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Increased cyclin D1 expression in cancer of the ampulla of Vater: relevance to nuclear ß catenin accumulation and k-ras gene mutation

¹ Department of Pathology, Teikyo University, Ichihara Hospital, Ichihara, 299-0111, Japan
² Department of Surgical Pathology, Tokyo Medical University, Shinjuku, Tokyo, 160-0023, Japan

Correspondence to:
Dr K Yamazaki
Department of Pathology, Teikyo University, Ichihara Hospital, 3426-3 Anesaki, Ichihara, Chiba, 299-0111, Japan; yamas{at}med.teikyo-u.ac.jp

Aims: Several studies have reported that dysregulation of ß catenin or k-ras mutation promotes cyclin D1 expression. This study investigated the relation between cyclin D1 expression and clinicopathological parameters in carcinoma of the ampulla of Vater (CAV), and also assessed the relation between increased cyclin D1 expression and ß catenin/k-ras status in this series.

Methods: Thirty CAVs were evaluated for cyclin D1 expression by immunohistochemistry in relation to patient clinicopathological features. Aberrant ß catenin expression and k-ras mutation were also investigated by immunostaining and direct sequencing, and related to cyclin D1 expression.

Results: Increased cyclin D1 expression was seen in 17 of 30 CAVs and was significantly correlated with tumour cell proliferation and disease free survival time (p = 0.018, p = 0.018, respectively). Nuclear accumulation of ß catenin was found in nine of 30 cases, including four cases with missense mutations in exon 3 of CTNNB-1, and was significantly correlated with increased cyclin D1 expression (p = 0.003). k-ras gene mutation was detected in 12 of 30 cases, and was also significantly correlated with increased cyclin D1 expression (p = 0.026). Overall, 14 of 17 CAVs with increased cyclin D1 expression showed nuclear accumulation of ß catenin and/or k-ras mutation.

Conclusions: Increased cyclin D1 expression appears to be associated with tumour proliferation and poorer clinical outcome in CAV. It is also associated with both aberrant ß catenin expression and k-ras mutation. These results are consistent with the in vitro data that cyclin D1 can be transactivated by activated ß catenin–T cell factor/LEF and k-ras pathways.

Keywords: carcinoma of ampulla of Vater; cyclin D1; ß catenin; k-ras; prognosis

Abbreviations: APC, adenomatous coli polyposis; CAV, carcinoma of the ampulla of Vater; GSK-3ß, glycogen synthase kinase 3ß; LEF, lymphoid enhancer factor; LI, labelling index; MAPK, mitogen activated protein kinase; PCR, polymerase chain reaction; pRb, retinoblastoma protein; TCF, T cell factor

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