Expression of β−catenin in gastroenteropancreatic endocrine tumours: a study of 229 cases Short title: β-catenin in digestive endocrine tumours

Aims: In order to clarify the role of β-catenin in digestive endocrine carcinogenesis, we analyzed a large and representative series of gastroenteropancreatic endocrine tumours in order to determine the incidence and pattern of β−catenin alterations and to analyze the clinical, and histological characteristics of the tumours presenting immunohistochemically detectable alterations in β−catenin expression. Methods: 229 cases of gastroenteropancreatic endocrine tumours (stomach, 11; duodenum and ampulla, 29; jejunum and ileum, 51; appendix, 13; colon and rectum, 17; pancreas, 108) were studied by immunohistochemistry in order to assess the pattern of distribution of βcatenin (membranous, cytoplasmic or nuclear); DNA analysis was performed to detect mutations in exon 3 of the CTNNB1 gene. Results: The distribution of immunoreactive β-catenin protein was membranous in 164 cases, cytoplasmic in 58 and nuclear in 7. No mutation was detected in exon 3 of the CTNNB1 gene in any case. The 7 cases with nuclear accumulation of β-catenin were large tumours (44±18.5 mm) with metastases, including liver metastases in 5 cases, high Ki67 index (mean±SD=34±16.5%) and cyclin D1 overexpression; p53 accumulation was detected in 6 cases. 5 patients died of disease; the mean survival (±SD) was 13.6±4.8 months. Conclusions: Our data show that immunohistochemically detectable nuclear accumulation of β-catenin is infrequent in gastroenteropancreatic endocrine tumours and is usually not associated with mutations in CNNTB1 exon 3. They suggest that alterations in β-catenin expression are late events in digestive endocrine carcinogenesis, associated with tumour progression and dissemination. Hervieu et al. β-catenin in enteropancreatic endocrine tumors 3 Take home messages: 1. Nuclear accumulation of β-catenin is infrequent in gastroenteropancreatic endocrine tumours. 2. It is usually not associated with mutations in CNNTB1 exon 3. 3. Alterations in β-catenin expression are likely to be late events in digestive endocrine carcinogenesis, associated with tumour progression and dissemination. Hervieu et al. β-catenin in enteropancreatic endocrine tumors 4