Novant Health Cancer Institute, Charlotte, NC.
Caris Life Sciences, Phoenix, AZ.
JCO Precis Oncol. 2023 Sep;7:e2300088. doi: 10.1200/PO.23.00088.
Recurrent gene mutations in speckle-type POZ protein (), the substrate-binding component of E3 ubiquitin ligase, are associated with tumor progression in prostate and endometrial cancers. Here, we characterized 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 values adjusted for multiple comparisons.
mutations were identified in 9.2% of prostate and 4.3% of endometrial cancers. Mutations clustered in the meprin and TRAF-C homology domain, with no significant overlap between cancer types. mutation was associated with differential comutation profiles and opposing tumor immune microenvironment signatures for each cancer, with greater immune infiltration in -mutated endometrial cancer. -mutated prostate and endometrial cancers displayed altered epigenetic gene expression, including opposite regulation of transcripts. In -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 -mutated tumors and differences in OS were highly dependent on the particular hotspot mutation and histologic subtype.
These data indicate that 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.
斑点型 POZ 蛋白 () 是 E3 泛素连接酶的底物结合组件，其重复基因突变更与前列腺癌和子宫内膜癌的肿瘤进展相关。在此，我们对这些癌症中的 突变进行了特征分析，并探讨了其与分子和免疫特征以及患者预后的关联。
在 Caris Life Sciences 对 7398 例前列腺癌和 19188 例子宫内膜癌样本进行了临床和分子特征分析。使用 Kaplan-Meier 生存曲线分析总生存期 (OS)。使用卡方检验和曼-惠特尼 U 检验分析统计学意义，校正多重比较。
在 9.2%的前列腺癌和 4.3%的子宫内膜癌中发现了 突变。突变集中在 meprin 和 TRAF-C 同源结构域，在不同癌症类型之间没有明显重叠。 突变与每个癌症的差异共突变谱和相反的肿瘤免疫微环境特征相关，在 -突变的子宫内膜癌中免疫浸润程度更高。-突变的前列腺癌和子宫内膜癌显示出改变的表观遗传基因表达，包括 转录物的相反调控。在 -突变的前列腺癌中，观察到雄激素受体调节转录物的高表达以及激素治疗后 OS 的改善。在子宫内膜癌中，-突变肿瘤的激素受体表达明显降低，OS 的差异高度依赖于特定的热点突变和组织学亚型。
这些数据表明， 突变在前列腺癌和子宫内膜癌中驱动了相反的分子和免疫景观-提示前列腺癌中存在功能丧失机制，而子宫内膜癌中存在功能获得机制-并为量身定制的治疗方法提供了依据。
