Pharmacogenomic Characterization of US FDA-approved Cytotoxic Drugs

Overview

Journal Pharmacogenomics

Specialties Genetics
Pharmacology

Date 2011 Oct 20

PMID 22008047

Citations 34

Authors

Eric J Peters

Alison Motsinger-Reif

Tammy M Havener

Lorraine Everitt

Nicholas E Hardison

Venita G Watson

Michael Wagner

Kristy L Richards

Mike A Province

Howard L McLeod

Affiliations

Soon will be listed here.

Abstract

Aims: Individualization of cancer chemotherapy based on the patient's genetic makeup holds promise for reducing side effects and improving efficacy. However, the relative contribution of genetics to drug response is unknown.

Materials & Methods: In this study, we investigated the cytotoxic effect of 29 commonly prescribed chemotherapeutic agents from diverse drug classes on 125 lymphoblastoid cell lines derived from 14 extended families.

Results: The results of this systematic study highlight the variable role that genetics plays in response to cytotoxic drugs, ranging from a heritability of <0.15 for gemcitabine to >0.60 for epirubicin.

Conclusion: Putative quantitative trait loci for cytotoxic response were identified, as well as drug class-specific signatures, which could indicate possible shared genetic mechanisms. In addition to the identification of putative quantitative trait locis, the results of this study inform the prioritization of chemotherapeutic drugs with a sizable genetic response component for future investigation.

Citing Articles

Pharmacogenomic Analyses Implicate B Cell Developmental Status and as Determinants of Sensitivity toward Anti-CD20 Monoclonal Antibody Therapy.

Small G, Akhtari F, Green A, Havener T, Sikes M, Quintanhila J Cells. 2023; 12(12).

PMID: 37371044 PMC: 10297299. DOI: 10.3390/cells12121574.

Cardiovascular Health Status And Genetic Risk In Survivors of Childhood Neuroblastoma and Nephroblastoma Treated With Doxorubicin: Protocol of the Pharmacogenetic Part of the LESS-Anthra Cross-Sectional Cohort Study.

Zolk O, von dem Knesebeck A, Graf N, Simon T, Hero B, Abdul-Khaliq H JMIR Res Protoc. 2022; 11(2):e27898.

PMID: 35175211 PMC: 8895281. DOI: 10.2196/27898.

High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs.

Akhtari F, Green A, Small G, Havener T, House J, Roell K PLoS Genet. 2021; 17(8):e1009732.

PMID: 34437536 PMC: 8439493. DOI: 10.1371/journal.pgen.1009732.

The Road so Far in Colorectal Cancer Pharmacogenomics: Are We Closer to Individualised Treatment?.

Simoes A, Fernandez-Rozadilla C, Maronas O, Carracedo A J Pers Med. 2020; 10(4).

PMID: 33228198 PMC: 7711884. DOI: 10.3390/jpm10040237.

Synergistic Chemotherapy Drug Response Is a Genetic Trait in Lymphoblastoid Cell Lines.

Roell K, Havener T, Reif D, Jack J, McLeod H, Wiltshire T Front Genet. 2019; 10:829.

PMID: 31681399 PMC: 6804467. DOI: 10.3389/fgene.2019.00829.

References

Smirnov D, Morley M, Shin E, Spielman R, Cheung V . Genetic analysis of radiation-induced changes in human gene expression. Nature. 2009; 459(7246):587-91. PMC: 3005325. DOI: 10.1038/nature07940. View

Duan S, Bleibel W, Huang R, Shukla S, Wu X, Badner J . Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res. 2007; 67(11):5425-33. PMC: 2735868. DOI: 10.1158/0008-5472.CAN-06-4431. View

Cohen D, Chumakov I, Weissenbach J . A first-generation physical map of the human genome. Nature. 1993; 366(6456):698-701. DOI: 10.1038/366698a0. View

Abecasis G, Cherny S, Cookson W, Cardon L . Merlin--rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2001; 30(1):97-101. DOI: 10.1038/ng786. View

Huang R, Duan S, Bleibel W, Kistner E, Zhang W, Clark T . A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity. Proc Natl Acad Sci U S A. 2007; 104(23):9758-63. PMC: 1887589. DOI: 10.1073/pnas.0703736104. View

Ratain M, Miller A, McLeod H, Venook A, Egorin M, Schilsky R . The cancer and leukemia group B pharmacology and experimental therapeutics committee: a historical perspective. Clin Cancer Res. 2006; 12(11 Pt 2):3612s-6s. DOI: 10.1158/1078-0432.CCR-06-9008. View

Watters J, Kraja A, Meucci M, Province M, McLeod H . Genome-wide discovery of loci influencing chemotherapy cytotoxicity. Proc Natl Acad Sci U S A. 2004; 101(32):11809-14. PMC: 511056. DOI: 10.1073/pnas.0404580101. View

Cheung V, Conlin L, Weber T, Arcaro M, Jen K, Morley M . Natural variation in human gene expression assessed in lymphoblastoid cells. Nat Genet. 2003; 33(3):422-5. DOI: 10.1038/ng1094. View

Huang R, Duan S, Shukla S, Kistner E, Clark T, Chen T . Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. Am J Hum Genet. 2007; 81(3):427-37. PMC: 1950832. DOI: 10.1086/519850. View

10.

Auman J, McLeod H . Cancer pharmacogenomics: DNA genotyping and gene expression profiling to identify molecular determinants of chemosensitivity. Drug Metab Rev. 2008; 40(2):303-15. DOI: 10.1080/03602530801952427. View

11.

Broman K, Murray J, Sheffield V, White R, Weber J . Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998; 63(3):861-9. PMC: 1377399. DOI: 10.1086/302011. View

12.

Choy E, Yelensky R, Bonakdar S, Plenge R, Saxena R, De Jager P . Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet. 2008; 4(11):e1000287. PMC: 2583954. DOI: 10.1371/journal.pgen.1000287. View

13.

Manolio T, Brooks L, Collins F . A HapMap harvest of insights into the genetics of common disease. J Clin Invest. 2008; 118(5):1590-605. PMC: 2336881. DOI: 10.1172/JCI34772. View