在前列腺癌和子宫内膜癌中，斑点型POZ蛋白（SPOP）的复发性基因突变与肿瘤进展有关。本研究对这些癌症中的SPOP突变进行了表征，并探讨了它们与分子和免疫特征以及患者预后的关联。在Caris Life Sciences分析了7,398例前列腺癌和19,188例子宫内膜癌样本的临床和分子特征。采用Kaplan-Meier生存曲线分析总生存（OS）。使用卡方检验和曼-惠特尼U检验进行统计学显著性分析，并对P值进行了多重比较调整。在前列腺癌和子宫内膜癌中，SPOP突变的发现率分别为9.2％和4.3％。突变主要集中在SPOP的酶和TRAF-C同源结构域，癌症类型之间没有显著的重叠。SPOP突变与差异性共突变谱和肿瘤免疫微环境特征呈对应关系，且肿瘤免疫浸润高于SPOP突变的子宫内膜癌。在SPOP突变的前列腺癌中，治疗激素剂后，雄激素受体调控转录本的表达较高，且OS得到改善。在子宫内膜癌中，SPOP突变肿瘤的激素受体表达显著较低，在OS上的差异高度依赖于特定热点突变和组织学亚型。这些数据表明，SPOP突变驱动着前列腺癌和子宫内膜癌中的相反分子和免疫景观，暗示前列腺癌中存在失活机制，而子宫内膜癌中存在增活机制，并为个体化治疗提供了理论依据。

Recurrent gene mutations in speckle-type POZ protein (SPOP), the substrate-binding component of E3 ubiquitin ligase, are associated with tumor progression in prostate and endometrial cancers. Here, we characterized SPOP 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 P values adjusted for multiple comparisons.SPOP mutations were identified in 9.2% of prostate and 4.3% of endometrial cancers. Mutations clustered in the SPOP meprin and TRAF-C homology domain, with no significant overlap between cancer types. SPOP mutation was associated with differential comutation profiles and opposing tumor immune microenvironment signatures for each cancer, with greater immune infiltration in SPOP-mutated endometrial cancer. SPOP-mutated prostate and endometrial cancers displayed altered epigenetic gene expression, including opposite regulation of BRD2 transcripts. In SPOP-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 SPOP-mutated tumors and differences in OS were highly dependent on the particular hotspot mutation and histologic subtype.These data indicate that SPOP 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.