Abstract
Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAF mutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Antineoplastic Agents / therapeutic use
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BRCA2 Protein / genetics
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Carcinoma, Adenosquamous / drug therapy
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Carcinoma, Adenosquamous / genetics*
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Carcinoma, Adenosquamous / pathology
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Carcinoma, Pancreatic Ductal / drug therapy
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Carcinoma, Pancreatic Ductal / genetics*
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Carcinoma, Pancreatic Ductal / pathology
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Cell Cycle / genetics
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DNA Copy Number Variations
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DNA Repair / genetics
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DNA-Binding Proteins
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Drug Resistance, Neoplasm / genetics
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Exome / genetics*
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Female
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Gene Amplification
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Genes, myc / genetics
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Genetic Variation*
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Humans
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Indoles / therapeutic use
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Kaplan-Meier Estimate
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Male
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Middle Aged
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Molecular Targeted Therapy
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Nuclear Proteins / genetics
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Pancreatic Neoplasms / drug therapy
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / pathology
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Prognosis
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins p21(ras) / genetics
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RNA-Binding Proteins / genetics
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Retinoblastoma Protein / genetics
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Sequence Analysis, DNA
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Sulfonamides / therapeutic use
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Transcription Factors / genetics
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Tumor Suppressor Protein p53 / genetics
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Vemurafenib
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Wnt Signaling Pathway / genetics
Substances
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ARID1A protein, human
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Antineoplastic Agents
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BRCA2 Protein
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BRCA2 protein, human
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DNA-Binding Proteins
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Indoles
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KRAS protein, human
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Nuclear Proteins
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RBM10 protein, human
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RNA-Binding Proteins
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Retinoblastoma Protein
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Sulfonamides
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TP53 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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Vemurafenib
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins p21(ras)