Genome-wide association study of myelosuppression in non-small-cell lung cancer patients with platinum-based chemotherapy

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Abstract

Platinum-induced myelosuppression severely impedes successful chemotherapy in non-small-cell lung cancer (NSCLC) patients. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy. We first carried out a genome-wide scan of 906 703 single-nucleotide polymorphisms (SNPs) to identify genetic variants associated with platinum-induced myelosuppression risk in 333 NSCLC patients with chemotherapy. Then, we replicated 24 SNPs that had P<1 × 10−4 in another independent cohort of 876 NSCLC patients. With P<0.05 as the criterion of statistical significance, we found that rs13014982 at 2q24.3 and rs9909179 at 17p12 exhibited consistently significant associations with myelosuppression risk in both the genome-wide association studies (GWAS) scan and the replication stage (rs13014982: odds ratio (OR)=0.55, 95% confidence intervals (CIs): 0.41–0.74, P=7.29 × 10−5 for GWAS scan and OR=0.77, 95% CI: 0.65–0.93, P=0.006 for replication stage; rs9909179: OR=0.51, 95% CI: 0.37–0.70, P=4.60 × 10−5 for GWAS scan and OR=0.82, 95% CI: 0.68–0.99, P=0.040 for replication stage; both in additive model). In combined samples of genome-wide scan and replication samples, the minor alleles of rs13014982 and rs9909179 remained significant associations with the decreased risk of myelosuppression (rs13014982: OR=0.71, 95% CI: 0.61–0.83, P =1.36 × 10−5; rs9909179: OR=0.76, 95% CI: 0.65–0.89, P=0.001). Rs13014982 at 2q24.3 and rs9909179 at 17p12 might be independent susceptibility markers for platinum-induced myelosuppression risk in NSCLC patients.

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Acknowledgements

This work is funded by the National Natural Science Foundation of China (81270044 and 81230067), National Outstanding Youth Science Foundation of China (81225020), Science Foundation for Distinguished Young Scholars of Jiangsu (BK2012042), Key Grant of Natural Science Foundation of Jiangsu Higher Education Institutions (11KJA330001), Natural Science Foundation of Jiangsu Province (BK2012042), New Century Excellent Talents in University (NCET-10-0178), Changjiang Scholars and Innovative Research Team in University (IRT0631), The Young Talents Support Program from the Organization Department of the CPC Central Committee, Jiangsu Province Clinical Science and Technology Projects (BL2012008) and Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

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Correspondence to H Ma or D Lu or H Shen.

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Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

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