title: Loss of INI1 expression in colorectal carcinoma is associated with high tumor grade, poor survival, BRAFV600E mutation, and mismatch repair deficiency.
abstract: SMARCB1 is a tumor suppressor gene that encodes for the protein INI1. SMARCB1 is commonly inactivated and INI1 correspondingly shows loss of expression in a range of malignant neoplasms including rhabdoid tumors, renal medullary carcinomas, and epithelioid sarcomas. Loss of INI1 expression has recently been reported in occasional gastrointestinal adenocarcinomas. We sought to investigate the incidence and clinicopathological significance of INI1 loss in colorectal adenocarcinoma (CRC). Immunohistochemistry for INI1 was performed in tissue microarray (TMA) format on a well-characterized and unselected cohort of CRCs undergoing surgical resection. If staining was negative or equivocal in the TMA sections, immunohistochemistry was repeated on whole sections. Focal or widespread negative staining for INI1 was identified in whole sections from 14 (0.46%) of 3051 CRCs. In 7 (50%) of 14 negative cases, the loss of staining was focal, whereas the remainder were characterized by negative staining in all neoplastic cells in whole sections. In the cases with focal staining, loss of staining was frequently found in areas of poor differentiation. Global or focal INI1 loss was strongly associated with higher histological grade, larger tumor size and poor overall survival (P<.001). We conclude that INI1 loss occurs rarely (0.46% when screened by TMA) in CRC, where it is associated with higher grade, larger tumor size, poorer survival, mismatch repair deficiency, and BRAFV600E mutation.
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065; Sydney Medical School, University of Sydney, NSW, Australia 2006.
authors.forename: Juliana
authors.initials: J
authors.lastname: Andrici
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065.
authors.forename: Loretta
authors.initials: L
authors.lastname: Sioson
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065.
authors.forename: Adele
authors.initials: A
authors.lastname: Clarkson
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065.
authors.forename: Amy
authors.initials: A
authors.lastname: Sheen
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Farzin
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Sydney Medical School, University of Sydney, NSW, Australia 2006; HistoPath Pathology, North Ryde, NSW, Australia 2113.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Toon
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065; Sydney Medical School, University of Sydney, NSW, Australia 2006.
authors.forename: John
authors.initials: J
authors.lastname: Turchini
authors.affiliation: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia 2065; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, Australia 2065; Sydney Medical School, University of Sydney, NSW, Australia 2006. Electronic address: affgill@med.usyd.edu.au.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D016208:Databases, Factual; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D000071796:SMARCB1 Protein / Q000032:analysis*; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D047368:Tumor Burden; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAFV600E; Colorectal carcinoma; INI1; Mismatch repair deficiency; SMARCB1