The 100,000 Genomes Project: Insights from the cancer programme

Recently published data from the cancer programme of the 100,000 Genomes Project, which maps out the genomic patterns of patients with different cancer types using whole-genome sequencing (WGS), have provided insights on integrating genomics into routine cancer care.

“Over the last decade, cancer incidence in the UK has increased by approximately 4 percent, driving the need for molecular cancer testing,” noted the researchers from the UK National Health Service (NHS). The 100,000 Genomes Project, a UK Government initiative conducted within NHS, aimed to sequence 100,000 genomes in patients with cancer or rare diseases by utilizing WGS. [Nat Med 2024;doi:10.1038/s41591-023-02682-0; www.genomicsengland.co.uk/initiatives/100000-genomes-project]

The researchers analyzed WGS data from 13,880 solid tumours spanning 33 cancer types between 2015 and 2019, focusing on clinically actionable genes and pangenomic markers. Tumour types with >1,000 sequenced genomes included breast invasive carcinoma (n=2,925), colon adenocarcinoma (n=1,948), sarcoma (n=1,617), and renal clear cell carcinoma (n=1,163). Genomes from haematological malignancies, paediatric cancers, carcinomas of unknown primary, and tumours not linked to external datasets were excluded.

“Results showed that WGS is a comprehensive single test that characterizes the clinical genomic landscape of a tumour,” wrote the researchers. “WGS can report somatic single nucleotide variants [SNVs], gene fusions and copy-number alterations [CNAs], along with potentially pathogenic germline mutations, and pangenomic markers such as mutational signatures and tumour mutational burden.”

Over 90 percent of brain tumours (glioblastoma multiforme, 95 percent; low-grade glioma, 93 percent) and nearly 70 percent of colon and lung cancers (69 percent and 68 percent, respectively) showed ≥1 genetic mutation. Sarcoma demonstrated the highest occurrence of actionable structural variants (13 percent).

“Forty percent of high-grade serous ovarian cancer had homologous recombination deficiency, with 30 percent linked to pathogenic germline variants, highlighting the value of combined somatic and germline analysis,” added the researchers.

Unlike targeted panel tests, WGS allows somatic and germline variants to be detected together.

TP53 was the most frequently mutated gene (n=5,311/13,800; 39 percent), followed by PIK3CA (n=2,750/13,880; 19.8 percent). The frequency of TP53 mutations varied across different cancer types and was highest in uterine corpus endometrial serous carcinoma, ovarian high-grade serous carcinoma, lung squamous cell carcinoma, rectum adenocarcinoma, oesophageal adenocarcinoma and oesophageal squamous cell carcinoma (>70 percent for all).

The analysis also revealed gene mutations in cancer types for which testing for those genes is not currently indicated. This suggests the presence of potentially actionable targets, which may enable new clinical trial recruitment or prompt further review. For example, testing for PIK3CA mutations is currently indicated in breast invasive carcinoma only, but these mutations were found to be present across multiple tumour types, including uterine corpus endometrial carcinoma (53.5 percent), ovarian endometrioid adenocarcinoma (49.0 percent), breast invasive carcinoma (42.2 percent), uterine corpus endometrial serous carcinoma (38.1 percent) and colon adenocarcinoma (26.5 percent), suggesting that clinical trials of PIK3CA inhibitors could be considered in the future, if clinically appropriate.

“The 100,000 Genomes Project is an important milestone in genomic medicine. We are starting to realize the promise of precision oncology that was envisioned 10 years ago,” commented the researchers. “By collecting long-term clinical data alongside genomic data, the study has created a first-of-its-kind resource for clinicians to better predict outcomes and tailor treatment plans, which will allow physicians to inform, prepare, and manage patients’ expectations more effectively.”