title: Subcellular differential expression of Ep-ICD in oral dysplasia and cancer is associated with disease progression and prognosis.
abstract: Identification of patients with oral dysplasia at high risk of cancer development and oral squamous cell carcinoma (OSCC) at increased risk of disease recurrence will enable rigorous personalized treatment. Regulated intramembranous proteolysis of Epithelial cell adhesion molecule (EpCAM) resulting in release of its intracellular domain Ep-ICD into cytoplasm and nucleus triggers oncogenic signaling. We analyzed the expression of Ep-ICD in oral dysplasia and cancer and determined its clinical significance in disease progression and prognosis.
  
  
  
  In a retrospective study, immunohistochemical analysis of nuclear and cytoplasmic Ep-ICD and EpEx (extracellular domain of EpCAM), was carried out in 115 OSCC, 97 oral dysplasia and 105 normal oral tissues, correlated with clinicopathological parameters and disease outcome over 60 months for oral dysplasia and OSCC patients. Disease-free survival (DFS) was determined by Kaplan-Meier method and multivariate Cox regression analysis.
  
  
  
  In comparison with normal oral tissues, significant increase in nuclear Ep-ICD and membrane EpEx was observed in dysplasia, and OSCC (p = 0.013 and < 0.001 respectively). Oral dysplasia patients with increased overall Ep-ICD developed cancer in short time period (mean = 47 months; p = 0.044). OSCC patients with increased nuclear Ep-ICD and membrane EpEx had significantly reduced mean DFS of 33.7 months (p = 0.018).
  
  
  
  Our study provided clinical evidence for Ep-ICD as a predictor of cancer development in patients with oral dysplasia and recurrence in OSCC patients, suggesting its potential utility in enhanced management of those patients detected to have increased risk of progression to cancer and recurrence in OSCC patients.
authors.affiliation: Alex and Simona Shnaider Laboratory, Laboratory Medicine in Molecular Onocolgy, Mount Sinia Hospital, Room 6-318, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
authors.forename: Raj Thani
authors.initials: RT
authors.lastname: Somasundaram
authors.affiliation: Alex and Simona Shnaider Laboratory, Laboratory Medicine in Molecular Onocolgy, Mount Sinia Hospital, Room 6-318, 600 University Avenue, Toronto, ON, M5G 1X5, Canada.
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, 600 University Avenue, 6-500, Toronto, ON, M5G 1X5, Canada.|Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
authors.forename: Iona
authors.initials: I
authors.lastname: Leong
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: MacMillan
authors.affiliation: Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.|Department of Otolaryngology - Head and Neck Surgery, Alex and Simona Shnaider Laboratory in Molecular Oncology, Mount Sinai Hospital, Joseph & Wolf Lebovic Health Complex, 600 University Avenue, 6-500, Toronto, ON, M5G 1X5, Canada.|Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, ON, M5G 2N2, Canada.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Witterick
authors.affiliation: Alex and Simona Shnaider Laboratory, Laboratory Medicine in Molecular Onocolgy, Mount Sinia Hospital, Room 6-318, 600 University Avenue, Toronto, ON, M5G 1X5, Canada. pwalfish@mtsinai.on.ca.|Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada. pwalfish@mtsinai.on.ca.|Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada. pwalfish@mtsinai.on.ca.|Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, ON, M5G 2N2, Canada. pwalfish@mtsinai.on.ca.|Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto, Joseph & Wolf Lebovic Health Complex, Room 413-7, 600 University Avenue, Toronto, ON, M5G 1X5, Canada. pwalfish@mtsinai.on.ca.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
authors.affiliation: Alex and Simona Shnaider Laboratory, Laboratory Medicine in Molecular Onocolgy, Mount Sinia Hospital, Room 6-318, 600 University Avenue, Toronto, ON, M5G 1X5, Canada. rralhan@mtsinai.on.ca.|Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada. rralhan@mtsinai.on.ca.|Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada. rralhan@mtsinai.on.ca.|Department of Otolaryngology - Head and Neck Surgery, Alex and Simona Shnaider Laboratory in Molecular Oncology, Mount Sinai Hospital, Joseph & Wolf Lebovic Health Complex, 600 University Avenue, 6-500, Toronto, ON, M5G 1X5, Canada. rralhan@mtsinai.on.ca.|Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, ON, M5G 2N2, Canada. rralhan@mtsinai.on.ca.
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018450:Disease Progression; D018572:Disease-Free Survival; D000071858:Epithelial Cell Adhesion Molecule / Q000032:analysis / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule
keywords: Dysplasia; Ep-ICD; EpCAM; Oral cancer; Oral lesion; Prognosis; Squamous cell carcinoma