[1833] Whole Genome Analyses of Pancreatic Acinar Cell Carcinomas

Laura D Wood, Yuchen Jiao, Raluca Yonescu, Johan A Offerhaus, David S Klimstra, Anirban Maitra, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Ralph H Hruban. Johns Hopkins University, Baltimore, MD; University Medical Center Utrecht, Utrecht, Netherlands; Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Acinar cell carcinoma, a rare pancreatic carcinoma, is morphologically distinct from other pancreatic neoplasms, with unique clinical and immunohistochemical features. However, the genetic alterations underlying the development of acinar cell carcinoma have not yet been systematically explored.
Design: Twenty-three fresh frozen acinar cell carcinomas were macrodissected to achieve a neoplastic cellularity of >70%. Whole exome sequencing was performed on each carcinoma and matched normal tissue using next generation sequencing technology. The data were filtered for quality, and the alterations in the matched tumor and normal tissues were compared to identify tumor-specific somatic mutations. In addition, copy number arrays were performed on each tumor to identify large genomic alterations.
Results: Acinar cell carcinomas were characterized by striking genomic instability. While some carcinomas exhibited microsatellite instability, as evidenced by enrichment for single-base substitution mutations, other carcinomas showed marked chromosomal instability, with numerous large gains and losses throughout the genome. Chromosomal instability was validated by FISH which highlighted dramatic chromosomal alterations. Sequencing also revealed numerous somatic mutations. Acinar cell carcinomas contained somatic mutations in multiple components of the WNT signaling pathway (including APC and CTNNB1). Somatic mutations were also identified in druggable targets, including multiple hotspot mutations in BRAF. Infrequent somatic mutations were identified in genes known to be involved in pancreatic ductal adenocarcinoma, such as TP53 and SMAD4, as well as genes involved in cystic neoplasms of the pancreas, such as GNAS. Acinar cell carcinomas lacked mutations in other genes implicated in pancreatic neoplasia, including KRAS and ATRX/DAXX (seen in pancreatic neuroendocrine tumors). In addition, acinar cell carcinomas contained somatic mutations in many genes not previously implicated in pancreatic neoplasia, indicating that these neoplasms are genetically distinct from the other neoplasms in the pancreas.
Conclusions: High-throughput molecular analyses of acinar cell carcinomas revealed that these carcinomas exhibit striking genomic instability. Although these carcinomas contain some genetic overlap with other pancreatic neoplasms, the results of this study indicate that acinar cell carcinomas are a genetically distinct neoplasm, possibly explaining their unique clinical behavior.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer

Tuesday, March 5, 2013 1:45 PM

Proffered Papers: Section H1, Tuesday Afternoon

 

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