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Journal Title: DNA sequencing and gene-expression profiling assists in making a tissue of origin diagnosis in cancer of unknown primary
Authors: Posner, A.
Prall, Owen W. J.
Sivakumaran, Tharani
Etemadamoghadam, D.
Thio, N.
Pattison, A.
Balachander, S.
Fisher, K.
Webb, S.
Wood, Colin
DeFazio, A.
Wilcken, Nicholas
Gao, Bo
Karapetis, Chris S.
Singh, Madhu
Collins, Ian M.
Richardson, Gary
Steer, Christopher
Warren, Mark
Karanth, Narayan
Wright, G.
Williams, S.
George, J.
Hicks, R. J.
Boussioutas, A.
Gill, A. J.
Solomon, B. J.
Xu, H.
Fellowes, A.
Fox, S. B.
Schofield, Penelope
Bowtell, D.
Mileshkin, Linda
Tothill, Richard W.
SWH Author: Collins, Ian M.
Keywords: Adult
Cancer Patient
Cancer Survival
Cohort Analysis
Controlled Study
Diagnostic Value
DNA Sequencing
Gene Expression
Gene Mutation
Gene Sequence
Genetic Transcription
High Throughput Sequencing
Human Tissue
Kidney Cancer
Major Clinical Study
Molecularly Targeted Therapy
Overall Survival
Protein Expression
Protein Fingerprinting
Retrospective Study
RNA Fingerprinting
Somatic Mutation
Survival Analysis
Tumor Gene
Tumor Virus
Virus Detection
Unclassified Drug
Issue Date: Jun-2022
Date Accessioned: 2023-04-12T02:09:37Z
Date Available: 2023-04-12T02:09:37Z
Description Affiliation: L. Mileshkin, 305 Grattan St, Melbourne, VIC 3000, Australia. E-mail:, R.W. Tothill, 305 Grattan St, Melbourne, VIC 3000, Australia. E-mail:
Database: Embase Preprint
Date: 2022
Abstract: Cancer 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.
Journal Title: medRxiv
Type: Journal Article
Appears in Collections:SWH Staff Publications

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