Precision oncology in the age of integrative genomics

Abstract

Precision oncology applies genomic and other molecular analyses of tumor biopsies to improve the diagnosis and treatment of cancers. In addition to identifying therapeutic options, precision oncology tracks the response of a tumor to an intervention at the molecular level and detects drug resistance and the mechanisms by which it occurs. Integrative genomics can include sequencing specific panels of genes, exomes, or the entire triad of the patient's germline, tumor exome, and tumor transcriptome. Although the capabilities of sequencing technologies continue to improve, widespread adoption of genomics-driven precision oncology in the clinic has been held back by logistical, regulatory, financial, and ethical considerations. Nevertheless, integrative clinical sequencing programs applied at the point of care have the potential to improve the clinical management of cancer patients.

Figure 1.. The progression of analytical tools in oncology.

The historical timeline highlights key developments in the assessment of cancer cells/tumor tissue, starting from the microscopic description of leukemia cells by Rudolf Virchow, up to the futuristic Cancer Breakthroughs 2020 project. It may be noted that the modern tool-kit for cancer analyses includes a range of old and new tools, and the high-throughput sequencing approaches add a highly informative component, complementary to other methods that include imaging, histopathology, and biochemical analyses.

Figure 2.. Integrative sequencing analysis to define the spectrum of cancer aberrations.

A. Bioinformatic workflow and classes of cancer aberrations identified. The primary sequencing data is subjected to different quality control metrics and aligned to the reference genome to define the indicated genomic and transcriptomic aberrations. B. Prediction of neo-antigens for immunotherapy. The flow chart indicates primary steps involved in in silico prediction of immunogenic cancer specific neo-antigens in tumor samples, for potential use in developing personalized peptide vaccines.

Figure 3.. Workflow of integrative clinical sequencing for precision oncology.

The patient, in consultation with the cancer physician, enters the clinical sequencing program upon signing the informed consent. Along with documentation of detailed clinical history, a genetic counselor obtains family history of the patient to assess likely hereditary predisposition to cancer. Patient’s tumor biopsy is flash frozen in OCT blocks, and, along with blood or buccal swab, the samples are sent to the CLIA-certified sequencing laboratory. Histology sections of the tumor biopsy blocks are evaluated by a clinical pathologist for diagnosis and tumor content. DNA and RNA from tissue blocks with the highest tumor content and DNA from blood/buccal samples are used to generate sequencing libraries. Exome capture libraries from germline and tumor samples and the transcriptome library from tumor RNA are analyzed for germline and somatic aberrations. Potentially actionable molecular observations are identified and discussed at the multidisciplinary precision medicine tumor board (see also BOX 1), and a summary report of clinical recommendations is provided to the attending physician.