c-MYC amplification and c-myc protein expression in pancreatic acinar cell carcinomas. New insights into the molecular signature of these rare cancers

Abstract

The molecular alterations of pancreatic acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MANECs) are not completely understood, and the possible role of c-MYC amplification in tumor development, progression, and prognosis is not known. We have investigated c-MYC gene amplification in a series of 35 ACCs and 4 MANECs to evaluate its frequency and a possible prognostic role. Gene amplification was investigated using interphasic fluorescence in situ hybridization analysis simultaneously hybridizing c-MYC and the centromere of chromosome 8 probes. Protein expression was immunohistochemically investigated using a specific monoclonal anti-c-myc antibody. Twenty cases had clones with different polysomies of chromosome 8 in absence of c-MYC amplification, and 5 cases had one amplified clone and other clones with chromosome 8 polysomy, while the remaining 14 cases were diploid for chromosome 8 and lacked c-MYC amplification. All MANECs showed c-MYC amplification and/or polysomy which were observed in 54% pure ACCs. Six cases (15.3%) showed nuclear immunoreactivity for c-myc, but only 4/39 cases showed simultaneous c-MYC amplification/polysomy and nuclear protein expression. c-myc immunoreactivity as well as c-MYC amplification and/or chromosome 8 polysomy was not statistically associated with prognosis. Our study demonstrates that a subset of ACCs shows c-MYC alterations including gene amplification and chromosome 8 polysomy. Although they are not associated with a different prognostic signature, the fact that these alterations are present in all MANECs suggests a role in the acinar-neuroendocrine differentiation possibly involved in the pathogenesis of MANECs.

Genomic analysis of pancreatic juice DNA assesses malignant risk of intraductal papillary mucinous neoplasm of pancreas

“…The 8q24 amplification was found in two of seven (28.57%) in LGD, one of 17 (5.88%) in HGD, six of 11 (54.55%) in INC ( P = 0.011). MYC is located in the 8q24 amplified regions in IPMNs (Table ), which is one of the most frequently altered genes by CNAs in pan‐cancer analysis and whose amplification has been found in pancreatic acinar cell carcinomas . The deletion region 17p13, which contains TP53 (Table ) was also found to co‐occur with TP53 point mutations in all of the malignant samples (INC) with TP53 mutations (Figure D), which might be consistent with the two‐hit theory of tumor suppressor genes.…”

Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: A Systematic Review of a Controversial and Underestimated Diagnosis

“…The histology of the non-neuroendocrine component was reported in 74 studies (n = 606) [11][12][13]64,65,68,[72][73][74][75][79][80][81][82][84][85][86][87]89,[91][92][93][95][96][97]101], and was consistent with an adenocarcinoma in 92.2% of cases (n = 559) (acinar cell carcinoma in 7.6% (n = 46)), an adenoma in 4.5% (n = 27), a squamous cell carcinoma in 2.5% (n = 15), a hepatocellular carcinoma in < 1% (n = 1), and a mixture of an adenocarcinoma and a squamous cell carcinoma in < 1% (n = 4). The grade of differentiation of the non-neuroendocrine component was specified in 38 studies (n = 124), and was well differentiated in 24.2% (n = 30), moderately differentiated in 35.5% (n = 44), and poorly differentiated in 39.5% (n = 49).…”

“…Twenty studies (n = 381) reported on the genetic/molecular alterations underlying MiNEN [29,30,35,58,59,64,67,71,72,77,79,81,82,85,89,[91][92][93]95,97]. In 49.1% of cases where genetic/molecular data was available, the site of origin of MiNEN was the colon-rectum.…”

“…Compared to the non-neuroendocrine component, the neuroendocrine component usually carried a higher number of aberrations and a higher allele imbalance [30,58,97], which are suggestive of a more aggressive biology. Some authors postulated that the non-neuroendocrine component may give rise to the neuroendocrine component through a trans-differentiation process and the acquisition of a more aggressive phenotype [30,58,81]. c-Myc and SMARC4A have been indicated as potential mediators of this trans-differentiation process [58,81].…”

“…Some authors postulated that the non-neuroendocrine component may give rise to the neuroendocrine component through a trans-differentiation process and the acquisition of a more aggressive phenotype [30,58,81]. c-Myc and SMARC4A have been indicated as potential mediators of this trans-differentiation process [58,81]. In some cases, the two components exhibited fairly distinct patterns of genetic or chromosomal alterations [93,95,97], raising the possibility of a polyclonal origin for at least a subtype of MiNENs.…”