2015 American Society of Clinical Oncology Annual Meeting:

Protein Expression by Genetic Mutations Identified in Gene Panels (Hotspots) and the Efficacy of Targeted Treatments

Protein expression by genetic mutations identified in gene panels (hotspots) and the efficacy of targeted therapies was the subject of a presentation given by Stephen Charles Benz, PhD, Cofounder, Five3 Genomics (Santa Cruz, CA). Dr. Benz spoke at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO).

Treatment Decisions Supported by Next-Generation Sequencing Are Limited
Treatment decisions support by next-generation sequencing of gene panels is limited to the analysis of somatic (tumor) data from DNA sequencing and does not take the expression of mutated genes into consideration.

Integrated Analysis of DNA and RNA Established the Therapeutic Relevance of Mutated Genes

  • A supercomputer-driven, cloud-based integrated analysis of genomic (DNA) and transcriptomic (RNA) sequenced data to directly identify driver variants between somatic and germline (normal) DNA
  • Determine the expression of identified mutations in a cohort of 3784 patients
  • Establish the therapeutic relevance of the mutated genes while overcoming limitations of the panels

Eight Oncogene Mutations Were Screened in More Than 3500 Patients
This large-scale 3784 patient genomic (DNA and RNA sequencing) data set from 19 anatomical tumor types was processed to (1) detect DNA variants (germline vs somatic) and RNA expression, and (2) to establish not only the existence but also the expression level of hotspot mutations in oncogenes PIK3CA, KRAS, NRAS, AKT1, BRAF, IDH1, CTNNB1, and IDH2.

Protein Expression of Mutated Genes Was Low
Of the 3784 patients in the analysis, 720 were found to have mutations in the above oncogenes. Only 38 (5.3%) of the patients had >90% expression by RNA sequencing. Thirty-six patients (5.0%) with identified hotspot mutations had no or low (<10%) expression.

For example, mutations at position E545 in the PI3K protein encoded by the PIK3CA gene, which has been targeted by both pan-PI3K and mutant-targeted drugs in clinical trials, showed low or no expression in 12% (5/41) of breast cancer patients. Not a single patient showed relatively maximal (> 90%) expression.

Similarly, of 204 thyroid cancer patients with a BRAF V600 hotspot mutation, 7.5% (15/204) had low or no expression, and none had relatively maximal expression.

Conclusion
These findings illustrate that genetic mutations in gene panels (hotspots) do not always result in protein expression. Given that many gene mutations were not expressed, an informed, molecularly driven clinical treatment decision requires insight into downstream protein expression rather than DNA alterations alone.

June 30, 2015

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