title: The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain.
abstract: OBJECTIVE
  Brain metastases affect 25% of patients with non-small cell lung cancer (NSCLC). We hypothesized that the expression of genes in primary NSCLC tumors could predict brain metastasis and be used for identification of high-risk patients, who may benefit from prophylactic therapy.
  
  
  METHODS
  The expression of 12 genes was measured by real-time quantitative reverse transcriptase PCR in 142 frozen NSCLC tissue samples. Univariate and multivariate Cox regression analysis was used to analyze the correlation between gene expression and the occurrence of brain metastasis. Immunohistochemistry on independent samples was used to verify the findings.
  
  
  RESULTS
  A score based on the expression levels of three genes, CDH2 (N-cadherin), KIFC1, and FALZ, was highly predictive of brain metastasis in early and advanced lung cancer. The probability of remaining brain metastasis-free at 2 years after diagnosis was 90.0+/-9.5% for patients with stage I/stage II tumors and low score compared with 62.7+/-12% for patients with high score (P<0.01). In patients with more advanced lung cancer, the brain metastasis-free survival at 24 months was 89% for patients with low score compared with only 37% in patients with high score (P<0.02). These results were confirmed by immunohistochemical detection of N-cadherin in independent cohort of primary NSCLC.
  
  
  CONCLUSIONS
  The expression levels of three genes in primary NSCLC tumors may be used to identify patients at high risk for brain metastasis who may benefit from prophylactic therapy to the central nervous system.
authors.affiliation: Cancer Research Center and Pathology Department, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Helena
authors.initials: H
authors.lastname: Grinberg-Rashi
authors.forename: Efrat
authors.initials: E
authors.lastname: Ofek
authors.forename: Marina
authors.initials: M
authors.lastname: Perelman
authors.forename: Jozef
authors.initials: J
authors.lastname: Skarda
authors.forename: Pnina
authors.initials: P
authors.lastname: Yaron
authors.forename: Marián
authors.initials: M
authors.lastname: Hajdúch
authors.forename: Jasmin
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Meir
authors.initials: M
authors.lastname: Krupsky
authors.forename: David A
authors.initials: DA
authors.lastname: Simansky
authors.forename: Zvi
authors.initials: Z
authors.lastname: Ram
authors.forename: Raphael
authors.initials: R
authors.lastname: Pfeffer
authors.forename: Ilana
authors.initials: I
authors.lastname: Galernter
authors.forename: David M
authors.initials: DM
authors.lastname: Steinberg
authors.forename: Issachar
authors.initials: I
authors.lastname: Ben-Dov
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics / Q000556:secondary; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D034961:Antigens, Nuclear / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000556:secondary; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics / Q000556:secondary; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D015703:Antigens, CD; D034961:Antigens, Nuclear; D014408:Biomarkers, Tumor; D015820:Cadherins; D016547:Kinesins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C050361:CDH2 protein, human; C114063:KIF1C protein, human; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins