An eQTL-based method identifies CTTN and ZMAT3 as pemetrexed susceptibility markers.

Wen Y, Gamazon ER, Bleibel WK, Wing C, Mi S, McIlwee BE, Delaney SM, Duan S, Im HK, Dolan ME
Hum Mol Genet. 2012 21 (7): 1470-80

PMID: 22171072 · PMCID: PMC3298275 · DOI:10.1093/hmg/ddr583

Pemetrexed, approved for the treatment of non-small cell lung cancer and malignant mesothelioma, has adverse effects including neutropenia, leucopenia, thrombocytopenia, anemia, fatigue and nausea. The results we report here represent the first genome-wide study aimed at identifying genetic predictors of pemetrexed response. We utilized expression quantitative trait loci (eQTLs) mapping combined with drug-induced cytotoxicity data to gain mechanistic insights into the observed genetic associations with pemetrexed susceptibility. We found that CTTN and ZMAT3 expression signature explained >30% of the pemetrexed susceptibility phenotype variation for pemetrexed in the discovery population. Replication using PCR and a semi-high-throughput, scalable assay system confirmed the initial discovery results in an independent set of samples derived from the same ancestry. Furthermore, functional validation in both germline and tumor cells demonstrates a decrease in cell survival following knockdown of CTTN or ZMAT3. In addition to our particular findings on genetic and gene expression predictors of susceptibility phenotype for pemetrexed, the work presented here will be valuable to the robust discovery and validation of genetic determinants and gene expression signatures of various chemotherapeutic susceptibilities.

MeSH Terms (16)

Antineoplastic Agents Carrier Proteins Cell Line, Tumor Cortactin Gene Expression Genome-Wide Association Study Glutamates Guanine Humans Linear Models Lymphocytes Nuclear Proteins Pemetrexed Polymorphism, Single Nucleotide Quantitative Trait Loci RNA-Binding Proteins

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