title: ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer.
abstract: OBJECTIVE
  Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naïve and crizotinib-resistant cancers.
  
  
  METHODS
  We reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib.
  
  
  RESULTS
  Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5' green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK-positive patients with sufficient tissue for testing.
  
  
  CONCLUSIONS
  Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib.
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.forename: Anna M
authors.initials: AM
authors.lastname: Varghese
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.forename: Sheheryar
authors.initials: S
authors.lastname: Kabraji
authors.forename: Mark M
authors.initials: MM
authors.lastname: Awad
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katayama
authors.forename: Amanda
authors.initials: A
authors.lastname: Pawlak
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins