Clinical and genomic features of SPOP ‐mutant prostate cancer
Autor: | Pedro Isaacsson Velho, Mike Fang, Mari Nakazawa, Tamara L. Lotan, Catherine Handy Marshall, Emmanuel S. Antonarakis |
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Rok vydání: | 2021 |
Předmět: |
Male
Urology Mutation Missense SPOP Article Androgen deprivation therapy chemistry.chemical_compound Prostate cancer Transcriptional Regulator ERG Androgen Receptor Antagonists medicine Humans Enzalutamide PTEN Wnt Signaling Pathway CHEK2 biology business.industry Serine Endopeptidases Wnt signaling pathway High-Throughput Nucleotide Sequencing Nuclear Proteins Prostatic Neoplasms Middle Aged medicine.disease Progression-Free Survival Repressor Proteins Treatment Outcome Oncology chemistry PARP inhibitor Disease Progression Cancer research biology.protein Gene Fusion business |
Zdroj: | Prostate |
ISSN: | 1097-0045 0270-4137 |
DOI: | 10.1002/pros.24269 |
Popis: | 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. |
Databáze: | OpenAIRE |
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