An EQTL-based Method Identifies CTTN and ZMAT3 As Pemetrexed Susceptibility Markers

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2011 Dec 16

PMID 22171072

Citations 11

Authors

Yujia Wen

Eric R Gamazon

Wasim K Bleibel

Claudia Wing

Shuangli Mi

Bridget E McIlwee

Shannon M Delaney

Shiwei Duan

Hae Kyung Im

M Eileen Dolan

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Upregulation of ZMAT3 is Associated with the Poor Prognosis of Breast Cancer.

Wu M, Wu S, Guo R Int J Gen Med. 2024; 17:4003-4014.

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Cortactin in Lung Cell Function and Disease.

Bandela M, Belvitch P, Garcia J, Dudek S Int J Mol Sci. 2022; 23(9).

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Mechanisms of resistance to pemetrexed in non-small cell lung cancer.

Liang J, Lu T, Chen Z, Zhan C, Wang Q Transl Lung Cancer Res. 2020; 8(6):1107-1118.

PMID: 32010588 PMC: 6976363. DOI: 10.21037/tlcr.2019.10.14.

Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma.

Gamazon E, Trendowski M, Wen Y, Wing C, Delaney S, Huh W Sci Rep. 2018; 8(1):733.

PMID: 29335598 PMC: 5768793. DOI: 10.1038/s41598-017-19004-3.

Utility of Lymphoblastoid Cell Lines for Induced Pluripotent Stem Cell Generation.

Kumar S, Curran J, Glahn D, Blangero J Stem Cells Int. 2016; 2016:2349261.

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