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
\ub1 3.2 RNA copies/\u3bcl in ACCs versus 56.77 \ub1 8.1 RNA copies/\u3bcl 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
