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A long-running genome project in the United Kingdom is reporting that whole genome sequencing (WGS) performs with high accuracy in detecting a variety of cancer biomarkers in the human genome, compared with standard methods. For cancer research, this study shows the first steps toward populationwide WGS with clinical reporting, Jason Park MD, PhD, DABCC, an associate professor of pathology at UT Southwestern Medical School and the Eugene McDermott Center for Human Growth and Development, told CLN Stat. Park and other experts not involved in this study indicate that certain clinical support systems need to be in place first, before WGS moves on to broader applications in the practice setting.

Researchers presented their findings on WGS at the 2019 European Society for Medical Oncology (ESMO) Congress in Barcelona and published an abstract of the results in the Annals of Oncology.

Created in 2012, the goal of Genomics England’s 100,000 Genomes Project is to leverage personalized medicine strategies to improve cancer care. So far, the project has produced WGS bioinformatics reports for more than 14,000 U.K. cancer patients, providing links to potential therapies and clinical trials. These WGS analyses include somatic small variants, somatic structural and copy number variants (SV/CNV) as well as germline pertinent findings and mutational burden and signatures. “To iteratively develop a high-quality bioinformatics pipeline and to monitor clinical utility of returned results, we are collecting feedback via the 100,000 Genomes Project Interpretation Portal from NHS (National Health System) Molecular Tumour Boards,” according to the researchers.

The team looked at samples from the genome project to compare results between WGS and the following methods:

  • Next-generation sequencing panels (96 patients, 156 clinically relevant single nucleotide variants (SNVs));
  • High-depth exome sequencing (10 patients, 3,150 SNVs, 140 indels);
  • Cytogenetic fluorescence in situ hybridization tests (70 patients, 259 SVs, 100 CNVs); and
  • Immunohistochemistry tests for mismatch repair deficiency (265 patients) and HER2 status (154 patients).

WGS detected with high accuracy cancer biomarkers for rare tumors, sarcomas, and hematological malignancies, Rodrigo Dienstmann, MD, a member of the ESMO Press and Media Affairs Committee and an oncology data scientist with Vall d’Hebron Institute of Oncology in Barcelona, told CLN Stat. Overall, WGS agreed >90% of the time and a false-positive rate of <5% in comparison with other methods. It also identified previously unknown, potentially actionable single-gene alterations and genomic signatures.

In future validation studies, the researchers spoke of using pangenomic markers to more effectively stratify patients.

To further advance the field of WGS and cancer research, “a very robust bioinformatics pipeline is critical for an automated and comprehensive interpretation process,” noted Dienstmann. In the transition from research to clinical application, many logistical aspects need to be taken into consideration, such as biopsy acquisition and report generation. In his view, “Genomics England is primed to provide a scalable solution.”

To fully implement WGS in practice, “we need clinical decision support systems in place for the interactive interpretation of cancer variants … and coordinated academic efforts that facilitate access to matched drugs,” Dienstmann continued. This includes off-label therapies in rare tumor types and experimental agents in clinical trials, he added.

Park, the clinical director of the Advanced Diagnostics Laboratory at Children’s Health, Children’s Medical Center Dallas, a clinical genomics laboratory, believes the U.K. project shows potential in demonstrating the feasibility of populationwide screening, similar to current newborn screening programs. Specifically, it will demonstrate approaches to testing, interpreting, sharing, and storing WGS data sets at a population scale. “Critically important will be data integrity and security. Once whole genome data is available at a population scale, the need and cost of future genetic testing will be significantly diminished,” Park said.

WGS data should also improve the ability of researchers and clinicians to interpret benign DNA variation from disease-causing mutations. However, Park cautioned, “the quality of whole genome sequencing needs to be proven to be equivalent to the testing modalities that are proposed for replacement.” It’s important to note that genomic tests such as exome and WGS often do not provide complete coverage of all clinically relevant genes. Physicians and patients alike need to understand the significant possibility of a false-negative result, he indicated.

Not every patient is going to need WGS or other genetic tests for that matter. WGS of entire populations may prove to be medically unnecessary. “If whole genome sequencing is only performed on a per patient medically necessary basis, then the cost of clinically validated whole genome sequencing needs to dramatically decrease from current levels,” suggested Park.