Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes Journal Article
| Authors: | Chmielecki, J.; Hutchinson, K. E.; Frampton, G. M.; Chalmers, Z. R.; Johnson, A.; Shi, C.; Elvin, J.; Ali, S. M.; Ross, J. S.; Basturk, O.; Balasubramanian, S.; Lipson, D.; Yelensky, R.; Pao, W.; Miller, V. A.; Klimstra, D. S.; Stephens, P. J. |
| Article Title: | Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes |
| Abstract: | 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. |
| Keywords: | immunohistochemistry; mitogen activated protein kinase; human tissue; unclassified drug; gene sequence; human cell; mutation; sorafenib; raf protein; nonhuman; polymerase chain reaction; animal cell; mouse; gene; gene expression profiling; pathology; brca2 protein; viral gene delivery system; hybrid protein; nucleotide sequence; immunoblotting; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; gene inactivation; oral antidiabetic agent; k ras protein; acinar cell carcinoma; beta catenin; dna extraction; b raf kinase; methionine; complementary dna; nuclear factor i; trametinib; dna repair gene; human; article; cell viability assay; tak 632 |
| Journal Title: | Cancer Discovery |
| Volume: | 4 |
| Issue: | 12 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2014-12-01 |
| Start Page: | 1398 |
| End Page: | 1405 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-14-0617 |
| PROVIDER: | scopus |
| PUBMED: | 25266736 |
| DOI/URL: | |
| Notes: | Export Date: 2 January 2015 -- Source: Scopus |
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