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SNPs in the TGF-β Signaling Pathway Are Associated with Increased Risk of Brain Metastasis in Patients with Non–Small-Cell Lung Cancer

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  • Qianxia Li
  • Huanlei Wu
  • Bei Chen
  • Guangyuan Hu
  • Liu Huang
  • Kai Qin
  • Yu Chen
  • Xianglin Yuan
  • Zhongxing Liao

Abstract

Purpose: 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. Patients and 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.

Suggested Citation

  • Qianxia Li & Huanlei Wu & Bei Chen & Guangyuan Hu & Liu Huang & Kai Qin & Yu Chen & Xianglin Yuan & Zhongxing Liao, 2012. "SNPs in the TGF-β Signaling Pathway Are Associated with Increased Risk of Brain Metastasis in Patients with Non–Small-Cell Lung Cancer," PLOS ONE, Public Library of Science, vol. 7(12), pages 1-11, December.
    • Handle: RePEc:plo:pone00:0051713
    DOI: 10.1371/journal.pone.0051713
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    1. Rik Derynck & Ying E. Zhang, 2003. "Smad-dependent and Smad-independent pathways in TGF-β family signalling," Nature, Nature, vol. 425(6958), pages 577-584, October.
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