title: Immunohistochemical detection of ARID1A in colorectal carcinoma: loss of staining is associated with sporadic microsatellite unstable tumors with medullary histology and high TNM stage.
abstract: AT-rich interactive domain-containing protein 1A (ARID1A), a chromatin remodeling gene recently discovered to be a tumor suppressor in ovarian cancers, has been found to be mutated at low frequencies in many other tumors including colorectal carcinoma (CRC). An association between ARID1A alteration and DNA mismatch repair (MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257 CRCs that fulfilled a set of relaxed criteria for Lynch syndrome screening; 59 (23%) were MMR deficient by immunohistochemistry (44 MLH1/PMS2 deficient, 9 MSH2/MSH6 deficient, 4 MSH6 deficient, and 2 PMS2 deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR-deficient tumors (14/59, 13 of the 14 being MLH1/PMS2 deficient) and 4% of MMR-normal tumors (8/198) (P < .05). MLH1 (mutL homolog 1) promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (P = .04), poor tumor differentiation (P < .01), medullary histology (P < .01), and an increased rate of nodal and distant metastasis (P = .03); these patients also trended toward a worse 5-year overall survival. Among MMR-normal tumors, no differences in clinicopathological features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable CRCs that may be medullary but is more likely to present with metastatic disease, warranting further investigation.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Jiqing
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
authors.affiliation: Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Mithat
authors.initials: M
authors.lastname: Gönen
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Tushar
authors.initials: T
authors.lastname: Samdani
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Ruben
authors.initials: R
authors.lastname: Bacares
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Deborah
authors.initials: D
authors.lastname: DeLair
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Ivelja
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 12705 York Ave, New York, NY, 10065. Electronic address: Shiaj@mskcc.org.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018276:Carcinoma, Medullary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010865:Pilot Projects; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D055815:Young Adult
chemical_list: C112476:ARID1A protein, human; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D000070957:MutL Protein Homolog 1
keywords: Colon cancer; Immunohistochemistry; MLH1 and PMS2; MLH1 methylation; Microsatellite instability