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A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary
Conway, Alicia M Pearce, Simon P Clipson, Alexandra Hill, Steven M Chemi, Francesca Slane-Tan, Dan Ferdous, Seba Hossain, A S Mukarram Kamieniecka, Katarzyna White, Daniel J
Conway, Alicia M
Pearce, Simon P
Clipson, Alexandra
Hill, Steven M
Chemi, Francesca
Slane-Tan, Dan
Ferdous, Seba
Hossain, A S Mukarram
Kamieniecka, Katarzyna
White, Daniel J
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Abstract
Cancers of Unknown Primary (CUP) remains a diagnostic and therapeutic challenge due to biological heterogeneity and poor responses to standard chemotherapy. Predicting tissue-of-origin (TOO) molecularly could help refine this diagnosis, with tissue acquisition barriers mitigated via liquid biopsies. However, TOO liquid biopsies are unexplored in CUP cohorts. Here we describe CUPiD, a machine learning classifier for accurate TOO predictions across 29 tumour classes using circulating cell-free DNA (cfDNA) methylation patterns. We tested CUPiD on 143 cfDNA samples from patients with 13 cancer types alongside 27 non-cancer controls, with overall sensitivity of 84.6% and TOO accuracy of 96.8%. In an additional cohort of 41 patients with CUP CUPiD predictions were made in 32/41 (78.0%) cases, with 88.5% of the predictions clinically consistent with a subsequent or suspected primary tumour diagnosis, when available (23/26 patients). Combining CUPiD with cfDNA mutation data demonstrated potential diagnosis re-classification and/or treatment change in this hard-to-treat cancer group.
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Date
2024
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Conway AM, Pearce SP, Clipson A, Hill SM, Chemi F, Slane-Tan D, et al. A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary. Nature communications. 2024 Apr 17;15(1):3292. PubMed PMID: 38632274. Pubmed Central PMCID: PMC11024142 Bioven, Amgen, Carrick Therapeutics, Merck AG, Taiho Oncology, GSK, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Epigene Therapeutics Inc, Angle PLC, Menarini, Clearbridge Biomedics, Thermo Fisher Scientific, Neomed Therapeutics. C.D. has received/receives honoraria/consultancy fees from Biocartis, Merck, AstraZeneca and GRAIL. Outside of the scope of work, research funding/educational research grants has been received from by the Experimental Cancer Medicine Team (PI: Cook) from AstraZeneca, Bayer, Pfizer, Orion, Taiho, Oncology, Roche, Starpharma, Eisai, RedX, UCB, Boeringher, Merck, Stemline Tarveda and Avacta. M.G.K has received consultancy/advisory board fees from Bayer, Guaradant Health, Janssen, Roche, Seattle Genetics; speakers fees from Janssen, Roche; research funding from Novartis, Roche and travel expenses from Immutep, Janseen and Roche. The remaining authors declare no competing interests. Epub 2024/04/18. eng.