title: SNPs in the TGF-β signaling pathway are associated with increased risk of brain metastasis in patients with non-small-cell lung cancer.
abstract: OBJECTIVE
  Brain metastasis (BM) from non-small cell lung cancer (NSCLC) is relatively common, but identifying which patients will develop brain metastasis has been problematic. We hypothesized that genotype variants in the TGF-β signaling pathway could be a predictive biomarker of brain metastasis.
  
  
  METHODS
  We genotyped 33 SNPs from 13 genes in the TGF-β signaling pathway and evaluated their associations with brain metastasis risk by using DNA from blood samples from 161 patients with NSCLC. Kaplan-Meier analysis was used to assess brain metastasis risk; Cox hazard analyses were used to evaluate the effects of various patient and disease characteristics on the risk of brain metastasis.
  
  
  RESULTS
  The median age of the 116 men and 45 women in the study was 58 years; 62 (39%) had stage IIIB or IV disease. Within 24 months after initial diagnosis of lung cancer, brain metastasis was found in 60 patients (37%). Of these 60 patients, 16 had presented with BM at diagnosis. Multivariate analysis showed the GG genotype of SMAD6: rs12913975 and TT genotype of INHBC: rs4760259 to be associated with a significantly higher risk of brain metastasis at 24 months follow-up (hazard ratio [HR] 2.540, 95% confidence interval [CI] 1.204-5.359, P = 0.014; and HR 1.885, 95% CI 1.086-3.273, P = 0.024), compared with the GA or CT/CC genotypes, respectively. When we analyzed combined subgroups, these rates showed higher for those having both the GG genotype of SMAD6: rs12913975 and the TT genotype of INHBC: rs4760259 (HR 2.353, 95% CI 1.390-3.985, P = 0.001).
  
  
  CONCLUSIONS
  We found the GG genotype of SMAD6: rs12913975 and TT genotype of INHBC: rs4760259 to be associated with risk of brain metastasis in patients with NSCLC. This finding, if confirmed, can help to identify patients at high risk of brain metastasis.
authors.affiliation: Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
authors.forename: Qianxia
authors.initials: Q
authors.lastname: Li
authors.forename: Huanlei
authors.initials: H
authors.lastname: Wu
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.forename: Guangyuan
authors.initials: G
authors.lastname: Hu
authors.forename: Liu
authors.initials: L
authors.lastname: Huang
authors.forename: Kai
authors.initials: K
authors.lastname: Qin
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Xianglin
authors.initials: X
authors.lastname: Yuan
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000556:secondary; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D051905:Smad6 Protein / Q000235:genetics; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; C504186:INHBC protein, human; C497802:SMAD6 protein, human; D051905:Smad6 Protein; D016212:Transforming Growth Factor beta; D028322:Inhibin-beta Subunits