title: An eQTL-based method identifies CTTN and ZMAT3 as pemetrexed susceptibility markers.
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.
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Wen
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Wasim K
authors.initials: WK
authors.lastname: Bleibel
authors.forename: Claudia
authors.initials: C
authors.lastname: Wing
authors.forename: Shuangli
authors.initials: S
authors.lastname: Mi
authors.forename: Bridget E
authors.initials: BE
authors.lastname: McIlwee
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.forename: Shiwei
authors.initials: S
authors.lastname: Duan
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Im
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D051356:Cortactin / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D055106:Genome-Wide Association Study; D005971:Glutamates / Q000633:toxicity*; D006147:Guanine / Q000031:analogs & derivatives* / Q000633:toxicity; D006801:Humans; D016014:Linear Models; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000068437:Pemetrexed; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D016601:RNA-Binding Proteins
chemical_list: D000970:Antineoplastic Agents; C495868:CTTN protein, human; D002352:Carrier Proteins; D051356:Cortactin; D005971:Glutamates; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C436503:ZMAT3 protein, human; D000068437:Pemetrexed; D006147:Guanine