Whole genome sequencing improves tissue-of-origin diagnosis and treatment options for cancer of unknown primary
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.
Authors
- Aidan Flynn (ORCID: https://orcid.org/0000-0002-1933-505X)
- Ruining Dong (ORCID: https://orcid.org/0000-0003-1433-0484)
- Sehrish Kanwal (ORCID: https://orcid.org/0000-0002-5044-4692)
- Owen W.J. Prall (ORCID: https://orcid.org/0000-0003-1600-5933)
- Tharani Sivakumaran (ORCID: https://orcid.org/0000-0001-9738-1580)
- Andrew Fellowes (ORCID: https://orcid.org/0000-0003-4267-3599)
- Hui‐Li Wong (ORCID: https://orcid.org/0000-0003-3803-2107)
- Voula Dimitriadis
- Anna DeFazio (ORCID: https://orcid.org/0000-0003-0057-4744)
- Samantha Webb
- David D.L. Bowtell (ORCID: https://orcid.org/0000-0001-9089-7525)
- Charles Shale (ORCID: https://orcid.org/0000-0002-4226-0252)
- Catherine Mitchell (ORCID: https://orcid.org/0000-0001-5596-9511)
- Kym Pham Stewart
- Clare G. Fedele (ORCID: https://orcid.org/0000-0003-2392-5754)
- Ian Collins (ORCID: https://orcid.org/0000-0001-6936-0942)
- Joseph H.A. Vissers (ORCID: https://orcid.org/0000-0003-0435-6824)
- Mark Warren (ORCID: https://orcid.org/0000-0002-7941-5254)
- Sean M. Grimmond (ORCID: https://orcid.org/0000-0002-8102-7998)
- Huiling Xu (ORCID: https://orcid.org/0000-0001-8195-8648)
- Atara Posner (ORCID: https://orcid.org/0000-0002-1592-6127)
- Penelope Schofield (ORCID: https://orcid.org/0000-0001-9495-9543)
- Alex Caneborg
- Nicholas Wilcken (ORCID: https://orcid.org/0000-0003-4006-0289)
- Rodney J. Hicks (ORCID: https://orcid.org/0000-0002-0758-0824)
- Shiva Balachander (ORCID: https://orcid.org/0000-0002-4765-6352)
- Camilla B. Mitchell (ORCID: https://orcid.org/0000-0002-0272-872X)
- Linda Mileshkin (ORCID: https://orcid.org/0000-0001-6826-6014)
- Richard J. Rebello (ORCID: https://orcid.org/0000-0001-6271-6678)
- Bo Gao (ORCID: https://orcid.org/0009-0003-1409-7405)
- Shannon Nicolson (ORCID: https://orcid.org/0000-0001-9580-3460)
- Narayan Karanth (ORCID: https://orcid.org/0000-0002-3374-6242)
- Christopher Steer (ORCID: https://orcid.org/0000-0002-7677-3339)
- Oliver Hofmann (ORCID: https://orcid.org/0000-0002-7738-1513)
- Richard W. Tothill (ORCID: https://orcid.org/0000-0003-4522-1184)
- Krista Fisher (ORCID: https://orcid.org/0000-0003-4066-3637)
- Peter Priestley (ORCID: https://orcid.org/0000-0002-4939-7104)
- Stephen B. Fox (ORCID: https://orcid.org/0000-0002-7648-8896)
- Sarah‐Jane Dawson (ORCID: https://orcid.org/0000-0002-8276-0374)
- Wenying Zhu
- Madhu Singh (ORCID: https://orcid.org/0000-0002-2770-9445)
Institutions
- The University of Sydney (AU)
- Barwon Health (AU)
- Deakin University (AU)
- The University of Melbourne (AU)
- La Trobe University (AU)
- Peter MacCallum Cancer Centre (AU)
- Westmead Hospital (AU)
- St Vincent's Hospital Melbourne (AU)
- Albury Wodonga Health (AU)
- Westmead Institute for Medical Research (AU)
- Bendigo Health (AU)
- Hartwig Medical Foundation (NL)
- Swinburne University of Technology (AU)
- Victoria University (AU)
- Cancer Council NSW (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1038/s41467-025-59661-x
- Citations
- 5
- Primary Topic
- Cancer Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 5.23
Funders
- Medical Research Council
- National Health and Medical Research Council