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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Hutchinson
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Chalmers
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Shi
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Julia
authors.initials: J
authors.lastname: Elvin
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts. Albany Medical College, Albany, New York.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Olca
authors.initials: O
authors.lastname: Basturk
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Sohail
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York. klimstrd@mskcc.org pstephens@foundationmedicine.com.
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts. klimstrd@mskcc.org pstephens@foundationmedicine.com.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
mesh_terms: D018267:Carcinoma, Acinar Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D016000:Cluster Analysis; D019295:Computational Biology; D004260:DNA Repair / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D023281:Genomics; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D015514:Oncogene Proteins, Fusion; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases