Whole genome sequencing improves tissue-of-origin diagnosis and treatment options for cancer of unknown primary

Rebello, Richard J.; Posner, Atara; Dong, Ruining; Prall, Owen W. J.; Sivakumaran, Tharani; Mitchell, Camilla B.; Flynn, Aidan; Caneborg, Alex; Mitchell, Catherine; Kanwal, Sehrish; Fedele, Clare; Webb, Samantha; Fisher, Krista; Wong, Hui-Li; Balachander, Shiva; Zhu, Wenying; Nicolson, Shannon; Dimitriadis, Voula; Wilcken, Nicholas; DeFazio, Anna; Gao, Bo; Singh, Madhu; Collins, Ian M.; Steer, Christopher; Warren, Mark; Karanth, Narayan; Xu, Huiling; Fellowes, Andrew; Hicks, Rodney J.; Stewart, Kym Pham; Shale, Charles; Priestley, Peter; Dawson, Sarah-Jane; Vissers, Joseph H. A.; Fox, Stephen B.; Schofield, Penelope; Bowtell, David; Hofmann, Oliver; Grimmond, Sean M.; Mileshkin, Linda; Tothill, Richard W.

Whole genome sequencing improves tissue-of-origin diagnosis and treatment options for cancer of unknown primary

Richard J. Rebello, Atara Posner, Ruining Dong, Owen W. J. Prall, Tharani Sivakumaran, Camilla B. Mitchell, Aidan Flynn, Alex Caneborg, Catherine Mitchell, Sehrish Kanwal, Clare Fedele, Samantha Webb, Krista Fisher, Hui-Li Wong, Shiva Balachander, Wenying Zhu, Shannon Nicolson, Voula Dimitriadis, Nicholas Wilcken, Anna DeFazio, Bo Gao, Madhu Singh, Ian M. Collins, Christopher Steer, Mark Warren, Narayan Karanth, Huiling Xu, Andrew Fellowes, Rodney J. Hicks, Kym Pham Stewart, Charles Shale, Peter Priestley, Sarah-Jane Dawson, Joseph H. A. Vissers, Stephen B. Fox, Penelope Schofield, David Bowtell, Oliver Hofmann, Sean M. Grimmond, Linda Mileshkin and Richard W. Tothill ()
Additional contact information
Richard J. Rebello: University of Melbourne
Atara Posner: University of Melbourne
Ruining Dong: University of Melbourne
Owen W. J. Prall: Peter MacCallum Cancer Centre
Tharani Sivakumaran: Peter MacCallum Cancer Centre
Camilla B. Mitchell: University of Melbourne
Aidan Flynn: University of Melbourne
Alex Caneborg: University of Melbourne
Catherine Mitchell: Peter MacCallum Cancer Centre
Sehrish Kanwal: University of Melbourne
Clare Fedele: University of Melbourne
Samantha Webb: Peter MacCallum Cancer Centre
Krista Fisher: Peter MacCallum Cancer Centre
Hui-Li Wong: Peter MacCallum Cancer Centre
Shiva Balachander: Peter MacCallum Cancer Centre
Wenying Zhu: University of Melbourne
Shannon Nicolson: University of Melbourne
Voula Dimitriadis: University of Melbourne
Nicholas Wilcken: The Westmead Institute for Medical Research
Anna DeFazio: The Westmead Institute for Medical Research
Bo Gao: Westmead Hospital
Madhu Singh: Barwon Health Cancer Services
Ian M. Collins: Warrnambool and Deakin University
Christopher Steer: Rural Clinical Campus
Mark Warren: Bendigo Health
Narayan Karanth: Alan Walker Cancer Centre
Huiling Xu: Peter MacCallum Cancer Centre
Andrew Fellowes: Peter MacCallum Cancer Centre
Rodney J. Hicks: University of Melbourne
Kym Pham Stewart: University of Melbourne
Charles Shale: Hartwig Medical Foundation
Peter Priestley: Hartwig Medical Foundation
Sarah-Jane Dawson: University of Melbourne
Joseph H. A. Vissers: University of Melbourne
Stephen B. Fox: Peter MacCallum Cancer Centre
Penelope Schofield: University of Melbourne
David Bowtell: University of Melbourne
Oliver Hofmann: University of Melbourne
Sean M. Grimmond: University of Melbourne
Linda Mileshkin: Peter MacCallum Cancer Centre
Richard W. Tothill: University of Melbourne

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59661-x

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