Figure 3 from The Germline and Somatic Origins of...

Figure 3 from The Germline and Somatic Origins of Prostate Cancer Heterogeneity

Abstract

Functional characterization of driver mutations. A, Network diagrams represent multimodal pathway enrichment analysis of driver genes. Mutation types (i.e., the type of driver analysis) are indicated by shading of circles. Circle size represents the number of patients. Heatmaps show mutations in the cohort that affect genes contributing to two exemplar pathways dysregulated by multiple mutation types. The apoptosis pathway (GO:0042771 – intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator), was identified to be significant only in the context of integrating statistical significance from all GR, and SNV, and indel driver analyses in coding and regulatory elements. The embryonic development pathway (GO:0043009 chordate embryonic development) was identified to be independently significant using SNVs and indels in regulatory elements, in coding elements, and in the Armenia and colleagues (<a href="#bib14" target="_blank">14</a>) dataset. Bottom covariates on the heatmaps show CNAs in pathway genes identified in driver CNA peaks (analyzed using GISTIC2). B, Associations between driver events and SBS signatures. Dot size and dot colors indicate median difference of signature activity. Background shading shows Q values from the Wilcoxon rank-sum test with FDR adjustment. Drivers and SBSs were ordered using hierarchical clustering. C, A summary of associations between driver events and mRNA abundance of driver genes. Dot size and colors indicate median difference of mRNA abundance. Background shading shows Q values from the Wilcoxon rank-sum test with FDR adjustment. D, Consensus clustering of 3,318 dysregulated mRNAs associated with driver mutations. Colors in the heatmap indicate median difference of mRNA abundance between patients with and without a specific driver mutation. Driver mutation type is on the left using colors from A. The right barplot shows the number of transcripts significantly associated with each driver mutation. E, Pathway enrichment analysis on the four mRNA subtypes from D. Clusters of biologically similar pathways are labeled and outlined for each subtype. The size of the pathway is indicative of the number of enriched genes. For (B and C) CNA drivers in patients with subclonal PGA >80% were excluded, and only driver events significantly associated with either SBS signatures or mRNA abundances are shown. (A, Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.)

Authors

Yamaguchi TN; Houlahan KE; Zhu H; Kurganovs N; Livingstone J; Fox NS; Yuan J; Sietsma Penington J; Jung C-H; Schwarz T

Publication Date

May 2, 2025

DOI

10.1158/2159-8290.28918327

Associated Experts

Katie Houlahan

Assistant Professor, Faculty of Health Sciences

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