Background—DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients.

Methods—Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan–Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage.

Results—Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared with those carrying AA alleles, with a HR of 1.36 [95% confidence interval (CI): 1.08–1.72, P = 0.01), but no association with survival was observed for patients carrying the AG genotype (HR = 1.04, 95% CI, 0.84–1.29, P = 0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR = 0.79; 95% CI, 0.61–1.02, P = 0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190.

Conclusions—We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors.

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Published in Clinical Cancer Research, v. 23, issue 24, p. 7550-7557.

© 2017 American Association for Cancer Research

The copyright holder has granted the permission for posting the article here.

The document available for download is the authors' post-peer-review final draft of the article.

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ILCCO Data Repository was supported by Cancer Care Ontario Research Chair of Population Health, NIH (U19 CA148127), and Lunenfeld-Tanenbuaum Research Institute and Sinai Health System. The Cancer de Pulmon en Asturias (CAPUA) study (PI: Adonina Tardón) was supported by Fondo de Investigación Aanitaria, Instituto de Salud Carlos III, Consorcio de Investigación Biomédica en Red (CIBER) del Área de Epidemiología y Salud Pública, and University of Oviedo.

Due to the large number of funding sources, only the first few are listed in this section. For the complete list of funding sources, please download this article.

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