Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: The role of the host Journal Article


Authors: Gallagher, D. J.; Vijai, J.; Hamilton, R. J.; Ostrovnaya, I.; Iyer, G.; Garcia-Grossman, I. R.; Kim, P. H.; Przybylo, J. A.; Alanee, S.; Riches, J. C.; Regazzi, A. M.; Milowsky, M. I.; Offit, K.; Bajorin, D. F.
Article Title: Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: The role of the host
Abstract: Background: Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. Patients and methods: DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. Results: Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10-7). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). Conclusions: Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Keywords: adult; controlled study; treatment response; aged; human cell; major clinical study; single nucleotide polymorphism; genetics; cisplatin; area under the curve; cancer adjuvant therapy; cancer patient; prospective study; biomarkers; allele; germline; carboplatin; genetic association; genetic variability; cancer cell culture; chemosensitivity; heterozygote; dna; scoring system; homozygote; ic 50; transitional cell carcinoma; receiver operating characteristic; urothelial; genotyping technique
Journal Title: Annals of Oncology
Volume: 24
Issue: 9
ISSN: 0923-7534
Publisher: Oxford University Press  
Date Published: 2013-09-01
Start Page: 2414
End Page: 2421
Language: English
DOI: 10.1093/annonc/mdt225
PROVIDER: scopus
PUBMED: 23897706
DOI/URL:
Notes: --- - "Export Date: 1 October 2013" - "Art. No.: mdt225" - "CODEN: ANONE" - "Source: Scopus"
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MSK Authors
  1. Dean Bajorin
    413 Bajorin
  2. Kenneth Offit
    511 Offit
  3. Gopakumar Vasudeva Iyer
    126 Iyer
  4. Ashley Regazzi
    35 Regazzi
  5. Jamie C Riches
    19 Riches