What's coming in clinical genomics?

Liz Carey Feature Writer Smg 2023 Headshot
Dna Sequencing Social

The genetics and genomics community is trying to raise awareness of whole genome sequencing (WGS) as a valuable tool in the clinician's diagnostic toolbox, especially for patients with rare and less-common cancers.

Five years ago during the throes of the COVID-19 pandemic, there were 187 genomic initiatives globally, of which 50% originated in the U.S. and 19% in Europe, clinical services firm IQVIA reported at the time. The company projected 52 million genomes would be analyzed by 2025, using techniques ranging from genotyping to WGS. 

With a grand vision and national health policy approach in England, more than 100,000 whole genomes from adults with cancer and rare disease have been sequenced as part of Genomics England's 100,000 Genomes Project. Genomics England started with a concept from Genomics Central Laboratory Hubs. 

Genomics laboratories would be configured around the concept of routine diagnostic clinical sequencing and complex genome analysis, supporting the full range of molecular and cytogenetic technologies, as well as the validation and clinical interpretation of genomic data at the level of the whole genome. 

Designers envisioned the consolidation of existing specialist genetic laboratories into state of the art, high-throughput laboratories for the NHS. Hubs, they planned, would emerge from and be formed with existing molecular pathology laboratories. 

Combined with the 100,000 Genomes Project, the work has led to the establishment of an infrastructure to embed genomics into routine clinical practice in the National Health Service (NHS), according to researchers who published points of interest in the British Journal of Cancer (BJC). 

The national genomic test directory, updated January 20, specifies which genomic tests are commissioned by NHS England, the technology by which they are available, and the patients who will be eligible to access to a test. 

Most genomics services use a combination of different sequencing techniques according to tumor type and standard of care pathways, according to Elaine Y. L. Leung, PhD, from the Institute of Cancer and Genomic Sciences at University of Birmingham in Birmingham, U.K., with Helen Robbins, PhD, and colleagues for their October 2024 BJC report. 

Notably, the 100,000 Genomes Project is one of the largest population-based genomics medicine trials with an overarching aim to introduce WGS within a publicly funded health system. The project has now turned to sequencing newborns for more than 200 treatable conditions, in a project that is currently underway using Qiagen's Clinical Knowledge Base variant content.

Called the Generation Study, this work will explore the potential of a newborn genome sequencing database to study people as they grow older and whether a person’s genome could possibly be used throughout their lives to inform healthcare decisions, the Guardian reported in 2022. Some have called the project "a step into the unknown." 

Bioinformatic bottleneck

Much has been said of the dramatic drop in the cost of next generation sequencing (NGS). However, it's the interpretation of a whole genome, validation, and reporting that may bring the most complexities. 

Mark Kiel, MD, PhD, Genomenon.Mark Kiel, MD, PhD, Genomenon.

Genomic sequencing has come so far that clinicians, geneticists, and pathologists now face a "bioinformatic bottleneck," according to Dr. Mark Kiel, PhD, chief scientific officer and co-founder of Genomenon in Ann Arbor, MI. The bottleneck is caused by massive amounts of data that molecular diagnostic laboratories and cancer pathology laboratories are generating so inexpensively. 

Founded in 2014, Genomenon has evolved to facilitate greater use of genomic data, and there's quite a lot of it held by molecular and genetic testing laboratories and public and private archives of reports of human variation, according to Kiel, a molecular genetic pathologist by training and clinical pathologist who practiced at the University of Michigan. 

With a primary focus on making genomic information actionable, the value Genomenon has created comes from looking at the decades of published scientific and medical literature that is relevant to clinical genomics, Kiel explained for LabPulse. Genomenon has collected information on nearly 27 million variants, is used by more than 2,000 clinical laboratories, and has partnerships with numerous industry players, including, including Fabric Genomics, Sophia, and others, Kiel said. 

In the clinical market, the company offers data, software, and services designed to supplement the post-analytical phase of molecular testing, specifically a built-for-purpose molecular diagnostic search engine for interpretation, reporting, and clinical decision-making. 

"Not only have we indexed all this evidence, but we've curated it and interpreted its significance to expedite diagnostic workflows and facilitate laboratory automation," Kiel said. 

"The most meaningful evidence is from clinical studies -- whether they be case reports of individual patients or families, where the variant recurs in affected individuals or large cohorts of patients. Additionally, functional studies of these variants carry a lot of weight," Kiel continued. "If you change the protein in this way, and it changes the protein's function, that is strong evidence the variant is disease-causing. 

"Our curation experts look at these data and not only assess individual cases and individual experimental results, but also look at it from a high level to identify patterns in the data and in some cases even influence change in the way that clinical diagnostics is practiced," Kiel said.

Oncology at the edge 

Oncology teeters on the leading edge of incorporating genomics into the diagnostic toolbox in the U.S., according to the National Human Genome Research Institute (NHGRI). Over the past five years while university projects have been spinning out ways to analyze the DNA dataset, health systems have been proactively engaging patients who are interested in genetic testing. 

In a potential sign of things to come, Labcorp Oncology now offers laboratories access to tissue and liquid genomic-profiling assays. After acquiring Personal Genome Diagnostics in 2022, Labcorp pursued U.S. Food and Drug Administration (FDA) de novo marketing authorization for the PGDx Elio Plasma Focus test that is designed as an alternative to Labcorp's tissue genomic profiling test, PGDx Elio Tissue Complete. 

In a step further, Labcorp and Myriad Genetics are now running some of their molecular residual disease (MRD) blood tests for cancer on Ultima Genomics' UG 100 platform. The companies have set their sights on large-scale, ultra-high throughput WGS clinical applications, and they are pitching them at low cost. 

Like other genomics upstarts, Ultima initially benefited from over $4 million in funding from the U.S. National Institutes of Health (NIH) between 2019 and 2021. In May 2022, Ultima emerged from stealth mode to launch with $600 million in backing from investors such as General Atlantic, Andreessen Horowitz, D1 Capital, Khosla Ventures, and others.

Newborn screening as an adjunct 

Elsewhere, initial results of the Genomic Uniform-screening Against Rare Disease in All Newborns (GUARDIAN) study -- conducted by Columbia University Irving Medical Center, New York-Presbyterian, the New York State Department of Health, Illumina, and GeneDx -- came out in October 2024. 

Like the newborn sequencing initiative in the U.K., the prospective, observational study also aimed to sequence 100,000 newborns as an adjunct to traditional newborn testing. Researchers have reported on nearly 4,000 patients assessed toward learning how genomic sequencing technology can be used to effectively expand the conditions screened on newborn screening. 

Families can choose to be part of the study or choose not to be part of the study and just have the routine newborn screening test. Newborns who screen positive are referred to appropriate providers for care. 

Authors of the October report believe that genome sequencing can pick up on rare diseases where standard screening falls short. The dried blood spot used for routine newborn screening was also used for genome sequencing. After improvements in laboratory and reporting processes, turnaround time ranged from 19 to 88 days, Dr. Alban Ziegler from the department of pediatrics at Columbia University and colleagues explained for JAMA Network Open.

"The declining cost of DNA sequencing, improved ability to interpret genomic data, and advancements in treatments have raised the questions of whether and how to implement first-tier targeted sequencing, exome sequencing, or genome sequencing to expand NBS for conditions lacking biomarkers," the authors noted, while acknowledging concerns about the downstream impact. 

Current and emerging trends 

There are bold visions for using whole human genomes in medical diagnostics and precision medicine. On a grand scale, one fashions millions of individual genomes around the globe connected and linked to a constantly updated anthology of medical evidence that connects genetic variation and risk of disease. 

On a smaller scale, sequencing a large sampling of genes related to a variety of disease states appears at the fingertips of the medical community.

Christina Lockwood, PhD, University of Washington.Christina Lockwood, PhD, University of Washington.

In January, researchers from departments of laboratory medicine and pathology at the University of Washington School of Medicine in Seattle, Brigham and Women's Hospital in Boston, the Mayo Clinic in Rochester, MN, and Washington University in St. Louis, established the landscape for current and emerging trends in genomics in the U.S. as part of a special edition and commentaries in Clinical Chemistry, the journal of the Association for Diagnostics and Laboratory Medicine. 

Lead author Christina Lockwood, PhD, and colleagues noted progress in the areas of improving genetic annotation, use of virtual gene panels customized with ongoing genomic discoveries, analyzing tumor-derived genetic alterations using liquid biopsies, and pharmacogenomics that examines the interplay of genetic variants and patient drug response. 

Furthermore, in the context of infectious diseases, genomics is essential for understanding and managing pathogens such as SARS-CoV-2 and Candida auris, tracing transmission patterns, and identifying variants of concern, the authors said. 

Addressing issues such as the need for specialized training in cytogenetics, logistical hurdles, and navigating the massive amounts of data out there is essential for genomic medicine to become fully integrated, they added. 

Regulatory limbo

Regulatory agencies in the U.S. are still deciding how oversight will work for genetic and genomic tests, according to the NHGRI. 

Regardless, many have already bet big on the wider use of WGS and next-generation sequencing technologies to expand precision oncology research, personalized cancer care, and newborn screening.

"Since clinical genomics is a relatively new field, frameworks to evaluate the clinical utility of genetic tests are still being developed," according to the NHGRI. "With time and experience, researchers, clinicians, health insurance companies, and regulators will have better information with which to establish the clinical utility of genetic tests."

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