Whole genome sequencing improves tissue-of-origin diagnosis and treatment options for cancer of unknown primary
- Author(s)
- Rebello, RJ; Posner, A; Dong, R; Prall, OWJ; Sivakumaran, T; Mitchell, CB; Flynn, A; Caneborg, A; Mitchell, C; Kanwal, S; Fedele, C; Webb, S; Fisher, K; Wong, HL; Balachander, S; Zhu, W; Nicolson, S; Dimitriadis, V; Wilcken, N; DeFazio, A; Gao, B; Singh, M; Collins, IM; Steer, C; Warren, M; Karanth, N; Xu, H; Fellowes, A; Hicks, RJ; Stewart, KP; Shale, C; Priestley, P; Dawson, SJ; Vissers, JHA; Fox, SB; Schofield, P; Bowtell, D; Hofmann, O; Grimmond, SM; Mileshkin, L; Tothill, RW;
- Journal Title
- Nature Communications
- Publication Type
- Research article
- Abstract
- Genomics can inform both tissue-of-origin (TOO) and precision treatments for patients with cancer of unknown primary (CUP). Here, we use whole genome and transcriptome sequencing (WGTS) for 72 patients and show diagnostic superiority of WGTS over panel testing (386-523 genes) in 71 paired cases. WGTS detects all reportable DNA features found by panel as well as additional mutations of diagnostic or therapeutic relevance in 76% of cases. Curated WGTS features and a CUP prediction algorithm (CUPPA) trained on WGTS data of known cancer types informs TOO in 71% of cases otherwise undiagnosed by clinicopathology review. WGTS informs treatments for 79% of patients, compared to 59% by panel testing. Finally, WGS of cell-free DNA (cfDNA) from patients with a high cfDNA tumour fraction (>7%), enables high-likelihood CUPPA predictions in 41% of cases. WGTS is therefore superior to panel testing, broadens treatment options, and is feasible using routine pathology samples and cfDNA.
- Publisher
- Springer Nature
- Keywords
- Humans; *Neoplasms, Unknown Primary/genetics/diagnosis/therapy; *Whole Genome Sequencing/methods; Female; Male; Mutation; Algorithms; Middle Aged; Genomics/methods; Aged; Transcriptome; Biomarkers, Tumor/genetics; Gene Expression Profiling
- Department(s)
- Pathology; Medical Oncology; Laboratory Research
- Publisher's Version
- https://doi.org/10.1038/s41467-025-59661-x
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-025-59661-x- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-06-03 07:20:31
Last Modified: 2025-06-03 07:20:41