title: Loss of ARID1A expression in colorectal carcinoma is strongly associated with mismatch repair deficiency.
abstract: ARID1A is a tumor suppressor gene involved in chromatin remodelling. ARID1A mutations and loss of protein expression occur commonly in endometrioid and gynecological clear cell carcinoma where they are associated with mismatch repair (MMR) deficiency. We assessed ARID1A expression in a large cohort of colorectal carcinomas (CRCs). Immunohistochemistry for ARID1A was performed on whole sections from 100 CRCs and on 1876 CRCs in tissue microarray format. There was complete concordance between the staining on whole slides and tissue microarray sections. Loss of staining was found in 110 (5.9%) of 1876 CRCs and was strongly associated with older age, right sided location, large size, BRAF V600E mutation, MMR deficiency, high histological grade and medullary morphology, (all P < .01). There was a trend towards loss of expression being more common in females (P = .06). When subclassified by combined BRAF V600E mutation and MMR status, loss of ARID1A expression was found most commonly in CRCs with the BRAF V600E mutated, MMR- deficient phenotype (58 of 232 cases, 25%, P < .01). In univariate and multivariate analysis, loss of ARID1A expression was not associated with overall survival-hazard ratio 1.05 (0.68-1.64) and 0.60 (0.24-1.44), respectively. All carcinomas arising in patients with known Lynch syndrome (n = 12) were ARID1A positive. We conclude that loss of ARID1A expression occurs in a small but significant proportion of CRCs where it is strongly correlated with mismatch repair deficiency and other clinical and pathological features associated with somatic hypermethylation.
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; Department of Anatomical Pathology, Sydpath, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia. Electronic address: achou@stvincents.com.au.
authors.forename: Angela
authors.initials: A
authors.lastname: Chou
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; Histopath Pathology, North Ryde, NSW 2113, Australia; Sydney Medical School, University of Sydney 2050, NSW, Australia.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Toon
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Clarkson
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
authors.forename: Loretta
authors.initials: L
authors.lastname: Sioson
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; Sydney Medical School, University of Sydney 2050, NSW, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Houang
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Watson
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
authors.forename: Keshani
authors.initials: K
authors.lastname: DeSilva
authors.affiliation: Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia; Sydney Medical School, University of Sydney 2050, NSW, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D048493:Proto-Oncogene Proteins B-raf
keywords: ARID1A; BAF250a; Colon cancer; Microsatellite instability; Mismatch repair deficiency