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dc.contributor.authorPosner, A.-
dc.contributor.authorPrall, Owen W. J.-
dc.contributor.authorSivakumaran, Tharani-
dc.contributor.authorEtemadamoghadam, D.-
dc.contributor.authorThio, N.-
dc.contributor.authorPattison, A.-
dc.contributor.authorBalachander, S.-
dc.contributor.authorFisher, K.-
dc.contributor.authorWebb, S.-
dc.contributor.authorWood, Colin-
dc.contributor.authorDeFazio, A.-
dc.contributor.authorWilcken, Nicholas-
dc.contributor.authorGao, Bo-
dc.contributor.authorKarapetis, Chris S.-
dc.contributor.authorSingh, Madhu-
dc.contributor.authorCollins, Ian M.-
dc.contributor.authorRichardson, Gary-
dc.contributor.authorSteer, Christopher-
dc.contributor.authorWarren, Mark-
dc.contributor.authorKaranth, Narayan-
dc.contributor.authorWright, G.-
dc.contributor.authorWilliams, S.-
dc.contributor.authorGeorge, J.-
dc.contributor.authorHicks, R. J.-
dc.contributor.authorBoussioutas, A.-
dc.contributor.authorGill, A. J.-
dc.contributor.authorSolomon, B. J.-
dc.contributor.authorXu, H.-
dc.contributor.authorFellowes, A.-
dc.contributor.authorFox, S. B.-
dc.contributor.authorSchofield, Penelope-
dc.contributor.authorBowtell, D.-
dc.contributor.authorMileshkin, Linda-
dc.contributor.authorTothill, Richard W.-
dc.description.abstractCancer of unknown primary (CUP) constitutes a group of metastatic cancers in which standardized clinical investigations fail to identify a tissue of origin (TOO). Gene-expression profiling (GEP) has been used to resolve TOO, and DNA sequencing to identify potential targeted treatments; however, these methods have not been widely applied together in CUP patients. To assess the diagnostic utility of DNA and RNA tests for TOO classification, we applied GEP classification and/or gene-panel DNA sequencing in 215 CUP patients. Based on a retrospective review of pathology reports and clinical data, 77% of the cohort were deemed True-CUPs (T-CUP). Among the remaining cases, a latent primary diagnosis (10%) (LP-CUP) or TOO was highly suspected based on combined clinicopathological data (13%) (histology-resolved CUP, HR-CUP). High-medium confidence GEP classifications were made for 80% of LP/HR-CUPs, and these classifications were consistent with a pathologist-assigned diagnosis in 94% of cases, while only 56% of T-CUPs had high-medium confidence predictions. The frequency of somatic mutations in cancer genes was similar to 2,785 CUPs from AACR GENIE Project. DNA features, GEP classification, and oncovirus detection assisted making a TOO diagnosis in 37% of T-CUPs. Gene mutations and mutational signatures of diagnostic utility were found in 31% T-CUPs. GEP classification was useful in 13% of cases and viral detection in 4%. Among resolved T-CUPs, lung and biliary were the most frequently identified cancer types, while kidney cancer represented another minor subset. Multivariate survival analysis showed that unresolved T-CUPs had poorer overall survival than LP/HR-CUPs (Hazard ratio=1.9, 95% CI 1.1 - 3.2, p=0.016), while the risk of death was similar in genomically-resolved T-CUPs and LP/HR-CUPs. In conclusion, combining DNA and RNA profiling with clinicopathological data supported a putative TOO diagnosis in over a third of T-CUPs. DNA sequencing benefited T-CUP tumors with atypical transcriptional patterns that hindered reliable GEP classification.Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.-
dc.subjectCancer Patient-
dc.subjectCancer Survival-
dc.subjectCohort Analysis-
dc.subjectControlled Study-
dc.subjectDiagnostic Value-
dc.subjectDNA Sequencing-
dc.subjectGene Expression-
dc.subjectGene Mutation-
dc.subjectGene Sequence-
dc.subjectGenetic Transcription-
dc.subjectHigh Throughput Sequencing-
dc.subjectHuman Tissue-
dc.subjectKidney Cancer-
dc.subjectMajor Clinical Study-
dc.subjectMolecularly Targeted Therapy-
dc.subjectOverall Survival-
dc.subjectProtein Expression-
dc.subjectProtein Fingerprinting-
dc.subjectRetrospective Study-
dc.subjectRNA Fingerprinting-
dc.subjectSomatic Mutation-
dc.subjectSurvival Analysis-
dc.subjectTumor Gene-
dc.subjectTumor Virus-
dc.subjectVirus Detection-
dc.subjectUnclassified Drug-
dc.titleDNA sequencing and gene-expression profiling assists in making a tissue of origin diagnosis in cancer of unknown primary-
dc.typeJournal Article-
dc.description.affiliationL. Mileshkin, 305 Grattan St, Melbourne, VIC 3000, Australia. E-mail:, R.W. Tothill, 305 Grattan St, Melbourne, VIC 3000, Australia. E-mail:
dc.identifier.databaseEmbase Preprint-
dc.contributor.swhauthorCollins, Ian M.-
Appears in Collections:SWH Staff Publications

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