In an article published on 11 January 2024 in the Nature Medicine, a group of researchers affiliated with the 100,000 Genomes Cancer Programme present an analysis of whole-genome sequencing (WGS) data from 13,880 solid tumours, focused on clinically actionable genes and pangenomic markers, linked to real-world longitudinal, life course clinical, treatment and long-term survival data to highlight the learnings from the Cancer Programme and the implications for current clinical care.
The findings underscore the potential for these data to provide additional prognostic insights based on the absence or presence of specific mutations. As data accumulate within the Research Environment with linkage of genomic, clinical and outcome data, more refined analyses using real-world data can take place, aided by more comprehensive tumour profiling. This will enable further refinement of prognostic and predictive molecular markers, not only with combinations of different genomic alterations, but beyond genomics, including emerging technologies to expand the reach of precision oncology to improve cancer outcomes.
The 100,000 Genomes Project, a transformational UK Government initiative conducted within the National Health Service (NHS) in England, aimed to establish standardised high-throughput WGS for patients with cancer and rare diseases via an automated, International Organization for Standardization-accredited bioinformatics pipeline. The role of WGS at scale for patients with cancer in the NHS was evaluated within the Cancer Programme of the 100,000 Genomes Project.
Participants gave written informed consent for their genomic data to be linked to anonymized longitudinal health records and shared with researchers in a secure Research Environment. The data generated were then used to establish a national molecular data platform (National Genomic Research Library) with secure links to longitudinal real-world data in the Research Environment.
The national clinical datasets include the National Cancer Registration and Analysis Service dataset consisting of cancer registration data and the Systemic Anti-Cancer Therapy dataset, as well as subsequent cancer episodes, including Hospital Episode Statistics and mortality data from the Office for National Statistics. This approach enables genomic research and discovery to be fed back into genomic healthcare.
A longer-term objective was to accelerate the delivery of molecular testing, including WGS, in NHS clinical cancer care. Building on evolving knowledge from the 100,000 Genomes Project and the existing molecular testing provision within the NHS, the NHS Genomic Medicine Service (GMS) was launched in October 2018 to deliver genomic testing, clinical care and interpretation for rare diseases and cancer across England, using a standardised National Genomic Test Directory, including targeted large gene panels and WGS, to enable equitable access and comprehensive genomic testing.
The project team sequenced 16,358 tumour-normal sample pairs from 15,241 patients diagnosed with cancer within the NHS who were recruited to the Cancer Programme of the 100,000 Genomes Project between 2015 and 2019, with almost half of the patients being recruited in 2018 and the remainder in this Project being recruited through the Rare Disease arm.
Integrative whole-genome analysis covered 33 tumour types of 13,880 tumour samples, consisting of 13,311 fresh-frozen (95.9%) and 569 formalin-fixed paraffin-embedded tumour samples (4.1%). Matched normal (germline) samples included 13,493 (99.1%) blood-derived, 100 (0.7%) from normal tissue and 23 (0.2%) from saliva samples.
Genomes from haematological tumours (n = 841), paediatric cancers (n = 333), carcinomas of unknown primary (n = 98) and tumours that were not linked to external datasets (n = 1,206) were excluded from this analysis.
Tumour types with more than 1,000 sequenced tumour genomes included breast invasive carcinoma (n = 2925), colon adenocarcinoma (n = 1948), sarcoma (n = 1617) and renal clear cell carcinoma (n = 1163). Early onset (median age less than 50 years) was observed for low-grade glioma and testicular germ cell tumours in agreement with incidence statistics.
Incidence of somatic mutations in genes recommended for standard-of-care testing varied across cancer types. For instance, in glioblastoma multiforme, small variants were present in 94% of cases and copy number aberrations in at least one gene in 58% of cases, while sarcoma demonstrated the highest occurrence of actionable structural variants (13%). Homologous recombination deficiency was identified in 40% of high-grade serous ovarian cancer cases with 30% linked to pathogenic germline variants, highlighting the value of combined somatic and germline analysis.
WGS results are discussed at multidisciplinary Molecular Tumour Boards to evaluate somatic and germline variants, determine clinical actionability and provide clinical recommendations.
The linkage of WGS and longitudinal life course clinical data allowed the assessment of treatment outcomes for patients stratified according to pangenomic markers. Findings from the Cancer Programme aided the selection of genomic targets in the NHS National Genomic Test Directory. Evaluation of WGS data provided support for the commissioning of clinical WGS for sarcoma, glioblastoma, ovarian high-grade serous carcinoma, and triple-negative breast cancers, to detect different types of mutations, including pangenomic markers, with a single test to inform clinical care.
The infrastructure generated from the 100,000 Genomes Project has been incorporated into the NHS GMS to enable standardised molecular characterisation of tumours and to extend the clinical benefit of prospective molecular characterisation to more patients with cancer.
Consistent with previous studies, the authors reported a high prevalence of genetic variants used to stratify patients toward approved therapies and clinical trials across different cancer types. Their approach aligns with similar programmes in other countries, such as St. Jude Children’s Research Hospital in the USA, BC Cancer in Canada, Zero Childhood Cancer Program in Australia, France Médecine Génomique and Genomic Medicine Sweden. These initiatives are either ongoing and have yet to publish on their cohort or represent a smaller cohort of childhood cancers.
Overall, the findings demonstrate the utility of linking genomic and real-world clinical data to enable survival analysis to identify cancer genes that affect prognosis and advance understanding of how cancer genomics impacts patient outcomes.
Among the authors, Drs. Alona Sosinsky, John Ambrose, William Cross, Mark Caulfield, and Nirupa Murugaesu contributed equally.
This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited, a wholly owned company of the Department of Health and Social Care. The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council also funded the research infrastructure.
The authors thanked the Illumina Laboratory Services team at Hinxton for their advice and for undertaking the WGS. They thanked University College London, Cancer Research Technology and the TRACERx Team for providing the lung tumour samples that were used in the WGS pipeline validation. They thanked staff of Great Ormond Street Hospital for Children NHS Foundation Trust and Manchester Centre for Genomic Medicine for sharing data from the orthogonal genomic tests that were used in the WGS pipeline validation.
Reference
Sosinsky A., Ambrose J, Cross W, et al. Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme. Nature Medicine; Published online 11 January 2024. DOI: https://doi.org/10.1038/s41591-023-02682-0
