Genomics and Spatial Multiomics Advance Precision Medicine from Research to Clinical Practice

Molecular signatures of diseases are integrating technological, biological, and computational advancements to transform genomics from research to practical clinical applications in oncology, neonatal medicine, rare diseases, and pharmacogenomics. An ecosystem of next-generation sequencing (NGS), functional genomics, pangenomics, genome engineering, and AI-based analytical tools is changing healthcare by shifting focus toward predictive, preventive, and personalized approaches.

Whole genome sequencing (WGS) has been added to standard diagnostics, revolutionizing pediatric and emergency medicine with the ability to make genetic diagnoses in as little as a few hours using ultra-rapid sequencing. Distributed cloud nanopore technologies enabled rapid diagnosis of genetic conditions in under 8 hours, facilitating life-saving treatments to critically ill patients in both pediatric and adult ICUs. The GUARDIAN initiative in New York City screened 100,000 newborns for genes associated with conditions warranting immediate clinical intervention, successfully identifying an actionable variant in approximately 3.7% of screened babies that would have been missed by conventional newborn screening panels. The UK and other major countries have decided to implement WGS for all newborns, demonstrating a paradigm shift in that precision medicine begins with a newborn, not simply a diagnosis of a disease.

Cancer care is evolving from organ-based treatment to biology-based treatment decisions, with comprehensive genomic profiling (CGP) foundational to this shift. Tumor-specific genomic analysis is considered the foundation of personalized medicine, used to determine the best treatment options and prognosis, as well as to assess and manage minimal residual disease (MRD) status. The most common driver mutations, like those in TP53, EGFR, KRAS, PIK3CA, and APC, are well known and present across a range of solid tumor types such as non-small cell lung cancer (NSCLC), breast cancer, colorectal cancer, prostate cancer, and melanoma. Many of these mutations driving cancers in different organs have a range of targeted therapies, allowing CGP to more precisely match patients with specific mutations to appropriate treatments.

The effectiveness of CGP has made the most impact to date for informing NSCLC treatments, driven by guidelines that encouraged broad biomarker testing in advanced disease to reveal actionable mutations that could be addressed with targeted therapies. CGP now influences treatment decisions in many of the most common and most lethal cancers. The OlympiA clinical trial of olaparib in patients with HER2-negative breast cancer with BRCA1 and BRCA2 mutations showed that they benefitted from the drug in the adjuvant setting, with data showing that treating them directly after frontline interventions such as surgery or radiation therapy lowered the risk of death by as much as 32% in the ensuing years.

Liquid biopsy and circulating tumor DNA (ctDNA) have further enhanced the utility of CGP in cancer care, allowing for the detection of resistance mutations and the monitoring of disease in a non-invasive manner. These technologies have enabled a shift in cancer care from a reactive to an anticipatory paradigm. Over the past 10 years, hybrid panels have emerged to capture insertions and deletions (indels), copy number variants, and structural variants. More complex signatures for tumor mutational burden (TMB) and microsatellite instability (MSI)-high, now included in these assays, can inform the selection of immunotherapies. The past five years have seen advances that include RNA-seq to improve detection of fusions and splice variants, with sequencing RNA associated with a 15 to 20% higher likelihood of identifying fusions while also providing a clearer snapshot of tumor activity.

Over 300 million people suffer from rare genetic disorders worldwide, many enduring years of testing with no conclusive results. Whole exome and genome sequencing have, in some studies, provided 60% of case study subjects with confirmed neurological diagnoses. Rapid molecular diagnoses support practitioners to potentially intervene sooner in order to facilitate medical and genetic testing in patients and their relatives, as well as facilitate more effective and efficient clinical decisions. The initiatives and goals of the world's population genome and human pangenome have demonstrated the ability to contribute to the equitability of global variant interpretation and diagnostics.

Pharmacogenomic testing anticipates and reveals the increased probability of adverse drug reactions and treatment failures. Evidence illustrates that genomics impacts the dosing of major drugs such as chemotherapy and antidepressants by determining the function of specific enzymes and how different drugs metabolize due to genetic variants. With increased utilization in daily practice, it is expected that pharmacogenomics will become one of the routine features in electronic health records and clinical decision support systems.

CRISPR technology is advancing from a lab-based and research-based tool toward clinical and therapeutic application. By 2025, CRISPR approaches will have clinical-grade therapeutic pipeline advancements and regulatory approvals expected.

Spatial multiomics allows scientists to directly interrogate patient samples in a way that was not possible before. Spatial biology allows researchers to answer two critical questions at the same time: which cells are in a sample, and what are they doing. Before spatial techniques emerged, researchers had to rely on bulk analyses, which would yield an overview of gene or protein expression in the whole sample. With the arrival of single-cell methods, it became possible to narrow down these results, but these techniques still cannot provide detailed information about the tissue architecture or interactions between cells.

At the Spatial Multiomics Core at the Mayo Clinic, the majority of requests received focus on oncology, where uncovering interactions between the tumor and immune cells is essential to understand the underlying biology. The core is actively developing omics technologies that go beyond initial discoveries, expanding into monitoring the course of disease and patient responses to medical interventions. Ongoing programs are tracking the effects of RNA and CRISPR-based therapeutics on their cellular targets within a spatial context.

In a recent study, researchers used high-resolution spatial transcriptomics to uncover how spatial context can influence gene expression and tumor cell plasticity in Merkel cell carcinoma (MCC), a rare but aggressive form of skin cancer. This led them to identify potential prognostic markers of tumor behavior and therapeutic targets to prevent resistance. If MCC cells are surrounded by normal keratinocytes, they also become more normal, even if they keep the same genetic background. Since researchers first started using spatial transcriptomics in their research work about four years ago, there have been significant technological advances in terms of the throughput, resolution, and coverage provided by commercially available equipment and tools.