title: MET and EGFR mutations identified in ALK-rearranged pulmonary adenocarcinoma: molecular analysis of 25 ALK-positive cases.
abstract: BACKGROUND
  Oncogenic ALK kinase activity associated with ALK gene rearrangement is the target of crizotinib, an ALK inhibitor recently approved by the Food and Drug Administration for the treatment of ALK-rearranged (ALK+) non-small cell lung cancers. ALK+ status is generally thought to be mutually exclusive of epidermal growth factor receptor (EGFR) and KRAS mutations. However, the mutation status of other genes is not widely known in ALK+ tumors. The aim of this study is to survey for mutations involving other genes in 25 ALK+ cases confirmed by fluorescent in situ hybridization.
  
  
  METHODS
  Using the DNA extracted from formalin-fixed paraffin-embedded tumor samples, a MassArray-based Lung Cancer Mutations Screening Panel was performed to test for 179 individual mutations in 10 genes, including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET and PIK3CA, which have been implicated in lung carcinogenesis and/or considered as potential therapeutic targets.
  
  
  RESULTS
  Five of 25 ALK+ cases showed additional genetic abnormalities, which were verified by gene sequencing. One patient had EGFR del L747-S752. The remaining four mutations were in the MET gene: MET N375S (n = 2) and MET R988C (n = 2). No MET amplification was found by fluorescent in situ hybridization in the four cases with MET mutation. No mutations were detected in the other genes tested.
  
  
  CONCLUSIONS
  In summary, additional mutations were found in 20% of ALK+ cases involving two of the 10 genes tested. Our study highlights that EGFR mutation can be present in ALK+ tumors, though uncommon. Clinical implication of MET mutation in our cases is uncertain and further study is needed.
authors: Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors: Jennifer M
authors: JM
authors: Boland
authors: Jin Sung
authors: JS
authors: Jang
authors: Jun
authors: J
authors: Li
authors: Adam M
authors: AM
authors: Lee
authors: Jason A
authors: JA
authors: Wampfler
authors: Michele R
authors: MR
authors: Erickson-Johnson
authors: Ibere
authors: I
authors: Soares
authors: Ping
authors: P
authors: Yang
authors: Jin
authors: J
authors: Jen
authors: Andre M
authors: AM
authors: Oliveira
authors: Eunhee S
authors: ES
authors: Yi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases