title: Mutation location on the RAS oncogene affects pathologic features and survival after resection of colorectal liver metastases.
abstract: In the past 3 decades, a better understanding of gene mutations and their role in carcinogenesis has led to improvement in our ability to treat patients with metastatic disease. The objective of the current study was to determine whether the location of a driver mutation within an affected gene impacts the biology of metastatic colorectal cancer.
  
  
  
  DNA was collected from 165 randomly selected specimens of patients who underwent margin-negative resection of colorectal liver metastases with curative intent. Sequenom analysis and Sanger sequencing were used to evaluate mutations in K/NRAS, PIK3CA, BRAF, and TP53.
  
  
  
  BRAF mutation was associated with early recurrence and death, whereas no impact of TP53 or PIK3CA mutation was identified. Although K/NRAS mutation was associated with worse survival in this cohort, this difference was no longer evident when those who had received anti-EGFR therapy were excluded. When stratifying patients according to the exon on which K/NRAS was mutated, there were dramatic differences in both survival and pathologic features. Exon 4 mutations were associated with large, solitary metastases occurring at long disease-free intervals compared with exon 3 mutations, which presented with small, numerous lesions. Patients who had exon 4 mutations recurred infrequently and had significantly longer survival compared with those who had wild type or other mutations.
  
  
  
  By using this model of curative-intent, margin-negative resection in patients at high risk of recurrence, the authors were able to establish a link between mutation location within the K/NRAS gene and the biology of metastatic colorectal cancer. Cancer 2017;123:568-575. © 2016 American Cancer Society.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Frankel
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Hari
authors.initials: H
authors.lastname: Nathan
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: DeMatteo
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: T Peter
authors.initials: TP
authors.lastname: Kingham
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Allen
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: William R
authors.initials: WR
authors.lastname: Jarnagin
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kemeny
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael I
authors.initials: MI
authors.lastname: D'Angelica
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D005091:Exons / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary / Q000601:surgery; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: colorectal metastases; hepatectomy; rat sarcoma (RAS) mutation; surgery; v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation