Abstract Untreated prostate tumors depend on androgen receptor (AR) for growth and thus are treated with hormonal therapy. However, resistance almost always emerges as tumors evolve into a castration-resistant state. The evolution of resistance can follow different paths, and castration-resistant prostate cancer (CRPC) exhibits multiple epigenomic subtypes: androgen receptor-dependent CRPC-AR, and lineage plastic subtypes CRPC-SCL (stem cell-like), CRPC-WNT (Wnt-dependent), and CRPC-NE (neuroendocrine). By transcriptomic profiling of tissue, and whole-genome sequencing (WGS) of tissue and cell-free DNA (cfDNA) from 500 patient samples, we relate genomic variants with epigenomic state. We annotate fractional contribution of each subtype for all patient samples using deconvolution approaches with a set of signature genes and accessible chromatin sites. We confirm that AR amplifications at the genomic level are associated with the emergence of CRPC-AR, and RB1 biallelic loss is associated with CRPC-NE. Importantly, we find chromosomal rearrangements in the YAP/TAZ pathway are associated with the presence of CRPC-SCL. In particular, we find complex rearrangements on chromosome 4, which are supported by patient-matched Hi-C data, and decrease promoter interactions of MOB1B, a YAP/TAZ pathway inhibitor, with its enhancers. Together, the genomic variants in the pathway can predict CRPC-SCL with 79% accuracy. By computing cancer cell fraction (CCF) of the genomic events, we find high concordance between the CCF of genomic events and the fraction of their associated epigenomic subtype. Thus, higher CCF of chr 4 rearrangements corresponds to higher tumor fraction of CRPC-SCL. Our study shows how genomic events enable transition to different CRPC states that exhibit differential therapeutic susceptibilities. Citation Format: Marjorie Roskes, Alexander Martinez-Fundichely, Sandra Cohen, Metin Balaban, Chen Khuan. Wong, Weiling Li, Tonatiuh A. Gonzalez, Anisha B. Tehim, Hao Xu, Shahd ElNaggar, Matthew Myers, Andrea Sboner, Benjamin J. Raphael, Yu Chen, Ekta Khurana. Chromosomal rearrangements at the YAP/TAZ pathway genes are associated with heterogeneity and stem cell-like castration-resistant prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85 (23Suppl): Abstract nr B013.
Roskes et al. (2025) studied this question.
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