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TGFβ1 Polymorphisms Predict Distant Metastasis-Free Survival in Patients with Inoperable Non-Small-Cell Lung Cancer after Definitive Radiotherapy.

Yuan X, Wei Q, Komaki R, Liu Z, Yang J, Tucker SL, Xu T, Heymach JV, Lu C, Cox JD, Liao Z - PLoS ONE (2013)

Bottom Line: Median follow-up time for all patients was 17 months (range, 1-97 months; 39 months for patients alive at the time of analysis).Multivariate analysis showed that the TGFβ1 rs1800469 CT/CC genotype was associated with poor OS (hazard ratio [HR] = 1.463 [95% confidence interval {CI} = 1.012-2.114], P = 0.043) and shorter DMFS (HR = 1.601 [95% CI = 1.042-2.459], P = 0.032) and that the TGFβ1 rs1982073 CT/CC genotype predicted poor DMFS (HR = 1.589 [95% CI = 1.009-2.502], P = 0.046) and poor brain MFS (HR = 2.567 [95% CI = 1.155-5.702], P = 0.021) after adjustment for age, sex, race, performance status, smoking status, tumor histology and volume, stage, receipt of concurrent radiochemotherapy, number of chemotherapy cycles, and radiation dose.Transfection with TGFβ1+29C (vs. +29T) stimulated the migration and invasion of A549 and PC9 cells, suggesting that TGFβ1+29C may be linked with increased metastatic potential.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT

Purpose: Transforming growth factor (TGF) -β1 signaling is involved in cancer-cell metastasis. We investigated whether single nucleotide polymorphisms (SNPs) at TGFβ1 were associated with overall survival (OS) and distant metastasis-free survival (DMFS) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiotherapy, with or without chemotherapy.

Methods: We genotyped TGFβ1 SNPs at rs1800469 (C-509T), rs1800471 (G915C), and rs1982073 (T+29C) by polymerase chain reaction-restriction fragment length polymorphism in blood samples from 205 NSCLC patients who had had definitive radiotherapy at one institution in November 1998-January 2005. We also tested whether the TGF-β1 rs1982073 (T+29C) SNP affected the migration and invasion of A549 and PC9 lung cancer cells.

Results: Median follow-up time for all patients was 17 months (range, 1-97 months; 39 months for patients alive at the time of analysis). Multivariate analysis showed that the TGFβ1 rs1800469 CT/CC genotype was associated with poor OS (hazard ratio [HR] = 1.463 [95% confidence interval {CI} = 1.012-2.114], P = 0.043) and shorter DMFS (HR = 1.601 [95% CI = 1.042-2.459], P = 0.032) and that the TGFβ1 rs1982073 CT/CC genotype predicted poor DMFS (HR = 1.589 [95% CI = 1.009-2.502], P = 0.046) and poor brain MFS (HR = 2.567 [95% CI = 1.155-5.702], P = 0.021) after adjustment for age, sex, race, performance status, smoking status, tumor histology and volume, stage, receipt of concurrent radiochemotherapy, number of chemotherapy cycles, and radiation dose. Transfection with TGFβ1+29C (vs. +29T) stimulated the migration and invasion of A549 and PC9 cells, suggesting that TGFβ1+29C may be linked with increased metastatic potential.

Conclusions: TGFβ1 genotypes at rs1800469 and rs1982073 could be useful for predicting DMFS among patients with NSCLC treated with definitive radiation therapy. These findings require validation in larger prospective trials and thorough mechanistic studies.

No MeSH data available.


Related in: MedlinePlus

Transfection of A549 cells and PC9 cells with TGFβ1 rs1892073+29C, but not with +29T, led to enhanced motility and invasion.(A,B) Fluorescence phase-contrast microscopic images show that at 24 hours, more of the +29C transfectants migrated into a “healing” area in a scratch assay than did +29T transfectants. These findings are depicted quantitatively as the distance migrated during the scratch assay in panels C and E. (D,F) The +29C transfectants showed greater invasiveness, as indicated by numbers of cells penetrating a membrane in a transwell assay. Results are given as means from 3 independent experiments; error bars representing standard deviation.
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pone-0065659-g003: Transfection of A549 cells and PC9 cells with TGFβ1 rs1892073+29C, but not with +29T, led to enhanced motility and invasion.(A,B) Fluorescence phase-contrast microscopic images show that at 24 hours, more of the +29C transfectants migrated into a “healing” area in a scratch assay than did +29T transfectants. These findings are depicted quantitatively as the distance migrated during the scratch assay in panels C and E. (D,F) The +29C transfectants showed greater invasiveness, as indicated by numbers of cells penetrating a membrane in a transwell assay. Results are given as means from 3 independent experiments; error bars representing standard deviation.

Mentions: Transfection efficiency for both A549 and PC9 lung cancer cell lines was approximately 99% (Figs. 2A,B). Transfection of A549 and PC9 cells with TGF-β1+29C or +29T induced the expected increases in the expression of both precursor and active forms of TGFβ1 (Figs. 2C,D). Both cell lines, upon transfection with the TGFβ1+29C construct, demonstrated increased motility (Figs. 3A,B,C,E) and increased invasion (Figs. 3D,F) relative to the +29T transfectants. These results suggest that the TGFβ1+29C genotype in both of these lung cancer cell lines induced a phenotype with increased potential for metastasis.


TGFβ1 Polymorphisms Predict Distant Metastasis-Free Survival in Patients with Inoperable Non-Small-Cell Lung Cancer after Definitive Radiotherapy.

Yuan X, Wei Q, Komaki R, Liu Z, Yang J, Tucker SL, Xu T, Heymach JV, Lu C, Cox JD, Liao Z - PLoS ONE (2013)

Transfection of A549 cells and PC9 cells with TGFβ1 rs1892073+29C, but not with +29T, led to enhanced motility and invasion.(A,B) Fluorescence phase-contrast microscopic images show that at 24 hours, more of the +29C transfectants migrated into a “healing” area in a scratch assay than did +29T transfectants. These findings are depicted quantitatively as the distance migrated during the scratch assay in panels C and E. (D,F) The +29C transfectants showed greater invasiveness, as indicated by numbers of cells penetrating a membrane in a transwell assay. Results are given as means from 3 independent experiments; error bars representing standard deviation.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3686751&req=5

pone-0065659-g003: Transfection of A549 cells and PC9 cells with TGFβ1 rs1892073+29C, but not with +29T, led to enhanced motility and invasion.(A,B) Fluorescence phase-contrast microscopic images show that at 24 hours, more of the +29C transfectants migrated into a “healing” area in a scratch assay than did +29T transfectants. These findings are depicted quantitatively as the distance migrated during the scratch assay in panels C and E. (D,F) The +29C transfectants showed greater invasiveness, as indicated by numbers of cells penetrating a membrane in a transwell assay. Results are given as means from 3 independent experiments; error bars representing standard deviation.
Mentions: Transfection efficiency for both A549 and PC9 lung cancer cell lines was approximately 99% (Figs. 2A,B). Transfection of A549 and PC9 cells with TGF-β1+29C or +29T induced the expected increases in the expression of both precursor and active forms of TGFβ1 (Figs. 2C,D). Both cell lines, upon transfection with the TGFβ1+29C construct, demonstrated increased motility (Figs. 3A,B,C,E) and increased invasion (Figs. 3D,F) relative to the +29T transfectants. These results suggest that the TGFβ1+29C genotype in both of these lung cancer cell lines induced a phenotype with increased potential for metastasis.

Bottom Line: Median follow-up time for all patients was 17 months (range, 1-97 months; 39 months for patients alive at the time of analysis).Multivariate analysis showed that the TGFβ1 rs1800469 CT/CC genotype was associated with poor OS (hazard ratio [HR] = 1.463 [95% confidence interval {CI} = 1.012-2.114], P = 0.043) and shorter DMFS (HR = 1.601 [95% CI = 1.042-2.459], P = 0.032) and that the TGFβ1 rs1982073 CT/CC genotype predicted poor DMFS (HR = 1.589 [95% CI = 1.009-2.502], P = 0.046) and poor brain MFS (HR = 2.567 [95% CI = 1.155-5.702], P = 0.021) after adjustment for age, sex, race, performance status, smoking status, tumor histology and volume, stage, receipt of concurrent radiochemotherapy, number of chemotherapy cycles, and radiation dose.Transfection with TGFβ1+29C (vs. +29T) stimulated the migration and invasion of A549 and PC9 cells, suggesting that TGFβ1+29C may be linked with increased metastatic potential.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT

Purpose: Transforming growth factor (TGF) -β1 signaling is involved in cancer-cell metastasis. We investigated whether single nucleotide polymorphisms (SNPs) at TGFβ1 were associated with overall survival (OS) and distant metastasis-free survival (DMFS) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiotherapy, with or without chemotherapy.

Methods: We genotyped TGFβ1 SNPs at rs1800469 (C-509T), rs1800471 (G915C), and rs1982073 (T+29C) by polymerase chain reaction-restriction fragment length polymorphism in blood samples from 205 NSCLC patients who had had definitive radiotherapy at one institution in November 1998-January 2005. We also tested whether the TGF-β1 rs1982073 (T+29C) SNP affected the migration and invasion of A549 and PC9 lung cancer cells.

Results: Median follow-up time for all patients was 17 months (range, 1-97 months; 39 months for patients alive at the time of analysis). Multivariate analysis showed that the TGFβ1 rs1800469 CT/CC genotype was associated with poor OS (hazard ratio [HR] = 1.463 [95% confidence interval {CI} = 1.012-2.114], P = 0.043) and shorter DMFS (HR = 1.601 [95% CI = 1.042-2.459], P = 0.032) and that the TGFβ1 rs1982073 CT/CC genotype predicted poor DMFS (HR = 1.589 [95% CI = 1.009-2.502], P = 0.046) and poor brain MFS (HR = 2.567 [95% CI = 1.155-5.702], P = 0.021) after adjustment for age, sex, race, performance status, smoking status, tumor histology and volume, stage, receipt of concurrent radiochemotherapy, number of chemotherapy cycles, and radiation dose. Transfection with TGFβ1+29C (vs. +29T) stimulated the migration and invasion of A549 and PC9 cells, suggesting that TGFβ1+29C may be linked with increased metastatic potential.

Conclusions: TGFβ1 genotypes at rs1800469 and rs1982073 could be useful for predicting DMFS among patients with NSCLC treated with definitive radiation therapy. These findings require validation in larger prospective trials and thorough mechanistic studies.

No MeSH data available.


Related in: MedlinePlus