Abstract 937: Opposing roles of SPOP mutations in human prostate and endometrial cancers
Authors: Cavalcante Ludimila , Desmukh Sachin K. , Carneiro Benedito A. , Angara Kartik , Mattox Tyler E. , Wu Sharon , Xiu Joanne , Walker Philip , Oberley Matthew , Nabhan Chadi , Antonarakis Emmanuel S. 
Published: April 2023

Abstract
Recurrent mutations in the gene encoding the Speckle Type POZ Protein, SPOP, the substrate-binding components of E3-ubiquitin ligase, have been identified as common alterations in prostate cancer (PCa) and endometrial cancer (EC). SPOP mutations are associated with PCa and EC growth and progression. Here, we characterized SPOP mutations in PCa and EC, and their association with molecular and immune signatures. 7,398 PCa and 19,188 EC samples were analyzed by next-generation sequencing (592, NextSeq; WES, NovaSeq), (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Real world overall survival (rwOS) was extracted from insurance claims and depicted using Kaplan-Meier survival curves for molecularly defined cohorts from tissue collection to last contact. Statistical significance was determined using chi-square and Mann-Whitney U tests, with p-values adjusted for multiple comparisons (q&lt;0.05). SPOP mutations were identified in 601 (8.1%) and 655 (3.4%) samples of PCa and EC, respectively. Mutations clustered in the SPOP MATH domain with hotspots at residues F133L (21.4%), F102C (11%), F133V (10.4%), F102V (7%) in PCa, and residues M117V (21.8%), R121Q (10.6 %), E47K (9%), E50K (8.5%) in EC. Importantly, no overlap of hotspot residues was noted in PCa and EC. SPOP-mutated PCa had higher frequency of APC (21.4% vs 5.8%) and BCOR (1.95% vs 0.2%) lesions, but SPOP-mutated EC had higher frequency of U2AF1 (4.28% vs 1.0%), POLE (5.24% vs 2.0%) and CASP8 (4.17% vs 1.79%) lesions (all q &lt;0.05) compared to non-mutant SPOP. Analysis of epigenetic markers showed lower BRD2 (245.4 vs 312 TPM) transcripts in SPOP-mutated PCa, but higher BRD2 (227.0 vs 200.6) (all q &lt;0.05) in SPOP-mutated EC, compared to non-mutant SPOP, the former diverging from earlier published data in PCa. Analysis of inferred immune cell infiltrates showed that in SPOP-mutated PCa, M1-MΦ (36.8% vs 48.1%), CD8 T cell (20.2% vs 30.4%) and DC (53.3% vs 79.4%) are decreased and M2-MΦ (100% vs 99.9%) are increased; while in SPOP-mutated EC, M1-MΦ (87.2% vs 83.3 %), CD8 T cells (56.8% vs 49.7%) and DC (94.9% vs 93.3%) are increased and M2-MΦ (98.8% vs 98.9%) are decreased (all q &lt;0.05). In PCa, higher AR expression was found in SPOP-mutated vs non-mutated tumors (98.5% vs 97.3%, p=0.09), with improved OS outcomes after hormone targeting agents leuprolide (2125 vs 1803 days; HR: 0.71, 95% CI (0.51-0.99), p=0.04) and bicalutamide (2538 vs 1854 days; HR: 0.57, 95% CI (0.41-0.79), p&lt;0.001). In EC, ER and PR expression was significantly lower in SPOP-mutated vs non-mutated tumors 50.8% vs 65.4% and 35.4 vs 49.5% (all q &lt;0.05), respectively, although no difference in OS was noted in the overall EC population. These data indicate that SPOP-mutations drive different molecular and immune microenvironments in PCa and EC, with apparently opposing roles in these malignancies, and provide a rationale for tailored therapeutic approaches in SPOP-mutated PCa and EC.
Citation Format: Ludimila Cavalcante, Sachin K. Desmukh, Benedito A. Carneiro, Kartik Angara, Tyler E. Mattox, Sharon Wu, Joanne Xiu, Philip Walker, Matthew Oberley, Chadi Nabhan, Emmanuel S. Antonarakis. Opposing roles of SPOP mutations in human prostate and endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 937.