Adverse prognostic impact of TGFB1 T869C polymorphism in non-small-cell lung cancer

Abstract

Previously, several polymorphisms in TGFB1 have been identified in non-small-cell lung cancer (NSCLC), and the variants, C-509T, T869C, and G915C, have been demonstrated to associate with higher circulating levels of TGF-β1. However, little is known about the prognostic value of TGF-β1 polymorphisms in cancers. In this study, by genotyping the TGF-β1 T869C polymorphism in a total of 261 patients with NSCLC using DNA from blood lymphocytes, we first found that NSCLC patients, especially those with allele C carriers, had significantly higher serum TGF-β1 levels than healthy individuals. By using chi-square (χ²) test and Fisher's exact test, we noticed that TC/CC genotypes were positively correlated with smoking, clinical TNM stage, lymph node, and distant metastasis in NSCLC patients. Kaplan-Meier analysis showed that patients with TT genotype had a better overall survival than the allele C carriers (TC + CC). Finally, multivariate analysis confirmed histology, lymph node, and distant metastasis but not T869C polymorphism as independent prognostic factors for NSCLC. Taken together, our data, as a proof of principle, suggest that T869C polymorphism in TGFB1 may act as a genetic modifier in NSCLC progression and a promising prognostic marker of survival in NSCLC patients.

Keywords: genotype and multivariate analysis; prognosis; single-nucleotide polymorphisms.

Figure 1

TGFB1 T869C polymorphism contributes to elevated serum TGF-β1 level in NSCLC. Notes: (A) The Leu10Pro substitution resulted from TGFB1 T869C polymorphism in the signal peptide of TGF-β1 protein. (B) The 3D structure of TGF-β1 protein. (C) The serum TGF-β1 level of NSCLC patients and healthy controls was tested by ELISA. (D) The serum TGF-β1 level among NSCLC patients with different genotypes. Data are shown as mean ± SD, P-value was calculated by two-sided Student’s t-test; *P<0.05, **P<0.01, and ***P<0.001. Abbreviations: NSCLC, non-small-cell lung cancer; 3D, three-dimensional; ELISA, enzyme-linked immunosorbent assay; aa, amino acid.

Figure 2

Kaplan–Meier curve of overall survival according to TGFB1 T869C polymorphism in NSCLC. Notes: (A) Survival analysis stratified by CC, TC and TT groups. (B) Survival analysis stratified by TC + CC and TT groups. P-value <0.05 was considered to be significant. Abbreviation: NSCLC, non-small-cell lung cancer.

Figure 3

Prognostic factors in Cox proportional hazards model. Notes: Univariate (A) and multivariable (B) analyses were performed to identify prognostic factors for NSCLC. All the bars correspond to 95% CI. Bold numbers represent P-values with significant differences. Abbreviations: NSCLC, non-small-cell lung cancer; CI, confidence interval; HR, hazard ratio.