title: Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions.
abstract: BACKGROUND
  Colorectal cancer is the second leading cause of cancer death in the United States, with over 50,000 deaths estimated in 2014. Molecular profiling for somatic mutations that predict absence of response to anti-EGFR therapy has become standard practice in the treatment of metastatic colorectal cancer; however, the quantity and type of tissue available for testing is frequently limited. Further, the degree to which the primary tumor is a faithful representation of metastatic disease has been questioned. As next-generation sequencing technology becomes more widely available for clinical use and additional molecularly targeted agents are considered as treatment options in colorectal cancer, it is important to characterize the extent of tumor heterogeneity between primary and metastatic tumors.
  
  
  RESULTS
  We performed deep coverage, targeted next-generation sequencing of 230 key cancer-associated genes for 69 matched primary and metastatic tumors and normal tissue. Mutation profiles were 100% concordant for KRAS, NRAS, and BRAF, and were highly concordant for recurrent alterations in colorectal cancer. Additionally, whole genome sequencing of four patient trios did not reveal any additional site-specific targetable alterations.
  
  
  CONCLUSIONS
  Colorectal cancer primary tumors and metastases exhibit high genomic concordance. As current clinical practices in colorectal cancer revolve around KRAS, NRAS, and BRAF mutation status, diagnostic sequencing of either primary or metastatic tissue as available is acceptable for most patients. Additionally, consistency between targeted sequencing and whole genome sequencing results suggests that targeted sequencing may be a suitable strategy for clinical diagnostic applications.
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Sylvester
authors.forename: Sasinya N
authors.initials: SN
authors.lastname: Scott
authors.forename: Gregory
authors.initials: G
authors.lastname: McDermott
authors.forename: Ronak H
authors.initials: RH
authors.lastname: Shah
authors.forename: Krishan
authors.initials: K
authors.lastname: Kania
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Dayna M
authors.initials: DM
authors.lastname: Oschwald
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vacic
authors.forename: Anne-Katrin
authors.initials: AK
authors.lastname: Emde
authors.forename: Andrea
authors.initials: A
authors.lastname: Cercek
authors.forename: Rona
authors.initials: R
authors.lastname: Yaeger
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kemeny
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.forename: Michael I
authors.initials: MI
authors.lastname: D'Angelica
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000429:Alcohol Oxidoreductases / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D015894:Genome, Human; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D017422:Sequence Analysis, DNA / Q000379:methods*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000429:Alcohol Oxidoreductases; C021496:lactate-malate transhydrogenase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins