Cancer pharmacogenomics

Abstract

Pharmacogenomics research is yielding molecular diagnostic tools that can be used to optimize the selection of medications and their doses for individual patients. Given the narrow therapeutic index of most anticancer agents and the serious consequences of undertreatment, cancer chemotherapy is a compelling therapeutic area for translation of pharmacogenomics to the clinic. This review addresses how inherited (germline) and acquired (somatic) sources of genome variability can alter the toxicity or efficacy of cancer chemotherapy.

Figure 1

In cancer pharmacogenomics, there are at least two genomes of importance: the patient’s germline genome (inherited genome variation) and the tumor genome (inherited genome variation plus acquired genome variation). Moreover, there may be additional acquired genome variations in metastatic or recurrent tumor cells that influence drug response and treatment outcome. A comprehensive pharmacogenomic strategy interrogates multiple mechanisms of genome variation in both germline and tumor genetic material (blue box), assessing their influence on multiple drug-response phenotypes (green box). GWAS, genome-wide association studies.

Figure 2

For drug-response phenotypes, it is not uncommon for an inherited variation in one gene to have a dominant effect on drug disposition or response phenotype (left panel). However, once the treatment is adjusted for the predominant inherited determinant of drug disposition or response (right panel), additional, less penetrant genetic polymorphisms may emerge as being significant (a recent example involves the use of mercaptopurine and polymorphisms of TPMT (thiopurine-S-methyltransferase) and ITPA (inosine triphosphate pyrophosphatase).