Clinical and genomic features of SPOP-mutant prostate cancer

Mari Nakazawa, Mike Fang, Catherine H. Marshall, Tamara L. Lotan, Pedro Isaacsson Velho, Emmanuel S. Antonarakis

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Inactivating missense mutations in the SPOP gene, encoding speckle-type poxvirus and zinc-finger protein, are one of the most common genetic alterations in prostate cancer. Methods: We retrospectively identified 72 consecutive prostate cancer patients with somatic SPOP mutations, through next-generation sequencing analysis, who were treated at the Johns Hopkins Hospital. We evaluated clinical and genomic characteristics of this SPOP-mutant subset. Results: SPOP alterations were clustered in the MATH domain, with hotspot mutations involving the F133 and F102 residues. The most frequent concurrent genetic alterations were in APC (16/72 [22%]), PTEN (13/72 [18%]), and TP53 (11/72 [15%]). SPOP-mutant cancers appeared to be mutually exclusive with tumors harboring the TMPRSS2-ERG fusion, and were significantly enriched for Wnt pathway (APC, CTNNB1) mutations and de-enriched for TP53/PTEN/RB1 alterations. Patients with mtSPOP had durable responses to androgen deprivation therapy (ADT) with a median time-to-castration-resistance of 42.0 (95% confidence interval [CI], 25.7–60.8) months. However, time-to-castration-resistance was significantly shorter in SPOP-mutant patients with concurrent TP53 mutations (hazard ratio [HR] 4.53; p = 0.002), HRD pathway (ATM, BRCA1/2, and CHEK2) mutations (HR 3.19; p = 0.003), and PI3K pathway (PTEN, PIK3CA, and AKT1) alterations (HR 2.69; p = 0.004). In the castration-resistant prostate cancer setting, median progression-free survival was 8.9 (95% CI, 6.7–NR) months on abiraterone and 7.3 (95% CI, 3.2–NR) months on enzalutamide. There were no responses to PARP inhibitor treatment. Conclusions: SPOP-mutant prostate cancers represent a unique subset with absent ERG fusions and frequent Wnt pathway alterations, with potentially greater dependency on androgen signaling and enhanced responsiveness to ADT. Outcomes are best for SPOP-altered patients without other concurrent mutations.

Original languageEnglish (US)
Pages (from-to)260-268
Number of pages9
JournalProstate
Volume82
Issue number2
DOIs
StateAccepted/In press - 2021

Bibliographical note

Funding Information:
E. S. Antonarakis is partially supported by National Institutes of Health Cancer Center Support Grant P30 CA006973, and by Department of Defense grant W81XWH‐17‐2‐0027 and W81XWH‐18‐2‐0015.

Publisher Copyright:
© 2021 Wiley Periodicals LLC

Keywords

  • RNA sequencing
  • SPOP
  • predictive biomarkers
  • somatic mutations

PubMed: MeSH publication types

  • Journal Article

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