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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-07-0230v1 15/4/1013    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Pizzi, S. Articles by Rindi, G PubMed PubMed Citation Articles by Pizzi, S. Articles by Rindi, G

S Pizzi, Pathology and Laboratory Medicine, University of Parma, Parma, Italy
C Azzoni, Pathology and Laboratory Medicine, University of Parma, Parma, Italy
E Tamburini, Pathology and Laboratory Medicine, University of Parma, Parma, Italy
L Bottarelli, Pathology and Laboratory Medicine, University of Parma, Parma, Italy
N Campanini, Pathology and Laboratory Medicine, University of Parma, Parma, Italy
T D'Adda, Pathology and Laboratory Medicine, University of Parma, Parma, Italy
G Fellegara, Pathology and Laboratory Medicine, University of Parma, Parma, Italy
T Luong, Pathology and Laboratory Medicine, University of Parma, Parma, Italy
C Pasquali, Medical and Surgical Sciences, University of Padua, Padua, Italy
R Camisa, Medical Oncology Unit, University Hospital of Parma, Parma, Italy
G Rossi, Pathologic Anatomy and Legal Medicine, University of Modena and Reggio Emilia, Modena, Italy
G Delle Fave, Digestive and Liver Disease, University La Sapienza II School of Medicine, Italy
C Bordi, Pathology and Laboratory Medicine, University of Parma, Parma, Italy
G Rindi, Pathology and Laboratory Medicine, University of Parma, Parma, 43100, Italy

Correspondence: G Rindi, Email: guido.rindi{at}unipr.it

Abstract

The role of Wnt pathway in digestive endocrine tumours is debated. 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 APC and E-cadherin promoters, loss of heterozygosity at APC locus, β-catenin and E-cadherin expression by immunohistochemistry. Tumours showing altered β-catenin localization were tested for β-catenin and APC mutations. APC promoter methylation was restricted to gastroduodenal tumours (21/59, 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 14/53 cases (26%, 10 gastroduodenal and 4 colorectal), prevalent in poorly differentiated carcinomas (P=0.002) and correlating with histology grade (P=0.012). β-catenin abnormal expression was found in 41/54 cases (76%), with nuclear staining correlating with APC alteration (P=0.047) and short survival (P=0.006). APC, but not β-catenin, gene mutations were found (7/35 tumours), four of which in the midgut. E-cadherin promoter methylation was rarely detected (2/52 cases), with cytoplasmic expression in 18/43 cases (42%), not correlating with any clinicopathologic feature. In conclusion, Wnt pathway alterations, as represented by abnormal β-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.