The Australian Translational Genomics Centre (ATGC) was established as a collaboration between the healthcare sector (Metro South Hospital and Health Service), higher education sector (Queensland University of Technology) to provide genomic profiling of cancer patients at the Princess Alexandra Hospital. The program was developed to integrate the ordering, processing and interpretation of large-scale next-generation sequencing (NGS) sequencing into clinical practice. Since establishment of the service in 2017, more than 1300 cancer patients have had matched tumour-normal samples analysed by whole-exome and gene panel spike-in sequencing. Furthermore, in June 2021, ATGC started performing RNA tumour sequencing, allowing concurrent assessment of tumour DNA and RNA and additionally collaborated with an external pathology provider to test targeted methylation sequencing.
The development of RNA and methylation tests to complement DNA profiling is a response to the growing number of clinical trials using biomarkers that cannot be attributed to a single DNA mutation: For example, the MoST clinical trial arm for TRK inhibitors in NTRK1/2/3 hi-expressing tumours and AstraZeneca clinical trials of PARPi inhibitors for tumours where any disruption of the homologous recombination repair (HRR) pathway are considered.
We demonstrate the use of an RNA expression-based tests that have identified patients with high NTRK gene expression, without corresponding NTRK fusion or copy number amplification and provide similar examples for other genes of clinical utility (RET, ROS etc).
We also demonstrate the utility of genomic mutational signatures, including examples that inform diagnosis, and confirm HRR status. We describe a subset of lung and prostate cancers, negative for DNA mutations or methylation defects in known HRD genes that may benefit from PARP inhibitors.
We demonstrate with these examples the current clinical utility the importance of multi-omics in clinical care and clinical trials and will describe our future plans in this space.