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Genomic and transcriptomic analyses show CUP tumors enriched for immune-related genes and pathways, with uniformly elevated tumor-infiltrating leukocytes and circulating T cells. The CUP genetic landscape resembles other metastatic cancers but supports a distinct immunophenotype.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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of unknown primary: A comparative analysis with other  \nmetastatic cancers  \nLaura Andersen 1,2,3 , Ditte S. Christensen 1,2,4, Asbjørn Kjær 1,2,3 , Michael Knudsen 1,2, Andreas K. Andersen4, Maria B. Laursen 1,2, Johanne Ahrenfeldt 1,2,3 , Britt E. Laursen 1,2,4  and Nicolai J. Birkbak 1,2,3   \n1 Department of Molecular Medicine, Aarhus University Hospital, Denmark  \n2 Department of Clinical Medicine, Aarhus University, Denmark  \n3 Bioinformatics Research Center, Aarhus University, Denmark  \n4 Department of Oncology, Aarhus University Hospital, Denmark  \nKeywords  \ncancer of unknown primary; genomic profile; immune response to cancer; transcriptomic profile  \nCorrespondence  \nN. J. Birkbak and B. E. Laursen, Science Center Skejby, Brendstrupgrdsvej 21A, 8200 Aarhus N, Denmark  \nTel: +45 7845 5347, +45 2539 4779 (NJB)  \nE-mail: [nbirkbak@clin.au.dk](nbirkbak@clin.au.dk) (NJB); E-mail: [britt@clin.au.dk](britt@clin.au.dk) (BEL)  \nLaura Andersen and Ditte S. Christensen contributed equally to this article  \n(Received 15 December 2023, revised 1 March 2024, accepted 3 May 2024, available online 15 May 2024)  \ndoi:10 . 1002/1878-0261 .13664  \nCancer of unknown primary (CUP) tumors are biologically very heterogeneous, which complicates stratification of patients for treatment. Consequently, these patients face limited treatment options and a poor prognosis. With this study, we aim to expand on the current knowledge of CUP biology by analyzing two cohorts: a well-characterized cohort of 44 CUP patients, and 213 metastatic patients with known primary. These cohorts were treated at the same institution and characterized by identical molecular assessments. Through comparative analysis of genomic and transcriptomic data, we found that CUP tumors were characterized by high expression of immune-related genes and pathways compared to other metastatic tumors. Moreover, CUP tumors uniformly demonstrated high levels of tumor-infiltrating leukocytes and circulating T cells, indicating a strong immune response. Finally, the genetic landscape of CUP tumors resembled that of other metastatic cancers and demonstrated mutations in established cancer genes. In conclusion, CUP tumors possess a distinct immunophenotype that distinguishes them from other metastatic cancers. These results may suggest an immune response in CUP that facilitates metastatic tumor growth while limiting growth of the primary tumor.  \n1. Introduction  \nCancer of unknown primary (CUP) is a type of metastatic cancer characterized by the absence of a detectable primary tumor, making up 3–5% of all cancer cases worldwide. CUP is diagnosed based on an extensive and  \nunsuccessful search for a primary tumor with standard diagnostic procedures as recently outlined by the European Society for Medical Oncology (ESMO) [1] . Due to the biological and phenotypic heterogeneity of the  \nAbbreviations  \nAUH, Aarhus University Hospital; CI, confidence interval; CIN, chromosomal instability; COSMIC, catalog of somatic mutations in cancer; CPI, check-point inhibitors; CUP, cancer of unknown primary; ESMO, European Society for Medical Oncology; FDR, false discovery rate; GSVA, gene set variation analysis; MSI, microsatellite instability; MSigDB, molecular signature database; OPRA, oncology precision medicine Aarhus; RNAseq, RNA sequencing; SBS, single base substitutions; SCNA, somatic copy number alterations; SD, standard deviation; SNV, single nucleotide variant; TCRA, T cell receptor alpha; TIL, tumor-infiltrating leukocyte; TMB, tumor mutation burden; TPM, transcript per million; TSG, tumor suppressor gene; WES, whole exome sequencing; wGII, weighted genome integrity index.  \nMolecular Oncology 18 (2024) 2393–2406 ª 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.  \nThis is an open access article under the terms of the Creative Commons Attribution License, which permits use,","cbCairJiPdshO9zo","https://ap.wps.com/l/cbCairJiPdshO9zo","pdf",3259609,14,"English","# Introduction\n## Cancer of unknown primary: diagnosis and treatment limitations\n## Study rationale: molecular modeling and metastatic progression","[{\"question\":\"Why is cancer of unknown primary (CUP) difficult to treat?\",\"answer\":\"CUP tumors are biologically heterogeneous and lack a detectable primary tumor, which complicates patient stratification and leaves limited treatment options, resulting in poor prognosis.\"},{\"question\":\"How does this study compare CUP tumors with other metastatic cancers?\",\"answer\":\"It analyzes two cohorts—44 well-characterized CUP patients and 213 metastatic patients with known primary—processed with identical molecular assessments at the same institution.\"},{\"question\":\"What molecular features distinguish CUP tumors from other metastatic tumors?\",\"answer\":\"CUP tumors show higher expression of immune-related genes and pathways and demonstrate uniformly elevated tumor-infiltrating leukocytes and circulating T cells, indicating a strong immune response.\"}]","Exploring the molecular landscape of cancer of unknown primary - A comparative analysis with other metastatic cancers | PDF",1790004510,35]