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Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer
BACKGROUND: A genome-wide association study (GWAS) suggested inherited genetic single-nucleotide polymorphisms (SNPs) affecting overall survival (OS) in advanced pancreatic cancer. To identify robust clinical biomarkers, we tested the strongest reported candidate loci in an independent patient cohor...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859408/ https://www.ncbi.nlm.nih.gov/pubmed/26857392 http://dx.doi.org/10.1093/jnci/djv387 |
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author | Schirmer, Markus A. Lüske, Claudia M. Roppel, Sebastian Schaudinn, Alexander Zimmer, Christian Pflüger, Ruben Haubrock, Martin Rapp, Jacobe Güngör, Cenap Bockhorn, Maximilian Hackert, Thilo Hank, Thomas Strobel, Oliver Werner, Jens Izbicki, Jakob R. Johnsen, Steven A. Gaedcke, Jochen Brockmöller, Jürgen Ghadimi, B. Michael |
author_facet | Schirmer, Markus A. Lüske, Claudia M. Roppel, Sebastian Schaudinn, Alexander Zimmer, Christian Pflüger, Ruben Haubrock, Martin Rapp, Jacobe Güngör, Cenap Bockhorn, Maximilian Hackert, Thilo Hank, Thomas Strobel, Oliver Werner, Jens Izbicki, Jakob R. Johnsen, Steven A. Gaedcke, Jochen Brockmöller, Jürgen Ghadimi, B. Michael |
author_sort | Schirmer, Markus A. |
collection | PubMed |
description | BACKGROUND: A genome-wide association study (GWAS) suggested inherited genetic single-nucleotide polymorphisms (SNPs) affecting overall survival (OS) in advanced pancreatic cancer. To identify robust clinical biomarkers, we tested the strongest reported candidate loci in an independent patient cohort, assessed cellular drug sensitivity, and evaluated molecular effects. METHODS: This study comprised 381 patients with histologically verified pancreatic ductal adenocarcinoma treated with gemcitabine-based chemotherapy. The primary outcome was the relationship between germline polymorphisms and OS. Functional assays addressed pharmacological dose-response effects in lymphoblastoid cell lines (LCLs) and pancreatic cancer cell lines (including upon RNAi), gene expression analyses, and allele-specific transcription factor binding. All statistical tests were two-sided. RESULTS: The A allele (26% in Caucasians) at SNP rs11644322 in the putative tumor suppressor gene WWOX conferred worse prognosis. Median OS was 14 months (95% confidence interval [CI] = 12 to 15 months), 13 months (95% CI = 11 to 15 months), and nine months (95% CI = 7 to 12 months) for the GG, GA, and AA genotypes, respectively (P (trend) < .001 for trend in univariate log-rank assuming a codominant mode of inheritance; advanced disease subgroup P (trend) < .001). Mean OS was 25 months (95% CI = 21 to 29 months), 19 months (95% CI = 15 to 22 months), and 13 months (95% CI = 10 to 16 months), respectively. This effect held true after adjustment for age, performance status according to Eastern Cooperative Oncology Group classification, TNM, grading, and resection status and was comparable with the strongest established prognostic factors in multivariable analysis. Consistently, reduced responsiveness to gemcitabine, but not 5-fluorouracil, along with lower WWOX expression was demonstrated in LCLs harboring the AA genotype. Likewise, RNAi-mediated WWOX knockdown in pancreatic cancer cells confirmed differential cytostatic drug sensitivity. In electrophoretic mobility shift assays, the A allele exhibited weaker binding of Sp family members Sp1/Sp3. CONCLUSIONS: WWOX rs11644322 represents a major predictive factor in gemcitabine-treated pancreatic cancer. Decreased WWOX expression may interfere with gemcitabine sensitivity, and allele-specific binding at rs11644332 might be a causative molecular mechanism behind the observed clinical associations. |
format | Online Article Text |
id | pubmed-4859408 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-48594082016-05-09 Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer Schirmer, Markus A. Lüske, Claudia M. Roppel, Sebastian Schaudinn, Alexander Zimmer, Christian Pflüger, Ruben Haubrock, Martin Rapp, Jacobe Güngör, Cenap Bockhorn, Maximilian Hackert, Thilo Hank, Thomas Strobel, Oliver Werner, Jens Izbicki, Jakob R. Johnsen, Steven A. Gaedcke, Jochen Brockmöller, Jürgen Ghadimi, B. Michael J Natl Cancer Inst Article BACKGROUND: A genome-wide association study (GWAS) suggested inherited genetic single-nucleotide polymorphisms (SNPs) affecting overall survival (OS) in advanced pancreatic cancer. To identify robust clinical biomarkers, we tested the strongest reported candidate loci in an independent patient cohort, assessed cellular drug sensitivity, and evaluated molecular effects. METHODS: This study comprised 381 patients with histologically verified pancreatic ductal adenocarcinoma treated with gemcitabine-based chemotherapy. The primary outcome was the relationship between germline polymorphisms and OS. Functional assays addressed pharmacological dose-response effects in lymphoblastoid cell lines (LCLs) and pancreatic cancer cell lines (including upon RNAi), gene expression analyses, and allele-specific transcription factor binding. All statistical tests were two-sided. RESULTS: The A allele (26% in Caucasians) at SNP rs11644322 in the putative tumor suppressor gene WWOX conferred worse prognosis. Median OS was 14 months (95% confidence interval [CI] = 12 to 15 months), 13 months (95% CI = 11 to 15 months), and nine months (95% CI = 7 to 12 months) for the GG, GA, and AA genotypes, respectively (P (trend) < .001 for trend in univariate log-rank assuming a codominant mode of inheritance; advanced disease subgroup P (trend) < .001). Mean OS was 25 months (95% CI = 21 to 29 months), 19 months (95% CI = 15 to 22 months), and 13 months (95% CI = 10 to 16 months), respectively. This effect held true after adjustment for age, performance status according to Eastern Cooperative Oncology Group classification, TNM, grading, and resection status and was comparable with the strongest established prognostic factors in multivariable analysis. Consistently, reduced responsiveness to gemcitabine, but not 5-fluorouracil, along with lower WWOX expression was demonstrated in LCLs harboring the AA genotype. Likewise, RNAi-mediated WWOX knockdown in pancreatic cancer cells confirmed differential cytostatic drug sensitivity. In electrophoretic mobility shift assays, the A allele exhibited weaker binding of Sp family members Sp1/Sp3. CONCLUSIONS: WWOX rs11644322 represents a major predictive factor in gemcitabine-treated pancreatic cancer. Decreased WWOX expression may interfere with gemcitabine sensitivity, and allele-specific binding at rs11644332 might be a causative molecular mechanism behind the observed clinical associations. Oxford University Press 2016-02-08 /pmc/articles/PMC4859408/ /pubmed/26857392 http://dx.doi.org/10.1093/jnci/djv387 Text en © The Author 2016. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Article Schirmer, Markus A. Lüske, Claudia M. Roppel, Sebastian Schaudinn, Alexander Zimmer, Christian Pflüger, Ruben Haubrock, Martin Rapp, Jacobe Güngör, Cenap Bockhorn, Maximilian Hackert, Thilo Hank, Thomas Strobel, Oliver Werner, Jens Izbicki, Jakob R. Johnsen, Steven A. Gaedcke, Jochen Brockmöller, Jürgen Ghadimi, B. Michael Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer |
title | Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer |
title_full | Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer |
title_fullStr | Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer |
title_full_unstemmed | Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer |
title_short | Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer |
title_sort | relevance of sp binding site polymorphism in wwox for treatment outcome in pancreatic cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859408/ https://www.ncbi.nlm.nih.gov/pubmed/26857392 http://dx.doi.org/10.1093/jnci/djv387 |
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