Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes.

Journal Article (Journal Article)

UNLABELLED: Pancreatic acinar cell carcinomas (PACC) account for approximately 1% (∼500 cases) of pancreatic cancer diagnoses annually in the United States. Oncogenic therapuetic targets have proven elusive in this disease, and chemotherapy and radiotherapy have demonstrated limited efficacy against these tumors. Comprehensive genomic profiling of a large series of PACCs (n=44) identified recurrent rearrangements involving BRAF and RAF1 (CRAF) in approximately 23% of tumors. The most prevalent fusion, SND1-BRAF, resulted in activation of the MAPK pathway, which was abrogated with MEK inhibition. SND1-BRAF-transformed cells were sensitive to treatment with the MEK inhibitor trametinib. PACCs lacking RAF rearrangements were significantly enriched for genomic alterations, causing inactivation of DNA repair genes (45%); these genomic alterations have been associated with sensitivity to platinum-based therapies and PARP inhibitors. Collectively, these results identify potentially actionable genomic alterations in the majority of PACCs and provide a rationale for using personalized therapies in this disease. SIGNIFICANCE: PACC is genomically distinct from other pancreatic cancers. Fusions in RAF genes and mutually exclusive inactivation of DNA repair genes represent novel potential therapeutic targets that are altered in over two thirds of these tumors.

Full Text

Duke Authors

Cited Authors

  • Chmielecki, J; Hutchinson, KE; Frampton, GM; Chalmers, ZR; Johnson, A; Shi, C; Elvin, J; Ali, SM; Ross, JS; Basturk, O; Balasubramanian, S; Lipson, D; Yelensky, R; Pao, W; Miller, VA; Klimstra, DS; Stephens, PJ

Published Date

  • December 2014

Published In

Volume / Issue

  • 4 / 12

Start / End Page

  • 1398 - 1405

PubMed ID

  • 25266736

Pubmed Central ID

  • 25266736

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-14-0617

Language

  • eng

Conference Location

  • United States