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Non-coding polymorphisms in nucleotide binding domain 1 in ABCC1 gene associate with transcript level and survival of patients with breast cancer.

Kunická T, Václavíková R, Hlaváč V, Vrána D, Pecha V, Rauš K, Trnková M, Kubáčková K, Ambruš M, Vodičková L, Vodička P, Souček P - PLoS ONE (2014)

Bottom Line: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells.The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540).The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic; 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.

ABSTRACT

Objectives: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells. Multidrug resistance-associated protein 1 coded by the ABCC1 gene has recently been suggested as a potential prognostic marker in breast cancer patients. This study aimed to explore tagged haplotype covering nucleotide binding domain 1 of ABCC1 in relation with corresponding transcript levels in tissues and clinical phenotype of breast cancer patients.

Methods: The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540).

Results: Tumors from carriers of the wild type genotype in rs35623 or rs35628 exhibited significantly lower levels of ABCC1 transcript than those from carriers of the minor allele (p = 0.003 and p = 0.004, respectively). The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype. Chemotherapy-treated patients carrying the T allele in rs4148353 had longer disease-free survival than those with the GG genotype (p = 0.043). On the other hand, hormonal therapy-treated patients with the AA genotype in rs35628 had significantly longer disease-free survival than carriers of the G allele (p = 0.012).

Conclusions: Taken together, our study shows that genetic variability in the nucleotide binding domain 1 has a significant impact on the ABCC1 transcript level in the target tissue and may modify survival of breast cancer patients.

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Related in: MedlinePlus

Significant associations between DFS of patients with breast carcinoma and SNPs in ABCC1.Kaplan-Meier survival curves for patients treated by chemotherapy (A) and hormonal therapy (B) were analyzed by Breslow test. In part A, dashed line represents DFS of patients with the GG genotype in rs4148353, while solid line indicates that of patients with the T allele. In part B, dashed line represents DFS of patients with the G allele in rs35628 and solid line DFS of those with the AA genotype. All SNPs have been analyzed but to retain concise style only significant associations are reported.
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pone-0101740-g004: Significant associations between DFS of patients with breast carcinoma and SNPs in ABCC1.Kaplan-Meier survival curves for patients treated by chemotherapy (A) and hormonal therapy (B) were analyzed by Breslow test. In part A, dashed line represents DFS of patients with the GG genotype in rs4148353, while solid line indicates that of patients with the T allele. In part B, dashed line represents DFS of patients with the G allele in rs35628 and solid line DFS of those with the AA genotype. All SNPs have been analyzed but to retain concise style only significant associations are reported.

Mentions: No association between age at diagnosis, menopausal status, tumor size, expression of progesterone receptor, and p53 and the SNPs followed was found (results not shown). Large tumor size (pT2-4), presence of lymph node metastasis (pN1-3), lack of expression of hormonal receptors (ER and PR), and triple-negative molecular subtype were significant predictors of poor prognosis, i.e. short DFS in the set of chemotherapy-treated patients (p<0.001, p = 0.001, p = 0.011, p = 0.001, and p = 0.003, respectively). Large tumor size (pT2-4), presence of lymph node metastasis (pN1-3), and lack of expression of PR were significant predictors of poor prognosis, i.e. short DFS in the set of hormonal therapy-treated patients (p = 0.001, p<0.001, and p = 0.031, respectively). Chemotherapy-treated patients carrying T allele in the rs4148353 SNP had longer DFS than those with wild type GG genotype in univariate analysis (n = 271, p = 0.043; Figure 4A). On the other hand, hormonal therapy-treated patients with the wild type AA genotype in the rs35628 had longer DFS than patients carrying the G allele (n = 353, p = 0.012; Figure 4B). Multivariate analysis using the Cox regression hazard model with pT, pN, ER, and PR expression, triple-negative molecular subtype, and individual SNPs has not confirmed association with DFS for rs4148353 (n = 252, p = 0.116). However, for rs35628 the association observed in univariate model remained significant in multivariate model with pT, pN, and PR expression (n = 323, p = 0.008). Survival analysis was not corrected for multiple testing.


Non-coding polymorphisms in nucleotide binding domain 1 in ABCC1 gene associate with transcript level and survival of patients with breast cancer.

Kunická T, Václavíková R, Hlaváč V, Vrána D, Pecha V, Rauš K, Trnková M, Kubáčková K, Ambruš M, Vodičková L, Vodička P, Souček P - PLoS ONE (2014)

Significant associations between DFS of patients with breast carcinoma and SNPs in ABCC1.Kaplan-Meier survival curves for patients treated by chemotherapy (A) and hormonal therapy (B) were analyzed by Breslow test. In part A, dashed line represents DFS of patients with the GG genotype in rs4148353, while solid line indicates that of patients with the T allele. In part B, dashed line represents DFS of patients with the G allele in rs35628 and solid line DFS of those with the AA genotype. All SNPs have been analyzed but to retain concise style only significant associations are reported.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4117604&req=5

pone-0101740-g004: Significant associations between DFS of patients with breast carcinoma and SNPs in ABCC1.Kaplan-Meier survival curves for patients treated by chemotherapy (A) and hormonal therapy (B) were analyzed by Breslow test. In part A, dashed line represents DFS of patients with the GG genotype in rs4148353, while solid line indicates that of patients with the T allele. In part B, dashed line represents DFS of patients with the G allele in rs35628 and solid line DFS of those with the AA genotype. All SNPs have been analyzed but to retain concise style only significant associations are reported.
Mentions: No association between age at diagnosis, menopausal status, tumor size, expression of progesterone receptor, and p53 and the SNPs followed was found (results not shown). Large tumor size (pT2-4), presence of lymph node metastasis (pN1-3), lack of expression of hormonal receptors (ER and PR), and triple-negative molecular subtype were significant predictors of poor prognosis, i.e. short DFS in the set of chemotherapy-treated patients (p<0.001, p = 0.001, p = 0.011, p = 0.001, and p = 0.003, respectively). Large tumor size (pT2-4), presence of lymph node metastasis (pN1-3), and lack of expression of PR were significant predictors of poor prognosis, i.e. short DFS in the set of hormonal therapy-treated patients (p = 0.001, p<0.001, and p = 0.031, respectively). Chemotherapy-treated patients carrying T allele in the rs4148353 SNP had longer DFS than those with wild type GG genotype in univariate analysis (n = 271, p = 0.043; Figure 4A). On the other hand, hormonal therapy-treated patients with the wild type AA genotype in the rs35628 had longer DFS than patients carrying the G allele (n = 353, p = 0.012; Figure 4B). Multivariate analysis using the Cox regression hazard model with pT, pN, ER, and PR expression, triple-negative molecular subtype, and individual SNPs has not confirmed association with DFS for rs4148353 (n = 252, p = 0.116). However, for rs35628 the association observed in univariate model remained significant in multivariate model with pT, pN, and PR expression (n = 323, p = 0.008). Survival analysis was not corrected for multiple testing.

Bottom Line: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells.The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540).The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic; 3rd Faculty of Medicine, Charles University, Prague, Czech Republic.

ABSTRACT

Objectives: ATP-Binding Cassette (ABC) transporters may cause treatment failure by transporting of anticancer drugs outside of the tumor cells. Multidrug resistance-associated protein 1 coded by the ABCC1 gene has recently been suggested as a potential prognostic marker in breast cancer patients. This study aimed to explore tagged haplotype covering nucleotide binding domain 1 of ABCC1 in relation with corresponding transcript levels in tissues and clinical phenotype of breast cancer patients.

Methods: The distribution of twelve ABCC1 polymorphisms was assessed by direct sequencing in peripheral blood DNA (n = 540).

Results: Tumors from carriers of the wild type genotype in rs35623 or rs35628 exhibited significantly lower levels of ABCC1 transcript than those from carriers of the minor allele (p = 0.003 and p = 0.004, respectively). The ABCC1 transcript levels significantly increased in the order CT-GT>CC-GT>CC-GG for the predicted rs35626-rs4148351 diplotype. Chemotherapy-treated patients carrying the T allele in rs4148353 had longer disease-free survival than those with the GG genotype (p = 0.043). On the other hand, hormonal therapy-treated patients with the AA genotype in rs35628 had significantly longer disease-free survival than carriers of the G allele (p = 0.012).

Conclusions: Taken together, our study shows that genetic variability in the nucleotide binding domain 1 has a significant impact on the ABCC1 transcript level in the target tissue and may modify survival of breast cancer patients.

Show MeSH
Related in: MedlinePlus