title: Co-evolution of somatic variation in primary and metastatic colorectal cancer may expand biopsy indications in the molecular era.
abstract: BACKGROUND
  Metastasis is thought to be a clonal event whereby a single cell initiates the development of a new tumor at a distant site. However the degree to which primary and metastatic tumors differ on a molecular level remains unclear. To further evaluate these concepts, we used next generation sequencing (NGS) to assess the molecular composition of paired primary and metastatic colorectal cancer tissue specimens.
  
  
  METHODS
  468 colorectal tumor samples from a large personalized medicine initiative were assessed by targeted gene sequencing of 1,321 individual genes. Eighteen patients produced genomic profiles for 17 paired primary:metastatic (and 2 metastatic:metastatic) specimens.
  
  
  RESULTS
  An average of 33.3 mutations/tumor were concordant (shared) between matched samples, including common well-known genes (APC, KRAS, TP53). An average of 2.3 mutations/tumor were discordant (unshared) among paired sites. KRAS mutational status was always concordant. The overall concordance rate for mutations was 93.5%; however, nearly all (18/19 (94.7%)) paired tumors showed at least one mutational discordance. Mutations were seen in: TTN, the largest gene (5 discordant pairs), ADAMTS20, APC, MACF1, RASA1, TP53, and WNT2 (2 discordant pairs), SMAD2, SMAD3, SMAD4, FBXW7, and 66 others (1 discordant pair).
  
  
  CONCLUSIONS
  Whereas primary and metastatic tumors displayed little variance overall, co-evolution produced incremental mutations in both. These results suggest that while biopsy of the primary tumor alone is likely sufficient in the chemotherapy-naïve patient, additional biopsies of primary or metastatic disease may be necessary to precisely tailor therapy following chemotherapy resistance or insensitivity in order to adequately account for tumor evolution.
authors.affiliation: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Kim
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schell
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States of America.
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.affiliation: Merck Co, Inc., Boston, MA, United States of America.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Greenawalt
authors.affiliation: Gibbs Cancer Center and Research Institute, Spartanburg, SC, United States of America.
authors.forename: Mingli
authors.initials: M
authors.lastname: Yang
authors.affiliation: Gibbs Cancer Center and Research Institute, Spartanburg, SC, United States of America.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Yeatman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000032:analysis; D019143:Evolution, Molecular; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D017422:Sequence Analysis, DNA; D018631:ras Proteins / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins