Genome-wide association study of chemotherapeutic agents-induced severe neutropenia/leucopenia for patients in Biobank Japan

Abstract

Summary

Chemotherapeutic agents are notoriously known to have narrow therapeutic range that often resulted in life-threatening toxicity. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy through a pharmacogenomics approach. In this study, we performed multiple genome-wide association studies (GWASs) of 13,122 cancer patients who received different chemotherapy regimen, including cyclophosphamide-based, platinum-based (cisplatin and carboplatin), anthracycline-based (doxorubicin and epirubicin), antimetabolite-based (5-fluorouracil and gemcitabine), antimicrotubule-agent (paclitaxel and docetaxel), and topoisomerase inhibitor (campthothecin and etoposide) as well as the combination therapy of paclitaxel and carboplatin, to identify genetic variants that are associated with the risk of severe neutropenia/leucopenia in the Japanese population. In addition, we have also carried out a weighted genetic risk scoring (wGRS) system to evaluate the cumulative effects of the suggestive genetic variants identified from GWAS in order to seek a possibility to predict the risk levels of individuals who carry multiple risk alleles. Although we failed to identify genetic variants that surpassed the genome-wide significance level (P<5.0x10^-8) through GWASs probably due to insufficient statistical power and complex clinical features, we were able to shortlist some of the suggestive associated loci. The current study is at the relatively preliminary state, but could highlight the complexity and problematic issues in retrospective pharmacogenomics studies. However, we hope that verification of these genetic variants through local and international collaborations could improve the clinical outcome of cancer patients."