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

2025-05-20

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

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

The Westmead Institute for Medical Research, Sydney, NSW, Australia.

The Westmead Institute for Medical Research, Sydney, NSW, Australia.

Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.

The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia.

Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW, Australia.

Department of Medical Oncology, Barwon Health Cancer Services, Geelong, VIC, Australia.

Department of Medical Oncology, Southwest HealthCare, Warrnambool and Deakin University, Geelong, VIC, Australia.

Border Medical Oncology, Albury Wodonga Regional Cancer Centre, Albury NSW, Australia and UNSW School of Clinical Medicine, Rural Clinical Campus, Albury, NSW, Australia.

Department of Medical Oncology, Bendigo Health, Bendigo, VIC, Australia.

Division of Medicine, Alan Walker Cancer Centre, Darwin, NT, Australia.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

The St Vincent's Hospital Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Hartwig Medical Foundation, Sydney, NSW, Australia.

Hartwig Medical Foundation, Sydney, NSW, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Department of Psychology, and Iverson Health Innovation Research Institute, Swinburne University, Melbourne, VIC, Australia.

School of Computing, Engineering and Mathematical Sciences, La Trobe University, Melbourne, VIC, Australia.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia. rtothill@unimelb.edu.au.

Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia. rtothill@unimelb.edu.au.

Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. rtothill@unimelb.edu.au.

Humans

Neoplasms, Unknown Primary

Whole Genome Sequencing

Female

Male

Mutation

Algorithms

Middle Aged

Genomics

Aged

Transcriptome

Biomarkers, Tumor

Gene Expression Profiling

Journal Article

Publication

0000-0001-6271-6678

0000-0002-1592-6127

0000-0003-1433-0484

0000-0002-0272-872X

0000-0001-5596-9511

0000-0002-5044-4692

0000-0003-3803-2107

0000-0002-4765-6352

0000-0001-9580-3460

0000-0003-0057-4744

0000-0001-6936-0942

0000-0002-7677-3339

0000-0003-4267-3599

0000-0002-0758-0824

0000-0002-4226-0252

0000-0002-8276-0374

0000-0003-0435-6824

0000-0002-7648-8896

0000-0002-8102-7998

0000-0001-6826-6014

0000-0003-4522-1184

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.

link

Nat Commun . 2025 May 20;16(1):4422. doi: 10.1038/s41467-025-59661-x.

2041-1723

https://pubmed.ncbi.nlm.nih.gov/40393956/?otool=iaurydwlib