title: Adenomatous polyposis coli alteration in digestive endocrine tumours: correlation with nuclear translocation of beta-catenin and chromosomal instability.
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.
authors.affiliation: Section of Pathological Anatomy, Department of Pathology and Laboratory Medicine, University of Parma, via Gramsci, 14, I-43100 Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pizzi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Azzoni
authors.forename: Elisa
authors.initials: E
authors.lastname: Tamburini
authors.forename: Lorena
authors.initials: L
authors.lastname: Bottarelli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Campanini
authors.forename: Tiziana
authors.initials: T
authors.lastname: D'Adda
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fellegara
authors.forename: Tu Vinh
authors.initials: TV
authors.lastname: Luong
authors.forename: Claudio
authors.initials: C
authors.lastname: Pasquali
authors.forename: Giulio
authors.initials: G
authors.lastname: Rossi
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Delle Fave
authors.forename: Roberta
authors.initials: R
authors.lastname: Camisa
authors.forename: Cesare
authors.initials: C
authors.lastname: Bordi
authors.forename: Guido
authors.initials: G
authors.lastname: Rindi
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D043171:Chromosomal Instability; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004701:Endocrine Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic; D051153:Wnt Proteins; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins; D051176:beta Catenin