From the Departments of Pathology and Laboratory Medicine (Bidot, Zhang, Deeb, Smith, Hill, Tinsley, Harik).
Department of Clinical and Translational Research, Caris Life Sciences, Phoenix, Arizona (Yin, Xiu).
Arch Pathol Lab Med. 2024 Mar 1;148(3):310-317. doi: 10.5858/arpa.2022-0274-OA.
CONTEXT.—: Genetic profiling data of prostatic adenocarcinoma are derived from predominantly White patients. In African Americans, prostatic adenocarcinoma has a poorer prognosis, raising the possibility of distinct genetic alterations.
OBJECTIVE.—: To investigate the genomic alterations of prostatic adenocarcinoma metastatic to regional lymph nodes in African American patients, with an emphasis on SPOP mutation.
DESIGN.—: We retrospectively reviewed African American patients with pN1 prostatic adenocarcinoma managed with radical prostatectomy and lymph node dissection. Comprehensive molecular profiling was performed, and androgen receptor signaling scores were calculated.
RESULTS.—: Nineteen patients were included. The most frequent genetic alteration was SPOP mutations (5 of 17; 29.4% [95% CI: 10.3-56.0]). While most alterations were associated with a high androgen receptor signaling score, mutant SPOP was exclusively associated with a low median and interquartile range (IQR) androgen receptor signaling score (0.788 [IQR 0.765-0.791] versus 0.835 [IQR 0.828-0.842], P = .003). In mutant SPOP, mRNA expression of SPOP inhibitor G3BP1 and SPOP substrates showed a significantly decreased expression of AR (33.40 [IQR 28.45-36.30] versus 59.53 [IQR 53.10-72.83], P = .01), TRIM24 (3.95 [IQR 3.28-5.03] versus 9.80 [IQR 7.39-11.70], P = .008), and NCOA3 (15.19 [IQR 10.59-15.93] versus 21.88 [IQR 18.41-28.33], P = .046).
CONCLUSIONS.—: African American patients with metastatic prostate adenocarcinoma might have a higher prevalence of mutant SPOP (30%), compared to ∼10% in unselected cohorts with lower expressions of SPOP substrates. In our study, in patients with mutant SPOP, the mutation was associated with decreased SPOP substrate expression and androgen receptor signaling, raising concern for suboptimal efficacy of androgen deprivation therapy in this subset of patients.
前列腺腺癌的基因谱数据主要来自白种人群体。在非裔美国人中，前列腺腺癌的预后较差，这表明可能存在不同的遗传改变。
研究非裔美国人转移性前列腺腺癌患者区域淋巴结的基因组改变，重点研究 SPOP 突变。
我们回顾性分析了接受根治性前列腺切除术和淋巴结清扫术治疗的 pN1 期前列腺腺癌的非裔美国患者。进行了全面的分子谱分析，并计算了雄激素受体信号评分。
纳入了 19 名患者。最常见的遗传改变是 SPOP 突变（17 例中有 5 例；29.4%[95%CI：10.3-56.0]）。虽然大多数改变与高雄激素受体信号评分相关，但突变 SPOP 仅与中值和四分位距（IQR）的低雄激素受体信号评分相关（0.788[IQR0.765-0.791]与 0.835[IQR0.828-0.842]，P=0.003）。在突变 SPOP 中，SPOP 抑制剂 G3BP1 和 SPOP 底物的 mRNA 表达显示 AR（33.40[IQR28.45-36.30]与 59.53[IQR53.10-72.83]，P=0.01）、TRIM24（3.95[IQR3.28-5.03]与 9.80[IQR7.39-11.70]，P=0.008）和 NCOA3（15.19[IQR10.59-15.93]与 21.88[IQR18.41-28.33]，P=0.046）的表达显著降低。
与未选择的、低表达 SPOP 底物的队列相比，转移性前列腺腺癌的非裔美国患者可能具有更高的突变 SPOP（30%）患病率。在我们的研究中，在具有突变 SPOP 的患者中，该突变与 SPOP 底物表达和雄激素受体信号降低相关，这引起了人们对该亚组患者雄激素剥夺治疗效果不佳的担忧。
