Introduction:

SPOP encodes the speckle-type POZ protein that may act as a tumor suppressor by promoting the degradation of DAXX, SRC3, and Hedgehog effectors GLI2 and GLI3. Recent evidence suggests that SPOP mutation (SPOPmut) in clinically advanced prostate cancer (CAPC) may be associated with prolonged response to novel hormonal therapies compared to SPOP wild type (SPOPwt) CAPC.

Methods:

12,254 CAPC cases underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3) with TPS 1-49% = low expression and TPS > 50% = high expression.

Results:

1,030 (8.4%) of CAPC were SPOPmut. All SPOPmut were short variant base substitutions with F113L (23.8%), F133V (15.9%), F102C (11.2%) and F102V (6.9%) being the most frequent GA. Compared to SPOPwt CAPC, SPOPmut CAPC featured minimal TMPRSS2-ERG fusions (2.3% v 35.8%;p<.0001) and had lower AR amplification (12.0% v 7.2%;p=.0001). SPOPmut CAPC had lower frequencies of GA in cell cycle regulatory genes (CDK12, CCND1, TP53 and RB1), MTOR pathway GA (PTEN 16.5% v 33.6%;p<.0001) and DDR genes including BRCA2 (6.5% v 9.6%;p=.0013). APC GA were more frequent in SPOPmut CAPC (26.8% v 7.4%;p<.0001). In contrast, biomarkers associated with immune-oncology (IO) drug response were more frequent in SPOPmut including MSI high status (4.04% v 2.63%;p=.012), TMB > 10 mut/.Mb (7.30% v 4.68%;p=.003), TMB > 20 mut/Mb (4.27% v 2.90%;p=.017), PD-L1 low expression (33.3% v 9.9%;p<.0001) and high expression (8.33% v 0.8%;p<.0001).

Conclusion:

SPOP mutation occurs in a moderate number of CAPC cases and is associated with lower TMPRSS2:ERG fusions, AR amplifications, cell cycle GA and MTOR pathway GA and higher frequencies of IO drug efficacy biomarkers including MSI, TMB and PD-L1 status. Further consideration of SPOP status in CAPC especially for planning hormonal and IO drug treatments appears warranted.

Funding: N/A