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

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.

[1]  C. Chien,et al.  The p53 target Wig-1: a regulator of mRNA stability and stem cell fate? , 2011, Cell Death and Differentiation.

[2]  Jun Liu,et al.  microRNA-182 inhibits the proliferation and invasion of human lung adenocarcinoma cells through its effect on human cortical actin-associated protein. , 2011, International journal of molecular medicine.

[3]  L. Kowalski,et al.  Cortactin is associated with perineural invasion in the deep invasive front area of laryngeal carcinomas. , 2011, Human pathology.

[4]  Brooke L. Fridley,et al.  Platinum Sensitivity–Related Germline Polymorphism Discovered via a Cell-Based Approach and Analysis of Its Association with Outcome in Ovarian Cancer Patients , 2011, Clinical Cancer Research.

[5]  E. Gamazon,et al.  Germline polymorphisms discovered via a cell-based, genome-wide approach predict platinum response in head and neck cancers. , 2011, Translational research : the journal of laboratory and clinical medicine.

[6]  Yoav Gilad,et al.  The effects of EBV transformation on gene expression levels and methylation profiles. , 2011, Human molecular genetics.

[7]  Y. Eishi,et al.  Localization of the Invadopodia-Related Proteins Actinin-1 and Cortactin to Matrix-Contact-Side Cytoplasm of Cancer Cells in Surgically Resected Lung Adenocarcinomas , 2011, Pathobiology.

[8]  Nancy J. Cox,et al.  A Study of CNVs As Trait-Associated Polymorphisms and As Expression Quantitative Trait Loci , 2011, PLoS genetics.

[9]  Yusuke Nakamura,et al.  Genome-wide associations and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  Ming-cong Mo,et al.  VEGF and cortactin expression are independent predictors of tumor recurrence following curative resection of gastric cancer , 2010, Journal of surgical oncology.

[11]  R. Zhao,et al.  Expression of Cortactin Correlates with a Poor Prognosis in Patients with Stages II–III Colorectal Adenocarcinoma , 2010, Journal of Gastrointestinal Surgery.

[12]  M. Eileen Dolan,et al.  Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci , 2010, Proceedings of the National Academy of Sciences.

[13]  Wei Zhang,et al.  PACdb: a database for cell-based pharmacogenomics. , 2010, Pharmacogenetics and genomics.

[14]  N. Cox,et al.  Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS , 2010, PLoS genetics.

[15]  Jorge S. Reis-Filho,et al.  Cortactin gene amplification and expression in breast cancer: a chromogenic in situ hybridisation and immunohistochemical study , 2010, Breast Cancer Research and Treatment.

[16]  G. Ceresoli,et al.  Second-line treatment for malignant pleural mesothelioma. , 2010, Cancer treatment reviews.

[17]  Wei Zhang,et al.  SCAN: SNP and copy number annotation , 2010, Bioinform..

[18]  Marisa Wong Medina,et al.  Pharmacogenomic Discovery Using Cell-Based Models , 2009, Pharmacological Reviews.

[19]  A. Rossi,et al.  Pemetrexed in the treatment of advanced non-squamous lung cancer. , 2009, Lung cancer.

[20]  D. Grandér,et al.  The p53 target Wig-1 regulates p53 mRNA stability through an AU-rich element , 2009, Proceedings of the National Academy of Sciences.

[21]  S. Mi,et al.  Population-specific genetic variants important in susceptibility to cytarabine arabinoside cytotoxicity. , 2009, Blood.

[22]  A. Arrondo-Velasco,et al.  [Acute myocardial infarction and pemetrexed]. , 2009, Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria.

[23]  M. Pío-Asín,et al.  Infarto agudo de miocardio y pemetrexed , 2009 .

[24]  Alissa M. Weaver.  Cortactin in tumor invasiveness. , 2008, Cancer letters.

[25]  C. Palmberg,et al.  The p53 target protein Wig‐1 binds hnRNP A2/B1 and RNA Helicase A via RNA , 2008, FEBS letters.

[26]  Soma Das,et al.  Genetic variants contributing to daunorubicin-induced cytotoxicity. , 2008, Cancer research.

[27]  Tyson A. Clark,et al.  Evaluation of genetic variation contributing to differences in gene expression between populations. , 2008, American journal of human genetics.

[28]  E. Schuuring,et al.  Cortactin expression predicts poor survival in laryngeal carcinoma , 2008, British Journal of Cancer.

[29]  N. Guevara,et al.  Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status , 2008, British Journal of Cancer.

[30]  S. Clarke,et al.  Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules , 2007, British Journal of Cancer.

[31]  P. Timpson,et al.  Aberrant expression of cortactin in head and neck squamous cell carcinoma cells is associated with enhanced cell proliferation and resistance to the epidermal growth factor receptor inhibitor gefitinib. , 2007, Cancer research.

[32]  Shiwei Duan,et al.  Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. , 2007, American journal of human genetics.

[33]  M. Eileen Dolan,et al.  A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity , 2007, Proceedings of the National Academy of Sciences.

[34]  J. Downward,et al.  Roles of cortactin in tumor pathogenesis. , 2007, Biochimica et biophysica acta.

[35]  H. Pospisil,et al.  In vitro chemosensitivity of freshly explanted tumor cells to pemetrexed is correlated with target gene expression , 2007, Investigational New Drugs.

[36]  D. Goldman,et al.  Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications , 2007, Molecular Cancer Therapeutics.

[37]  J. Bertino,et al.  Role of Pemetrexed in Non-Small Cell Lung Cancer , 2007, Cancer investigation.

[38]  Sunita J Shukla,et al.  Effect of population and gender on chemotherapeutic agent–induced cytotoxicity , 2006, Molecular Cancer Therapeutics.

[39]  K. Wiman,et al.  The p53‐induced Wig‐1 protein binds double‐stranded RNAs with structural characteristics of siRNAs and miRNAs , 2006, FEBS letters.

[40]  Laura J. Scott,et al.  SNP Function Portal: a web database for exploring the function implication of SNP alleles , 2006, ISMB.

[41]  S. Grossman,et al.  Alteration of Pemetrexed Excretion in the Presence of Acute Renal Failure and Effusions: Presentation of a Case and Review of the Literature , 2006, Cancer investigation.

[42]  P. Timpson,et al.  Cortactin overexpression inhibits ligand-induced down-regulation of the epidermal growth factor receptor. , 2005, Cancer research.

[43]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[44]  G. Corthals,et al.  A Cortactin-CD2-associated Protein (CD2AP) Complex Provides a Novel Link between Epidermal Growth Factor Receptor Endocytosis and the Actin Cytoskeleton* , 2003, Journal of Biological Chemistry.

[45]  Robert L. Sutherland,et al.  Cyclin D1, EMS1 and 11q13 Amplification in Breast Cancer , 2003, Breast Cancer Research and Treatment.

[46]  S. Baker,et al.  Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. , 2002, Molecular cancer therapeutics.

[47]  U. Gatzemeier,et al.  Phase I trials of pemetrexed. , 2002, Seminars in oncology.

[48]  C. Méndez-Vidal,et al.  Human wig-1, a p53 target gene that encodes a growth inhibitory zinc finger protein , 2001, Oncogene.

[49]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[50]  W. Hunter,et al.  Paclitaxel selectively induces mitotic arrest and apoptosis in proliferating bovine synoviocytes. , 1997, Arthritis and rheumatism.

[51]  E. Schuuring.  The involvement of the chromosome 11q13 region in human malignancies: cyclin D1 and EMS1 are two new candidate oncogenes--a review. , 1995, Gene.

[52]  M. Relling,et al.  A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity , 2011, Leukemia.

[53]  J. Nally,et al.  Pemetrexed-induced acute renal failure, nephrogenic diabetes insipidus, and renal tubular acidosis in a patient with non-small cell lung cancer , 2006, Medical oncology.

[54]  G. Abecasis,et al.  A general test of association for quantitative traits in nuclear families. , 2000, American journal of human genetics.