Whole genome and transcriptome sequencing (WGTS) is proving significantly more effective than conventional gene panel testing in diagnosing and treating cancer of unknown primary (CUP), according to new research involving 72 patients.
The study demonstrated that WGTS outperformed panel testing (covering 386–523 genes) in 71 paired cases, detecting all DNA features identified by panels while uncovering additional mutations with diagnostic or therapeutic relevance in 76% of patients. These insights led to broader and more precise treatment options.
Researchers also developed a CUP prediction algorithm (CUPPA), trained on WGTS data from known cancer types. When combined with curated WGTS features, CUPPA successfully identified the tissue of origin in 71% of cases where standard clinicopathological methods had failed.
Importantly, WGTS informed treatment strategies for 79% of patients, compared to just 59% using panel testing alone, highlighting its potential to transform clinical management of CUP. The approach was also effective using routine pathology samples and even cell-free DNA (cfDNA) from blood, with whole genome sequencing of cfDNA allowing CUPPA to make high-confidence origin predictions in 41% of patients with elevated tumour DNA levels.
This study reinforces the diagnostic and therapeutic value of WGTS, suggesting it should become a key tool in managing CUP, where identifying the tumour’s origin remains one of oncology’s biggest challenges.
Reference
Rebello RJ et al. Whole genome sequencing improves tissue-of-origin diagnosis and treatment options for cancer of unknown primary. Nat Commun. 2025;16(1):4422.
