Over the past decade, the incidence of cancer in the UK has increased by about 4%, underscoring the need for molecular cancer testing, including germline testing and pharmacogenomic markers. The 100,000 Genomes Project, a UK Government initiative within the NHS in England, aimed to implement standardised high-throughput whole-genome sequencing (WGS) for patients with cancer and rare diseases. This project involved an automated, ISO-accredited bioinformatics pipeline for clinically accredited variant calling and prioritisation. The Cancer Programme of the project assessed WGS's role in the NHS, with participants consenting to link their genomic data to anonymized health records for research. The data created a national molecular data platform, the National Genomic Research Library, linking to extensive clinical datasets, including cancer registration, therapy, hospital episodes, and mortality data.
The project aimed to expedite molecular testing integration into NHS cancer care. Building on this, the NHS Genomic Medicine Service (GMS) was launched in October 2018 to provide standardised genomic testing and clinical care across England. The National Genomic Test Directory ensures consistent testing methodologies and gene targets, enabling equitable genomic testing access.
Large-scale sequencing studies, such as the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), have catalogued somatic mutations in cancer, while more recent initiatives like The Hartwig Medical Foundation have reported on metastatic solid tumours. A recent study published in Nature Medicine presents an analysis of WGS data from 13,880 solid tumours, focusing on clinically actionable genes and markers, linked to comprehensive real-world clinical and survival data, to inform current clinical care.
Comprehensive Whole-Genome Analysis of 15,241 NHS Cancer Patients
The authors sequenced 16,358 tumor-normal sample pairs from 15,241 cancer patients within the NHS recruited to the Cancer Programme of the 100,000 Genomes Project from 2015 to 2019. Nearly half were recruited in 2018, and the rest through the Rare Disease arm. Their whole-genome analysis (WGA) covered 33 tumor types from 13,880 tumor samples, mainly fresh-frozen (95.9%) with some formalin-fixed (4.1%). Normal samples were primarily blood-derived (99.1%). Tumor and normal samples were sequenced to 100× and 30× coverage, respectively, for high variant calling sensitivity. Exclusions from analysis included hematological tumors, pediatric cancers, carcinomas of unknown primary, and tumors not linked to external datasets. Diagnoses were confirmed via NCRAS and HES datasets.
Breast invasive carcinoma, colon adenocarcinoma, sarcoma, and kidney renal clear cell carcinoma had over 1,000 sequenced genomes each. Recruitment spanned 13 NHS GMCs across England, involving over 80 hospital trusts. Early onset cancers, such as low-grade glioma and testicular germ cell tumors, were noted. Staging data were available for 86.7% of tumors, with 11.9% being stage 4 advanced metastatic disease. Specific cancers like ovarian high-grade serous carcinoma and skin cutaneous melanoma showed higher stages, while breast cancers were mostly early-stage. Most samples were from surgical resections, with a small percentage from metastatic or diagnostic biopsies. Tumor purity challenges, especially in lung and pancreatic adenocarcinomas, were noted.
Infrastructure and Impact of the 100,000 Genomes Project
The 100,000 Genomes Project established critical infrastructure for integrating genomic data with longitudinal clinical life course data. This integration facilitated the selection of genomic targets for the NHS National Genomic Test Directory. Specifically, the evaluation of whole-genome sequencing (WGS) data supported the commissioning of clinical WGS for cancers such as sarcoma, glioblastoma, ovarian high-grade serous carcinoma, and triple-negative breast cancers. This single test approach aimed to detect various types of mutations, including pangenomic markers, thereby informing clinical care more effectively. The project’s infrastructure has been incorporated into the NHS Genomic Medicine Service (GMS) to standardize tumor molecular characterization and extend these benefits to more cancer patients.
High Prevalence of Actionable Genetic Variants
The findings revealed a high prevalence of genetic variants that are instrumental in stratifying patients for approved therapies and clinical trials across different cancer types. This is consistent with other international programs, such as those at St. Jude Children’s Research Hospital in the USA, BC Cancer in Canada, and the Zero Childhood Cancer Program in Australia, among others. These initiatives, although still developing, or focusing on smaller cohorts, mirror the comprehensive approach taken by the 100,000 Genomes Project. The study underscores that while WGS provides a solid foundation for molecular cancer stratification, future advancements will likely include multi-omics data (like cell-free DNA, RNA sequencing, methylation, gene expression profiling, proteomics, long-read sequencing, and single-cell sequencing) alongside genomic data. Integrating these with clinical data, including digital pathology and radiology, is expected to maximize the benefits of precision cancer care.
Integrating Real-World Clinical Data with Genomic Insights
As genomic testing becomes more prevalent, combining these data with real-world clinical and treatment data is essential for advancing our understanding of the long-term impacts of clinical cancer genomics on patient outcomes. This study demonstrated the value of linked real-world data in evaluating outcomes and identifying adverse molecular markers consistent with clinical trials. Comprehensive datasets, including staging, pathology, treatment, and outcomes, enrich the genomic data, enhancing biomarker selection. Understanding the co-occurrence of genetic variants in the same or different genes can improve the prognostic and predictive value of biomarkers and detect long-term signals of benefit or harm, aiding clinical and regulatory decision-making. The therapeutic implications of co-occurring copy number alterations (CNAs) and somatic variants, not always available from large cancer panel data, were also highlighted.
Navigating Challenges in Clinical WGS Implementation: Strategies and Solutions for the NHS
Challenges remain in implementing clinical WGS in the NHS, primarily due to costs compared to large gene panel testing. To provide a cutting-edge UK genomics service, there is a need for improved sequencing and analytical infrastructure, operational enhancements in tissue pathways, faster turnaround times, and the development of skills among the multiprofessional workforce supporting cancer care. Multidisciplinary Molecular Tumor Boards (GTABs) play a vital role in evaluating WGS results, determining clinical actionability, and providing recommendations. These boards ensure actionable results are communicated to treating teams, explore eligibility for therapies and trials, and guide clinical decision-making. This approach aligns with adaptive basket trials like DETERMINE, which evaluate licensed treatments in unlicensed indications, similar to the DRUP trial, aiming for more equitable and comprehensive molecular testing within the NHS.
The Research Environment platform by Genomics England and NHS England allows approved researchers secure access to genomic and associated health data, advancing fundamental research and driving changes in clinical practice. The study highlighted the potential for these data to provide prognostic insights based on specific mutations. As data within the Research Environment grows, linked genomic, clinical, and outcome data will enable refined analyses, enhancing the prognostic and predictive power of molecular markers. This comprehensive approach, integrating various genomic alterations and emerging technologies, aims to expand precision oncology and improve cancer outcomes.
Source: Nature Medicine
Image Credit: iStock
