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 G. 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 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 D.L. Bowtell, Oliver Hofmann, Sean M. Grimmond, Linda Mileshkin, Richard W. Tothill
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. Patients with metastatic cancers of unknown primary (CUP) are currently unable to gain access to drugs through standard of care or clinical trials. Here, the authors perform whole-genome and transcriptome sequencing (WGTS) on 72 patients with CUP and demonstrate the feasibility of using WGTS to determine the specific cancer types of CUP, thereby clinically benefiting patients with CUP.