Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability

Abstract

Pancreatic acinar cell carcinoma (ACC) is an aggressive exocrine tumor with largely unknown biology. Here, to identify potential targets for personalized treatment, we perform integrative genome-wide and epigenome-wide analyses. The results show frequently aberrant DNA methylation, abundant chromosomal amplifications and deletions, and mutational signatures suggesting defective DNA repair. In contrast to pancreatic ductal adenocarcinoma, no recurrent point mutations are detected. The tumor suppressors ID3, ARID1A, APC, and CDKN2A are frequently impaired also on the protein level and thus potentially affect ACC tumorigenesis. Consequently, this work identifies promising therapeutic targets in ACC for drugs recently approved for precision cancer therapy.

Pancreatic acinar cell carcinoma is associated with BRCA2 germline mutations: a case report and literature review

“…Acinar cell carcinoma (ACC) is a rare pancreatic malignancy with poor prognosis accounting for <2% of all pancreatic tumors in adults and for about 15% in pediatric cases. [1][2][3] At time of diagnosis, 50-60% of patients have distant metastasis and an advanced stage of disease leading to low survival rate and overall dismal prognosis. 1,4 Nonetheless, 5-year survival of ACC patients is 45% which is higher compared to only 7% in conventional pancreatic ductal adenocarcinoma (PDAC).…”

“…1,4 The genomic landscape of ACC is distinct from other pancreatic tumors. 3,[5][6][7][8] Typical genetic alterations observed in PDAC are normally not detected in ACC or occur rarely, i.e., mutations in KRAS (~2% ACCs vs. >90% PDACs), TP53 (9-23% vs. 75%), CDKN2A (14% vs. 90%), SMAD4 (14-19% vs. 55%). 6,9 Rare mutations in BRAF, GNAS and JAK1 and fusions in BRAF and RAF (detected in 23% of ACCs) indicate that a minority of ACCs can evolve due to driver events in oncogenes.…”

“…8 The lack of highly recurrent mutations suggests that other genetic mechanisms drive tumor progression in ACC. 3 Indeed, extensive chromosomal instability appears to be a defining feature of ACC distinguishing it from other pancreatic malignancies, potentially contributing to disease severity, progression and chemotherapy resistance. 2,3,6,7,10 Amongst others loss of heterozygosity (LOH) of chromosomes 11p (~50% of ACCs), 17p (TP53 locus; 39%), and 18q (SMAD4 locus; 57%) is frequently detected.…”

“…3 Indeed, extensive chromosomal instability appears to be a defining feature of ACC distinguishing it from other pancreatic malignancies, potentially contributing to disease severity, progression and chemotherapy resistance. 2,3,6,7,10 Amongst others loss of heterozygosity (LOH) of chromosomes 11p (~50% of ACCs), 17p (TP53 locus; 39%), and 18q (SMAD4 locus; 57%) is frequently detected. [6][7][8] Importantly, despite the genetic heterogeneity, approximately 44% of ACCs harbor potentially targetable genetic abnormalities in DNA repair by homologous recombination (BRCA1/2, PALB2, BRIP1, BAP1, and ATM), JAK-STAT signaling cascade (JAK1), MAPK pathway (BRAF), and cell cycle control (CDKN2A, ID3, and APC).…”

The Network of Cancer Genes (NCG): a comprehensive catalogue of known and candidate cancer genes from cancer sequencing screens

“…NCG is widely used by the community. Recent examples of its use include studies identifying and validating cancer genes [23][24][25] and miRNA cancer biomarkers [26].…”