Evidence map›Paper›PMID 41987223›Full record

ArticleGenome biology2026

Convergent evolution of complex structural variants drives therapy resistance in metastatic prostate cancer.

Thaidy Moreno-Rodriguez, Meng Zhang, Arian Lundberg, Raunak Shrestha, Martin Sjöström, Anupama Pasam, Joanna Chan, Lisa Devereux, Adam Foye, Xiaolin Zhu and 13 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors.

Thaidy Moreno-RodriguezDepartment of Urology, UCSF, San Francisco, CA, USA.
Meng ZhangDepartment of Radiation Oncology, UCSF, San Francisco, CA, USA.
Arian LundbergDepartment of Radiation Oncology, UCSF, San Francisco, CA, USA.
Raunak ShresthaDepartment of Radiation Oncology, UCSF, San Francisco, CA, USA.
Martin SjöströmDepartment of Radiation Oncology, UCSF, San Francisco, CA, USA.
Anupama PasamPeter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Joanna ChanPeter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Lisa DevereuxDepartment of Oncology, Sir Peter MacCallum, University of Melbourne, Melbourne, VIC, Australia.
Adam FoyeDivision of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
Xiaolin ZhuDivision of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
Alana S WeinsteinDepartment of Radiation Oncology, UCSF, San Francisco, CA, USA.
Anna S TrigosPeter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Alexander W WyattDepartment of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
Joshi J AlumkalDepartment of Internal Medicine, Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
Eric J SmallDivision of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
Rahul AggarwalDivision of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA.
Scott M DehmMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Matthew L BootsmaDepartment of Human Oncology, University of Wisconsin, Madison, WI, USA.
Shuang G ZhaoDepartment of Human Oncology, University of Wisconsin, Madison, WI, USA.
Mathieu LupienPrincess Margaret Cancer Centre, Toronto, ON, Canada.
Felix Y FengDepartment of Urology, UCSF, San Francisco, CA, USA.
Shahneen Sandhu *Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
David A Quigley *Department of Urology, UCSF, San Francisco, CA, USA. david.quigley@ucsf.edu.

Funding

UCSF Specialized Programs of Research Excellence (SPOREs) in Prostate CancerP50CA275741 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI PETER R CARROLL · 2024 to 2026
$8.8M
NCI NIH HHS P50 CA275741NIH/NCI 1R01CA230516-01U.S. Department of Defense W81XWH1910682
6 · The paper itself

Abstract

backgroundTargeted therapy prolongs the lives of men with metastatic castration-resistant prostate cancer (mCRPC) but mCRPC is ultimately lethal. DNA copy gains that amplify the Androgen Receptor (AR) gene locus are a key driver of resistance to targeted therapy in mCRPC. Our group has recently shown that extra-chromosomal DNA (ecDNA) frequently drives this amplification. We hypothesized that ecDNA and other complex structural variants (cSVs) also affect other established drivers of therapy resistance in mCRPC and continue to evolve over time. To test this hypothesis, we reconstructed cSV profiles in 193 mCRPC tumors using whole genome and transcriptome sequencing, with matched Hi-C data for 77 tumors.

resultsWe identify ecDNA in more than half of mCRPC biopsies and show it frequently amplifies driver genes such as AR and MYC and their non-coding enhancers. The presence of ecDNA is significantly associated with whole genome doubling, chromothripsis, and inactivating TP53 alterations. Deep sequencing analysis of 53 rapid autopsy samples shows cSVs amplifying AR can arise independently within distinct tumors in a single patient. Phylogenetic analysis of tumor evolution implicates this cSV as an early event during metastatic spread. Additionally, a paired analysis of mCRPC samples as patients developed resistance to AR pathway inhibitor (ARPI) therapy demonstrates cSVs evolve in response to ARPI and can be detected in both tumor tissue and circulating tumor DNA.

conclusionsWe conclude that cSVs, particularly ecDNA, are a pervasive contributor to intra-patient heterogeneity in late-stage mCRPC and a key driver of targeted therapy resistance.

Indexed as

Drug Resistance, NeoplasmEvolution, MolecularGenomic Structural VariationProstatic Neoplasms, Castration-ResistantHumansMaleNeoplasm MetastasisReceptors, AndrogenReceptors, Androgen

Identifiers

PMID41987223
PMCPMC13191960

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.