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.

• Authors: Markus A Schirmer, Claudia M Lüske, Sebastian Roppel, Alexander Schaudinn, Christian Zimmer, Ruben Pflüger, Martin Haubrock, Jacobe Rapp, Cenap Güngör, Maximilian Bockhorn, Thilo Hackert, Thomas Hank, Oliver Strobel, Jens Werner, Jakob R Izbicki, Steven A Johnsen, Jochen Gaedcke, Jürgen Brockmöller, B Michael Ghadimi
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 108 Issue 5 (May 2016) ISSN: 1460-2105 [Electronic] United States
• PMID: 26857392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2016. Published by Oxford University Press.

Chemical References

• Biomarkers, Tumor
• Sp Transcription Factors
• Tumor Suppressor Proteins
• Deoxycytidine
• Oxidoreductases
• WW Domain-Containing Oxidoreductase
• WWOX protein, human
• Gemcitabine

Topics

• Adenocarcinoma (drug therapy, genetics, mortality)
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, mortality)
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacology)
• 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 (genetics)
• Pancreatic Neoplasms (drug therapy, genetics, mortality)
• Polymorphism, Single Nucleotide
• Predictive Value of Tests
• Prognosis
• Sp Transcription Factors (genetics)
• Treatment Outcome
• Tumor Suppressor Proteins (genetics)
• WW Domain-Containing Oxidoreductase
• Gemcitabine