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

Publication ,  Journal Article
Chmielecki, J; Hutchinson, KE; Frampton, GM; Chalmers, ZR; Johnson, A; Shi, C; Elvin, J; Ali, SM; Ross, JS; Basturk, O; Balasubramanian, S ...
Published in: Cancer Discov
December 2014

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.

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

December 2014

Volume

4

Issue

12

Start / End Page

1398 / 1405

Location

United States

Related Subject Headings

  • Translocation, Genetic
  • Proto-Oncogene Proteins B-raf
  • Pancreatic Neoplasms
  • Oncogene Proteins, Fusion
  • Humans
  • Genomics
  • Gene Silencing
  • Gene Expression Profiling
  • Extracellular Signal-Regulated MAP Kinases
  • DNA Repair
 

Citation

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Chmielecki, J., Hutchinson, K. E., Frampton, G. M., Chalmers, Z. R., Johnson, A., Shi, C., … Stephens, P. J. (2014). Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov, 4(12), 1398–1405. https://doi.org/10.1158/2159-8290.CD-14-0617
Chmielecki, Juliann, Katherine E. Hutchinson, Garrett M. Frampton, Zachary R. Chalmers, Adrienne Johnson, Chanjuan Shi, Julia Elvin, et al. “Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes.Cancer Discov 4, no. 12 (December 2014): 1398–1405. https://doi.org/10.1158/2159-8290.CD-14-0617.
Chmielecki J, Hutchinson KE, Frampton GM, Chalmers ZR, Johnson A, Shi C, et al. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014 Dec;4(12):1398–405.
Chmielecki, Juliann, et al. “Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes.Cancer Discov, vol. 4, no. 12, Dec. 2014, pp. 1398–405. Pubmed, doi:10.1158/2159-8290.CD-14-0617.
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. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014 Dec;4(12):1398–1405.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

December 2014

Volume

4

Issue

12

Start / End Page

1398 / 1405

Location

United States

Related Subject Headings

  • Translocation, Genetic
  • Proto-Oncogene Proteins B-raf
  • Pancreatic Neoplasms
  • Oncogene Proteins, Fusion
  • Humans
  • Genomics
  • Gene Silencing
  • Gene Expression Profiling
  • Extracellular Signal-Regulated MAP Kinases
  • DNA Repair