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By cutting the cancer cells out from the surrounding scar tissue before sequencing 109 tumours, this study got cleaner mutation calls and found that MYC gain marks the worst outcomes, that codon-61 KRAS and RBM10 changes go with longer survival, and that BRAF-mutant tumours lack KRAS and respond to BRAF drugs in models.
109 microdissected pancreatic ductal adenocarcinomas underwent whole-exome sequencing; microdissection enriched cellularity and mutation calling. Environmental stress and DNA repair gene alterations associated with distinct mutation spectra. Amplification of MYC was uniquely associated with poor outcome and the adenosquamous subtype. RBM10 mutations associated with longer survival despite aggressive histology. KRAS mutations were observed in more than 90%, but codon Q61 alleles were selectively associated with improved survival. Oncogenic BRAF mutations were mutually exclusive with KRAS and defined sensitivity to vemurafenib in models. High-frequency alterations in Wnt, chromatin remodelling, Hedgehog, DNA repair and cell cycle processes were observed.
Deposited as paad_utsw_2015 on cBioPortal (KRAS 100 of 109; MYC amplified in 13; BRAF V600E in 3).
The microdissected cohort is the cleanest exome reference for allele-level KRAS and copy-number calls, and it first tied MYC amplification to the squamous, chemotherapy-resistant end of the disease.
Shares RNF43, Nature Communications, Wnt / β-catenin, Whole-exome & whole-genome sequencing.
Shares MYC, MYC, Pancreatic ductal adenocarcinoma.
Shares KRAS mutation subtypes (G12C, G12D, G12V), RAS / RAF / MEK / ERK (MAPK), KRAS, Pancreatic ductal adenocarcinoma.
Shares RNF43, Whole-exome & whole-genome sequencing, BRAF, RAS / RAF / MEK / ERK (MAPK).
Shares KRAS mutation subtypes (G12C, G12D, G12V), RAS / RAF / MEK / ERK (MAPK), KRAS, Pancreatic ductal adenocarcinoma.
Shares KRAS mutation subtypes (G12C, G12D, G12V), RAS / RAF / MEK / ERK (MAPK), KRAS, Pancreatic ductal adenocarcinoma.
Shares RNF43, Wnt / β-catenin, Pancreatic ductal adenocarcinoma.
Shares MYC, MYC, Pancreatic ductal adenocarcinoma.