting this non-invasive test’s value in interrogating ARID1A. ARID1A cfDNA alterations were most frequent in endometrial cancer, 21.3% of patients; bladder cancer, 12.9%; gastric cancer, 11%; cholangiocarcinoma, 10.9%; and hepatocellular carcinoma, 10.6%. Blood samples with a functional ARID1A abnormality had more alterations/sample (median, 6 versus 4; p < 0.0001) and more frequent co-alterations in ≥1 gene in key oncogenic pathways: signal transduction, RAS/RAF/MAPK, PI3K/Akt/mTor, and the cell cycle. Taken together, our data suggest that liquid (blood) biopsies identify ARID1A alterations at a frequency similar to that found in primary tumor material. Furthermore, co-alterations in key pathways, some of which are pharmacologically tractable, occurred more frequently in samples with functional (deleterious) ARID1A alterations than in those without such aberrations, which may inform therapeutic strategies.