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.
Nat Commun. 2025 May 20;16(1):4422. doi: 10.1038/s41467-025-59661-x.
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.
基因组学可为原发灶不明的癌症（CUP）患者提供组织起源（TOO）信息及精准治疗方案。在此，我们对72例患者进行了全基因组和转录组测序（WGTS），并在71对配对病例中显示出WGTS相对于基因检测板检测（386 - 523个基因）的诊断优势。WGTS能检测到基因检测板所发现的所有可报告DNA特征，以及在76%的病例中发现的具有诊断或治疗相关性的其他突变。基于已知癌症类型的WGTS数据精心策划的WGTS特征和CUP预测算法（CUPPA），在71%经临床病理检查无法诊断的病例中明确了TOO。WGTS为79%的患者提供了治疗信息，而基因检测板检测为59%的患者提供了治疗信息。最后，对游离DNA（cfDNA）肿瘤比例高（>7%）的患者进行cfDNA的全基因组测序（WGS），在41%的病例中实现了高可能性的CUPPA预测。因此，WGTS优于基因检测板检测，拓宽了治疗选择，并且使用常规病理样本和cfDNA是可行的。
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