Adenomatous polyposis coli alteration in digestive endocrine tumours: correlation with nuclear translocation of beta-catenin and chromosomal instability

Guido Rindi, S Pizzi, C Azzoni, E Tamburini, L Bottarelli, N Campanini, T D'Adda, G Fellegara, Tv Luong, C Pasquali, G Rossi, G Delle Fave, R Camisa, C Bordi

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Abstract

The role of Wnt pathway in digestive endocrine tumours is debated. The aim of this work is to investigate key players in Wnt pathway by a multimodal approach. Sixty cases (49 well-differentiated and 11 poorly differentiated) were investigated for methylation of adenomatous polyposis coli (APC) and E-cadherin promoters, the loss of heterozygosity (LOH) at APC locus and beta-catenin and E-cadherin expression by immunohistochemistry. Tumours showing altered beta-catenin localization were tested for beta-catenin and APC mutations. APC promoter methylation was restricted to gastroduodenal tumours (21 out of 59, 36%), prevalent in poorly differentiated carcinomas (P=0.042) and correlating with aggressive features (high histology grade, P<0.02; tumour death, P=0.026; high fractional allelic loss, P=0.002, in turn correlating with short survival, P=0.017). LOH at APC locus was found in 14 out of 53 cases (26%, 10 gastroduodenal and 4 colorectal), prevalent in poorly differentiated carcinomas (P=0.002) and correlating with histology grade (P=0.012). beta-catenin abnormal expression was found in 41 out of 54 cases (76%), with nuclear staining correlating with APC alteration (P=0.047) and short survival (P=0.006). APC, but not beta-catenin, gene mutations were found (7 out of 35 tumours), 4 of which in the midgut. E-cadherin promoter methylation was rarely detected (2 out of 52 cases), with cytoplasmic expression in 18 out of 43 cases (42%), not correlating with any clinico-pathological feature. In conclusion, Wnt pathway alterations, as represented by abnormal beta-catenin localization, are common events in digestive endocrine tumours, but only nuclear expression correlates with tumour aggressiveness. Though with different alteration mechanisms according to anatomical site, APC plays a major role in Wnt pathway activation and in determining the high chromosomal instability observed in aggressive endocrine carcinomas.
Original languageEnglish
Pages (from-to)1013-1024
Number of pages12
JournalEndocrine-Related Cancer
Volume15
DOIs
Publication statusPublished - 2008

Keywords

  • Adenomatous Polyposis Coli Protein
  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Nucleus
  • Chromosomal Instability
  • Cytoplasm
  • DNA Methylation
  • Endocrine Gland Neoplasms
  • Female
  • Gastrointestinal Neoplasms
  • Humans
  • Immunoenzyme Techniques
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Mutation
  • Promoter Regions, Genetic
  • Wnt Proteins
  • Young Adult
  • beta Catenin

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