title: Epigenetic inactivation of the E-cadherin gene in eyelid sebaceous gland carcinoma.
abstract: BACKGROUND
  E-cadherin and β-catenin are crucial components of the cell-cell adhesion complex. Their loss has often been associated with tumour metastasis and poor clinical outcome. Both loss of E-cadherin at the cell membrane and a stabilizing mutation in CTNNB1 (β-catenin gene) have been associated with ovarian, colorectal, hepatocellular and nonmelanoma skin cancer, such as squamous and basal cell carcinomas. Absence of E-cadherin may be caused by promoter hypermethylation of the E-cadherin gene (CDH1).
  
  
  OBJECTIVE
  To determine the role of E-cadherin promoter hypermethylation and CTNNB1 gene mutation in the aggressive behaviour of sebaceous gland carcinoma of the eyelid.
  
  
  METHODS
  Thirty-six cases of sebaceous gland carcinoma were subjected to E-cadherin methylation-specific polymerase chain reaction and mutational analysis for the CTNNB1 gene. E-cadherin and β-catenin staining was evaluated by immunohistochemistry. Results were correlated with the clinicopathological features of sebaceous gland carcinoma.
  
  
  RESULTS
  nMethylation of the E-cadherin promoter region was detected in 72% of eyelid sebaceous gland carcinoma cases and loss of E-cadherin immunostaining in 83%. E-cadherin promoter hypermethylation showed a significant association with the loss of membranous E-cadherin (P = 0·038) and it was of borderline significance with reduced disease-free survival (P = 0·05). It was also found to be associated with advanced age (73%), tumour size ≥ 2 cm (77%), orbital invasion (83%), lymph node metastasis (60%), tumour recurrence (60%) and poor histological differentiation (90%). DNA sequencing revealed no stabilizing β-catenin gene mutation in sebaceous gland carcinoma. Loss of membranous β-catenin was observed in 61% cases, which associated significantly with both E-cadherin promoter methylation (P = 0·0262) and loss of E-cadherin membranous localization (P=0·0015).
  
  
  CONCLUSIONS
  Epigenetic inactivation of the E-cadherin gene causes loss of membrane-bound E-cadherin and could contribute to the reduced disease-free survival in eyelid sebaceous gland carcinoma. Mutations in the β-catenin gene do not seem to be involved in the pathogenesis of eyelid sebaceous gland carcinoma.
authors.affiliation: Department of Ocular Pathology, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: P
authors.initials: P
authors.lastname: Jayaraj
authors.forename: S
authors.initials: S
authors.lastname: Sen
authors.forename: A
authors.initials: A
authors.lastname: Sharma
authors.forename: K
authors.initials: K
authors.lastname: Chosdol
authors.forename: S
authors.initials: S
authors.lastname: Kashyap
authors.forename: A
authors.initials: A
authors.lastname: Rai
authors.forename: N
authors.initials: N
authors.lastname: Pushker
authors.forename: M S
authors.initials: MS
authors.lastname: Bajaj
authors.forename: S
authors.initials: S
authors.lastname: Ghose
mesh_terms: D000328:Adult; D000368:Aged; D015820:Cadherins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004252:DNA Mutational Analysis; D044127:Epigenesis, Genetic / Q000235:genetics; D005142:Eyelid Neoplasms / Q000235:genetics*; D005260:Female; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012626:Sebaceous Gland Neoplasms / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D015820:Cadherins; D051176:beta Catenin