Acinar cell carcinomas of the pancreas: a molecular analysis in a series of 57 cases

Abstract

Pancreatic acinar cell carcinomas (PACs) are rare but are distinct aggressive neoplasms that phenotypically differ from pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine neoplasms (PNENs). Despite recent work on the genetic changes of PACs, their molecular pathogenesis is still poorly understood. In this study, we focus on a comparative genomic hybridization analysis. Based on frequent chromosomal imbalances, the involvement of DCC and c-MYC in the pathogenesis of PACs is further investigated. Moreover, we examine markers harboring potential therapeutic relevance (K-RAS, BRAF, EGFR, MGMT, HSP90, L1CAM, Her2). PACs revealed a microsatellite stable, chromosomal unstable genotype, defined by recurrent chromosomal losses of 1p, 3p, 4q, 5q, 6q, 8p, 9p, 11q, 13q, 16q, and 18, as well as gains of 1q, 7, 8q, 12, 17q, and 20q. Subsets of PAC displayed reduction/loss of DCC (79 %) and c-MYC-amplification (17 %). Significant EGFR expression occurred in 42 %, HSP90 expression in 98 %, L1CAM expression in 72 %, and loss of MGMT in 26 %. Two cases carried a K-RAS mutation. Mutations of EGFR or BRAF were not detected. All cases were Her2/neu-negative. PACs display characteristic chromosomal imbalances which are distinctly different from those in pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms. Our findings suggest that DCC and c-MYC alterations may play an important role in the pathogenesis of PACs. Furthermore, EGFR, MGMT, HSP90, and L1CAM may be useful as therapeutic markers and predictors of response to therapy in a subset of PACs.

Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology

“…Mutational analysis of EGFR (exons 18–21) has been investigated recently in 57 ACCs and no mutations have been found (48). In the same study, EGFR immunoreactivity at the cell membrane level was observed in 19/45 (42%) cases.…”

“…BRAF mutations have been investigated in only two studies using either whole-exome sequencing analysis (47) or immunohistochemistry with the anti-BRAF V600E antibody (48). BRAF mutations were found in two mixed acinar-ductal carcinomas and in only 1 out of 17 pure ACCs (47).…”

“…BRAF mutations were found in two mixed acinar-ductal carcinomas and in only 1 out of 17 pure ACCs (47). Among the 42 immunohistochemically investigated ACCs none were positive for the anti-BRAF antibody (48). Although BRAF mutations are very rare, it has recently been demonstrated that about 23% of ACCs harbor rearrangements involving BRAF and RAF1 and the most prevalent fusion was SND1-BRAF .…”

“…Another interesting aspect of APC alterations in ACCs is the well-known correlation between chromosome instability and loss of APC function, which, being involved in mitosis regulation, leads to polyploidy. Interestingly, low APC mRNA levels were directly correlated to high frequency of copy number alterations and chromosome instability (37, 48). …”

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“…MYCN is also deregulated in many tumors of neuroectodermal origin [9]. In pancreatic neuroendocrine tumors (PanNET) the role of MYC proteins is largely unknown, although c-MYC has been suggested to act as an oncogene in a fraction of acinar cell carcinomas [10] and ductal adenocarcinomas [11]. PanNETs, which synthesize and secrete hormones, are hormonally syndromic or non-syndromic.…”