Opposing Roles of <i>SPOP</i> Mutations in Human Prostate and Endometrial Cancers.

Abstract

Recurrent gene mutations in speckle-type POZ protein (<i>SPOP</i>), the substrate-binding component of E3 ubiquitin ligase, are associated with tumor progression in prostate and endometrial cancers. Here, we characterized <i>SPOP</i> mutations in these cancers and explored their association with molecular and immune signatures and patient outcomes. There were 7,398 prostate cancer and 19,188 endometrial cancer samples analyzed for clinical and molecular profiles at Caris Life Sciences. Overall survival (OS) was analyzed using Kaplan-Meier survival curves. Statistical significance was determined using chi-square and Mann-Whitney U tests, with <i>P</i> values adjusted for multiple comparisons. <i>SPOP</i> mutations were identified in 9.2% of prostate and 4.3% of endometrial cancers. Mutations clustered in the <i>SPOP</i> meprin and TRAF-C homology domain, with no significant overlap between cancer types. <i>SPOP</i> mutation was associated with differential comutation profiles and opposing tumor immune microenvironment signatures for each cancer, with greater immune infiltration in <i>SPOP</i>-mutated endometrial cancer. <i>SPOP</i>-mutated prostate and endometrial cancers displayed altered epigenetic gene expression, including opposite regulation of <i>BRD2</i> transcripts. In <i>SPOP</i>-mutant prostate cancer, higher expression of androgen receptor-regulated transcripts and improved OS after treatment with hormonal agents were observed. In endometrial cancer, hormone receptor expression was significantly lower in <i>SPOP</i>-mutated tumors and differences in OS were highly dependent on the particular hotspot mutation and histologic subtype. These data indicate that <i>SPOP</i> mutations drive opposing molecular and immune landscapes in prostate and endometrial cancers-suggesting a loss-of-function mechanism in prostate cancer and gain-of-function mechanism in endometrial cancer-and provide a rationale for tailored therapeutic approaches.