Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice

Abstract

Somatic mutation analysis of human cancers has become the standard of practice. Whether screening for single gene variants or sequencing hundreds of cancer-related genes, this genomic information is the basis for precision medicine initiatives in oncology. Genomic profiling results in information that allows oncologists to make a more educated selection of appropriate therapeutic strategies that more often combine traditional cytotoxic chemotherapy and radiation with novel targeted therapies. Here we discuss the nuances of implementing somatic mutation testing in a clinical setting. Keywordsclinical genomics, oncology, precision medicine, pharmacogenomics, somatic mutation Novel therapies, including the use of directed monoclonal antibodies, tyrosine kinase inhibitors, and immunotherapies, have come to fruition as our understanding of the etiology of human cancer expands. From the identification of the first oncogenes and tumor-suppressor genes to current full gene sequencing for the identification of somatic mutations, knowledge of tumor-cell genetic variant profiles has become critical to the management of the cancer patient.1-3 One projection of the Human Genome Project was to gain a more fundamental understanding of human disease at the genomic level such that novel therapeutics could be designed to provide a more personalized approach to disease management. The identification of numerous driver mutations in various human cancers, which are causally implicated in establishing growth advantages to a cell, have also become the target of novel therapies that confer more efficacious outcomes. 4,5 The rapid development of targeted therapies is also resulting in more advanced and focused clinical trial designs whereby testing protocols aim to match patients whose tumors harbor specific somatic mutations with those specific therapies targeting the gene or pathway affected. 6,7 Precision Medicine in OncologyWith respect to the cancer patient, the concept of targeted or individualized therapy can include 2 aspects of what is often termed pharmacogenomics. The first is the more traditional concept that encompasses how an individual may metabolize, absorb, transport, and excrete therapeutic drugs differently based on polymorphisms in the genes that code for these functions. This type of individual variation in metabolism was first described in 510 BC when Pythagoras recognized hemolytic anemia developing in some individuals who consumed fava beans.8 This phenotype was later attributed to a glucose-6-phosphate dehydrogenase deficiency. 9 We have termed pharmacogenomic concepts linked to drug metabolism PGX m , which corresponds to genetic variants that determine drug disposition, also referred to as drug pharmacokinetics.10,11 The conversion of a parent compound to an inactive metabolite or to one that is more easily excreted and the conversion of a prodrug to its active metabolite are examples of PGX m .PGX t is the second aspect of pharmacogenomics that involves the selection of a therapeutic drug based on the...

Standing in the Shifting Sands of Molecular Targeting and Precision Medicine Is the Oasis of 21st‐Century Oncology Therapeutics

“…In oncology, this is heavily reliant on the determination of the presence of targetable mutations in the somatic neoplastic tissue. Tsongalis and Coleman provide guidance through some of the successes and challenges of assays testing for such mutations/variations in tumor cell DNA. In the era of targeted therapies, within oncology and beyond, pharmacogenomics plays an increasingly important role in optimizing therapies with the use of biomarkers.…”