Opposing Roles of SPOP Mutations in Human Prostate and Endometrial Cancers

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Recurrent gene mutations in speckle-type POZ protein (SPOP), a key component of the E3 ubiquitin ligase, are linked to tumor progression in prostate and endometrial cancers.
• Understanding the specific roles of SPOP mutations in these distinct cancer types is crucial for developing targeted treatments.

Purpose of the Study:

• To characterize SPOP mutations in prostate and endometrial cancers.
• To explore the association of SPOP mutations with molecular, immune, and clinical features.
• To investigate the impact of SPOP mutations on patient outcomes.

Main Methods:

• Analysis of clinical and molecular profiles from 7,398 prostate and 19,188 endometrial cancer samples.
• Kaplan-Meier survival analysis for overall survival (OS).
• Statistical significance determined using chi-square and Mann-Whitney U tests with adjustments for multiple comparisons.

Main Results:

• SPOP mutations were found in 9.2% of prostate and 4.3% of endometrial cancers, with distinct mutation clustering.
• SPOP mutations were associated with opposing immune microenvironment signatures and differential comutation profiles in each cancer type.
• SPOP-mutant prostate cancer showed increased androgen receptor activity and improved OS with hormonal therapy, while SPOP-mutant endometrial cancer had lower hormone receptor expression and OS varied by mutation type and histology.

Conclusions:

• SPOP mutations induce divergent molecular and immune landscapes in prostate and endometrial cancers, suggesting loss-of-function in prostate cancer and gain-of-function in endometrial cancer.
• These findings provide a strong rationale for developing tailored therapeutic strategies based on SPOP mutation status and cancer type.