Application of next generation sequencing to CEPH cell lines to discover variants associated with FDA approved chemotherapeutics

BMC Research Notes

Alison A Motsinger-Reif¹  Michael J Wagner²  Howard L McLeod³  Pui-Yan Kwok⁵  Tammy Havener²  Ernest J Lam⁵  Gunjan D Hariani⁴ 

[1] Department of Statistics, North Carolina State University, Raleigh, NC, USA;Center for Institute of Pharmacogenomics and Individualized Therapy, UNC Chapel Hill, Chapel Hill, NC, USA;Moffitt Cancer Center, Tampa, FL, USA;Bioinformatics Research Center, North Carolina State University, 307 Ricks Hall, 1 Lampe Dr, Raleigh, NC 27695 CB7566, USA;Cardiovascular Research Institute, UCSF School of Medicine, San Francisco, CA, USA

关键词: Candidate gene;    Pharmacogenomics;    Lymphoblastoid cell lines;    Next generation sequencing;    Cytotoxicity;   

Others  :  1132498
DOI  :  10.1186/1756-0500-7-360

 received in 2013-09-30, accepted in 2014-05-30,  发布年份 2014

【 摘 要 】

Background

The goal of this study was to perform candidate gene association with cytotoxicity of chemotherapeutics in cell line models through resequencing and discovery of rare and low frequency variants along with common variations. Here, an association study of cytotoxicity response to 30 FDA approved drugs was conducted and we applied next generation targeted sequencing technology to discover variants from 103 candidate genes in 95 lymphoblastoid cell lines from 14 CEPH pedigrees. In this article, we called variants across 95 cell lines and performed association analysis for cytotoxic response using the Family Based Association Testing method and software.

Results

We called 2281 variable SNP genotypes across the 103 genes for these cell lines and identified three genes of significant association within this marker set. Specifically, ATP-binding cassette, sub-family C, member 5 (ABCC5), metallothionein 1A (MT1A) and NAD(P)H dehydrogenase quinone1 (NQO1) were significantly associated with oxaliplatin drug response. The significant SNP on NQO1 (rs1800566) has been linked with poor survival rates in patients with non-small cell lung cancer treated with cisplatin (which belongs to the same class of drugs as oxaliplatin). A SNP (rs1846692) near the 5′ region of MT1A was associated with arsenic trioxide.

Conclusions

The results from this study are promising and this serves as a proof-of-principle demonstration of the use of sequencing data in the cytotoxicity models of human cell lines. With increased sample sizes, such studies will be a fast and powerful way to associate common and rare variants with drug response; while overcoming the cost and time limitations to recruit cohorts for association study.

【 授权许可】

   
2014 Hariani et al.; licensee BioMed Central Ltd.

【 图 表 】

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