title: Next generation sequencing identifies 'interactome' signatures in relapsed and refractory metastatic colorectal cancer.
abstract: BACKGROUND
  In the management of metastatic colorectal cancer (mCRC),KRAS,NRASandBRAFmutational status individualizes therapeutic options and identify a cohort of patients (pts) with an aggressive clinical course. We hypothesized that relapsed and refractory mCRC pts develop unique mutational signatures that may guide therapy, predict for a response and highlight key signaling pathways important for clinical decision making.
  
  
  METHODS
  Relapsed and refractory mCRC pts (N=32) were molecularly profiled utilizing commercially available next generation sequencing (NGS) platforms. Web-based bioinformatics tools (Reactome/Enrichr) were utilized to elucidate mutational profile linked pathways-networks that have the potential to guide therapy.
  
  
  RESULTS
  Pts had progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab and/or panitumumab. Most common histology was adenocarcinoma (colon N=29; rectal N=3). Of the mutations TP53 was the most common, followed byAPC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1andHER3. Pts had on average had ≥5 unique mutations. The most frequent activated signaling pathways were: HER2, fibroblast growth factor receptor (FGFR), p38 through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2.
  
  
  CONCLUSIONS
  Dominant driver oncogene mutations do not always equate to oncogenic dependence, hence understanding pathogenic 'interactome(s)' in individual pts is key to both clinically relevant targets and in choosing the next best therapy. Mutational signatures derived from corresponding 'pathway-networks' represent a meaningful tool to (I) evaluate functional investigation in the laboratory; (II) predict response to drug therapy; and (III) guide rational drug combinations in relapsed and refractory mCRC pts.
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Benny
authors.initials: B
authors.lastname: Johnson
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ 85719, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Cooke
authors.affiliation: The University of Arizona Cancer Center, Tucson, AZ 85719, USA.
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
keywords: BRAF; Metastatic colorectal cancer (mCRC); RAS; interactome; mutational signatures; next generation sequencing (NGS)