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

• Type of Material: Article
• Authors: Carlos S Moreno, Emory University; Cynthia Leigh Winham, Emory University; Mehrdad Alemozaffar, Emory University; Emma R. Klein, Emory University; Ismaheel Opeyemi Lawal, Emory University; Olayinka Abiodun Ojo, Emory University; Datta Patil, Emory University; Benjamin Barwick, Emory University; Yijian Huang, Emory University; David Michael Schuster, Emory University; Martin Sanda, Emory University; Adeboye O. Osunkoya, Emory University
• Language: English
• Date: 2023-11-30
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.3390/cancers15235671
• Title of Journal or Parent Work: Cancers (Basel)
• Volume: 15
• Issue: 23
• Start Page: 5671
• Grant/Funding Information: This work was supported by NIH grants R21-CA256375 and U01-CA113913. Research reported in this publication was supported in part by the Emory University Integrated Genomics Core (EIGC) of the Winship Cancer Institute of Emory University and NIH/NCI under award number, 2P30CA138292-04.
• Keywords: prostate cancer; metastasis; tumor heterogeneity; cancer genomics
• Research Categories: Biology, Genetics; Health Sciences, Oncology; Biology, Molecular

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 3929 primary tumors and 2721 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 found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.