title: Loss of Hes1 expression is associated with poor prognosis in colorectal adenocarcinoma.
abstract: Alterations in the Notch signaling pathway play a role in colorectal cancer (CRC). Hes1, a Notch-induced transcription factor, has recently been reported to show decreased expression by immunohistochemistry in sessile serrated adenomas. Variable staining patterns have been reported in tubular adenomas, and existing data on Hes1 expression in CRC are limited and inconsistent. We therefore sought to investigate the expression of Hes1 by immunohistochemistry in a large and well-characterized cohort of CRC patients to determine clinicopathological associations and prognostic significance. Immunohistochemistry for Hes1 was performed on 2775 consecutive CRCs in tissue microarray format. Hes1 expression was classified into 3 categories: absent, 1302 cases (46.9%); cytoplasmic staining only with loss of nuclear staining, 1002 cases (36.1%); and nuclear with or without cytoplasmic staining, 471 cases (17%). In univariate analysis, loss of nuclear expression of HES1 was significantly associated with older age, female sex, right-sided location, mucinous or medullary histology, higher histological grade, microsatellite instability, BRAFV600E mutation, and larger tumor size. Strong and statistically significant associations with female sex, right-sided location, BRAFV600E mutation, microsatellite instability, and larger size remained in multivariate analysis. Patients with loss of nuclear expression of Hes1 had a significantly worse all-cause 5-year survival in both univariate (P = .002) and multivariate (P = .009) analysis. We conclude that loss of nuclear expression of Hes1 occurs in 83% of CRCs when studied in tissue microarray format and is associated with female sex, right-sided location, BRAFV600E mutation, microsatellite instability, larger tumor size, and significantly worse survival.
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia, 2065; Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia, 2065.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Ahadi
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia, 2065; 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.
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.
authors.forename: Amy
authors.initials: A
authors.lastname: Sheen
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia, 2065; 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.
authors.forename: Adele
authors.initials: A
authors.lastname: Clarkson
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia, 2065; 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. 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; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002467:Cell Nucleus / Q000737:chemistry* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D003593:Cytoplasm / Q000737:chemistry; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D016017:Odds Ratio; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012307:Risk Factors; D046888:Tissue Array Analysis; D000072056:Transcription Factor HES-1 / Q000032:analysis*; D016896:Treatment Outcome; D047368:Tumor Burden; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Biomarker; Colorectal carcinoma; HES1; Immunohistochemistry; Notch