Epigenetic and Genetic Changes of APC Gene in Acinar Cell Carcinoma of the Pancreas
Stefano La Rosa, Daniela Furlan, Nora Sahnane, Michele Stefanoli, Maria Grazia Tibiletti, Barbara Bernasconi, Volkan Adsay, Sofia Asioli, Selenia Casnedi, Alessandro Marando, Kenji Notohara, Alessandro Vanoli, Lizhi Zhang, Fausto Sessa, Carlo Capella. Ospedale di Circolo, Varese, Italy; University of Insubria, Varese, Italy; Emory University, Atlanta, GA; University of Turin, Turin, Italy; Hospital De Hautepierre, Strasbourg, France; Kurashiki Central Hospital, Kurashiki, Japan; University of Pavia, Pavia, Italy; Mayo Clinic, Rochester, MN
Background: Genetic and epigenetic alterations involved in the pathogenesis of pancreatic acinar cell carcinoma (ACC) are largely unknown. ACCs generally lack mutations of KRAS, p53, DPC4 and p16, while mutations of the APC gene have been previously described in 17.6% of ACCs. However, it is not known whether loss of function of APC gene in ACC can occur through multiple alternative genetic mechanisms.
Design: We investigated promoter methylation and copy number of APC gene using MS-MLPA and FISH analysis in 14 ACCs. Droplet Digital PCR (ddPCR, Biorad Instrument) and immunohistochemistry were employed to evaluate APC mRNA and protein expression in the same tumors.
Results: APC methylation was found in 10/14 (71.4%) cases and FISH analysis revealed loss of APC in 7 ACCs. Interestingly 4 ACCs (4/14 28.6% %) revealed both methylation and loss of APC. Only one case did not show any loss and methylation. Absolute quantification of APC mRNA levels demonstrated a significant reduction of the transcript in all investigated ACCs compared with normal control pancreases (10.5 ± 3.2 RNA copies/μl in ACCs versus 56.77 ± 8.1 RNA copies/μl in normal controls; p<0.0001). APC protein expression was not found in any case investigated. APC gene methylation and loss did not correlate with stage, grade and prognosis.
Conclusions: APC gene inactivation is a frequent event in ACCs. Gene methylation and loss might be considered as a mechanism of APC haploinsufficiency. Moreover, our data suggest that APC gene alterations are an early event in ACC tumorigenesis.
Tuesday, March 5, 2013 1:00 PM
Proffered Papers: Section F, Tuesday Afternoon