Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis

Carlos S. Moreno
* ORCID logo ,
Cynthia L. Winham
,
Mehrdad Alemozaffar
,
Emma R. Klein
,
Ismaheel O. Lawal
,
Olayinka A. Abiodun-Ojo
,
Dattatraya Patil
,
Benjamin G. Barwick
ORCID logo ,
Yijian Huang
,
David M. Schuster
,
Martin G. Sanda
,
Osunkoya O. Adeboye
Version 1 : Received: 24 October 2023 / Approved: 25 October 2023 / Online: 25 October 2023 (05:15:54 CEST)

A peer-reviewed article of this Preprint also exists.

Moreno, C.S.; Winham, C.L.; Alemozaffar, M.; Klein, E.R.; Lawal, I.O.; Abiodun-Ojo, O.A.; Patil, D.; Barwick, B.G.; Huang, Y.; Schuster, D.M.; Sanda, M.G.; Osunkoya, A.O. Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis. Cancers 2023, 15, 5671. Moreno, C.S.; Winham, C.L.; Alemozaffar, M.; Klein, E.R.; Lawal, I.O.; Abiodun-Ojo, O.A.; Patil, D.; Barwick, B.G.; Huang, Y.; Schuster, D.M.; Sanda, M.G.; Osunkoya, A.O. Integrated Genomic Analysis of Primary Prostate Tumor Foci and Corresponding Lymph Node Metastases Identifies Mutations and Pathways Associated with Metastasis. Cancers 2023, 15, 5671.

Abstract

Prostate cancer is a highly heterogeneous disease, and mortality is mainly due to metastases, but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3,929 primary tumors and 2,721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and find that mutations in EYA1 and CSMD3 are associated with poor outcome in prostate cancer.

Keywords

Cancer Genomics; Metastasis; Prostate Cancer; Tumor Heterogeneity

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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