Repertoire and clinical hierarchy of AR locus alterations in castration-resistant prostate cancer

作者：Tuomo Virtanen, Edmond M. Kwan, Kinnari Parekh, Jack V. W. Bacon, Chia-Chi Flora Huang, Ivan Pak Lok Yu, Lauri Ryyppö, C. Bernales, Gráinne Donnellan, Constantine S. Tam, Joonatan Sipola, Jussi Nikkola, Gillian Vandekerkhove, Sofie H. Tolmeijer, Konsta Kukkonen, Adelia, Bernhard J. Eigl, Daygen L. Finch, R Gagnon, Y Takieldeen, E Hardy, Daniel Khalaf, Christian Kollmannsberger, Jean‐Michel Lavoie, Corinne Maurice‐Dror, S. Miller, Lucia Nappi, Krista Noonan, Sunil Parimi, Anna Riminchan, E Sartori-Mueller, Mohammad Soleimani, Joanna Vergidis, Muhammad Zulfiqar, Aaron R. Hansen, Sebastién J. Hotte, Mariam Jafri, Michael Kolinsky, Som D. Mukherjee, Michael Ong, April A. N. Rose, Wei Tu, E. Winquist, Andries M. Bergman, Kim van der Zande, Wilbert Zwart, Niven Mehra, Nielka P. van Erp, Jimmy L. Zhao, D. Rathkopf, Christopher E. Barbieri, David A. Quigley, Matti Nykter, Nathan A. Lack, K.N. Chi, Matti Annala, Alexander W. Wyatt · 发表于：Annals of Oncology · 年份：2025 · DOI：10.1016/j.annonc.2025.10.1236 · 被引用次数：2 · 研究领域：Prostate Cancer Treatment and Research、Prostate Cancer Diagnosis and Treatment、Radiopharmaceutical Chemistry and Applications

BACKGROUND: Somatic alterations to the androgen receptor (AR) gene are pivotal drivers of treatment resistance in metastatic castration-resistant prostate cancer (mCRPC), but their prevalence, clinical impact, and etiology remain incompletely understood. PATIENTS AND METHODS: We assembled a meta-cohort of 3048 plasma cell-free DNA and matched leukocyte DNA samples from 1751 mCRPC patients, accrued from eight clinical trials and a regional biobank. Samples were sequenced with successive generations of a custom targeted hybridization capture panel with extensive coverage of the AR locus and 71 prostate cancer genes, enabling comprehensive characterization of AR genotypes including enhancer and gene copy number amplification, and mutations or structural rearrangements. RESULTS: Somatic AR alterations, detected in 84% of mCRPC, were shaped by underlying genomics, including TP53 and DNA repair defects. Wnt-mutant tumors showed unique AR amplification structures characterized by preferential incorporation of an alternative downstream enhancer and low copy number. AR mutations were present in 19.7% of mCRPC, often subclonal, and enriched in tumors with AR enhancer-only gain. We establish a functional hierarchy of AR genotypes based on treatment responses and identify a specific class of AR rearrangements truncating the ligand-binding domain within intron 4 or exon 4 (ALTR4) that are under robust positive selection and strongly impact AR pathway inhibitor outcomes, distinct from othe...