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Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer

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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.

In: JNCI-J NATL CANCER I, Vol. 108, No. 5, 05.2016, p. djv387.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Schirmer, MA, Lüske, CM, Roppel, S, Schaudinn, A, Zimmer, C, Pflüger, R, Haubrock, M, Rapp, J, Güngör, C, Bockhorn, M, Hackert, T, Hank, T, Strobel, O, Werner, J, Izbicki, JR, Johnsen, SA, Gaedcke, J, Brockmöller, J & Ghadimi, BM 2016, 'Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer', JNCI-J NATL CANCER I, vol. 108, no. 5, pp. djv387. https://doi.org/10.1093/jnci/djv387

APA

Schirmer, M. A., Lüske, C. M., Roppel, S., Schaudinn, A., Zimmer, C., Pflüger, R., Haubrock, M., Rapp, J., Güngör, C., Bockhorn, M., Hackert, T., Hank, T., Strobel, O., Werner, J., Izbicki, J. R., Johnsen, S. A., Gaedcke, J., Brockmöller, J., & Ghadimi, B. M. (2016). Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer. JNCI-J NATL CANCER I, 108(5), djv387. https://doi.org/10.1093/jnci/djv387

Vancouver

Schirmer MA, Lüske CM, Roppel S, Schaudinn A, Zimmer C, Pflüger R et al. Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer. JNCI-J NATL CANCER I. 2016 May;108(5):djv387. https://doi.org/10.1093/jnci/djv387

Bibtex

@article{f7967907e91d42f89e3f7978b70ad0c1,
title = "Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer",
abstract = "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.",
keywords = "Adenocarcinoma, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Carcinoma, Pancreatic Ductal, Deoxycytidine, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Resistance, Neoplasm, Electrophoretic Mobility Shift Assay, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Germ-Line Mutation, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Oxidoreductases, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, Predictive Value of Tests, Prognosis, Sp Transcription Factors, Treatment Outcome, Tumor Suppressor Proteins, Journal Article, Research Support, Non-U.S. Gov't",
author = "Schirmer, {Markus A} and L{\"u}ske, {Claudia M} and Sebastian Roppel and Alexander Schaudinn and Christian Zimmer and Ruben Pfl{\"u}ger and Martin Haubrock and Jacobe Rapp and Cenap G{\"u}ng{\"o}r and Maximilian Bockhorn and Thilo Hackert and Thomas Hank and Oliver Strobel and Jens Werner and Izbicki, {Jakob R} and Johnsen, {Steven A} and Jochen Gaedcke and J{\"u}rgen Brockm{\"o}ller and Ghadimi, {B Michael}",
note = "{\textcopyright} The Author 2016. Published by Oxford University Press.",
year = "2016",
month = may,
doi = "10.1093/jnci/djv387",
language = "English",
volume = "108",
pages = "djv387",
journal = "JNCI-J NATL CANCER I",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "5",

}

RIS

TY - JOUR

T1 - Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer

AU - Schirmer, Markus A

AU - Lüske, Claudia M

AU - Roppel, Sebastian

AU - Schaudinn, Alexander

AU - Zimmer, Christian

AU - Pflüger, Ruben

AU - Haubrock, Martin

AU - Rapp, Jacobe

AU - Güngör, Cenap

AU - Bockhorn, Maximilian

AU - Hackert, Thilo

AU - Hank, Thomas

AU - Strobel, Oliver

AU - Werner, Jens

AU - Izbicki, Jakob R

AU - Johnsen, Steven A

AU - Gaedcke, Jochen

AU - Brockmöller, Jürgen

AU - Ghadimi, B Michael

N1 - © The Author 2016. Published by Oxford University Press.

PY - 2016/5

Y1 - 2016/5

N2 - 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.

AB - 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.

KW - Adenocarcinoma

KW - Adult

KW - Aged

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Biomarkers, Tumor

KW - Carcinoma, Pancreatic Ductal

KW - Deoxycytidine

KW - Dose-Response Relationship, Drug

KW - Drug Administration Schedule

KW - Drug Resistance, Neoplasm

KW - Electrophoretic Mobility Shift Assay

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Gene Knockdown Techniques

KW - Germ-Line Mutation

KW - Humans

KW - Kaplan-Meier Estimate

KW - Male

KW - Middle Aged

KW - Oxidoreductases

KW - Pancreatic Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Predictive Value of Tests

KW - Prognosis

KW - Sp Transcription Factors

KW - Treatment Outcome

KW - Tumor Suppressor Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/jnci/djv387

DO - 10.1093/jnci/djv387

M3 - SCORING: Journal article

C2 - 26857392

VL - 108

SP - djv387

JO - JNCI-J NATL CANCER I

JF - JNCI-J NATL CANCER I

SN - 0027-8874

IS - 5

ER -