Hernández-Llodrà Silvia, Segalés Laura, Juanpere Nuria, Marta Lorenzo Tech, Salido Marta, Nonell Lara, David López Tech, Rodríguez-Vida Alejo, Bellmunt Joaquim, Fumadó Lluís, Cecchini Lluís, Lloreta-Trull Josep
Departament of Health and Experimental Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
Prostate. 2021 Dec;81(16):1267-1277. doi: 10.1002/pros.24218. Epub 2021 Sep 17.
In the non-ETS fusion of prostate cancer (PCa) pathway, SPOP mutations emerge as a distinct oncogenic driver subclass. Both SPOP downregulation and mutation can lead to SPOP target stabilization promoting dysregulation of key regulatory pathways. CHD1 gene is commonly deleted in PCa. CHD1 loss significantly co-occurs with SPOP mutations, resulting in a PCa subclass with increased AR transcriptional activity and with a specific epigenetic pattern.
In this study, SPOP alterations at mutational and protein levels and CHD1 copy number alterations have been analyzed and correlated with ERG and PTEN protein expression and with the clinical pathological features of the patients.
SPOP protein loss has been detected in 42.9% of the cases, and it has been strongly associated with PTEN protein loss (p < .001). CHD1 gene loss has been detected in 24.5% and SPOP mutations in 5.9% of the cases. Loss of CHD1 has been strongly associated with SPOP mutations (p = .003) and has shown a trend to be associated with ERG wt cancers (p = .08). The loss of SPOP protein (p = .01) and the combination of PTEN and SPOP protein loss (p = .002) were both statistically more common in grade group 5 cancers, with a prevalence of 60% and 37.5%, respectively. Furthermore, SPOP loss/PTEN loss and SPOP wt/PTEN loss phenotypes were strongly associated with extraprostatic perineural infiltration (p = .007). Strong CHD1 loss was associated with a shorter time to PSA recurrence in the univariate (p = .04), and showed a trend to be associated with the PSA recurrence risk in the multivariate analysis (p = .058).
The results of the present study suggest that the loss of SPOP protein expression, either alone or in combination with loss of PTEN and, on the other hand, a marked loss of the CHD1 gene are very promising prognostic biomarkers in PCa.
在前列腺癌（PCa）通路的非ETS融合中，SPOP突变是一种独特的致癌驱动子类型。SPOP下调和突变均可导致SPOP靶点稳定，从而促进关键调控通路的失调。CHD1基因在PCa中常发生缺失。CHD缺失与SPOP突变显著共现，导致一类具有增强雄激素受体（AR）转录活性和特定表观遗传模式的PCa亚型。
在本研究中，分析了SPOP在突变和蛋白水平的改变以及CHD1拷贝数改变，并将其与ERG和PTEN蛋白表达以及患者的临床病理特征进行关联分析。
在42.9%的病例中检测到SPOP蛋白缺失，且与PTEN蛋白缺失密切相关（p < 0.001）。在24.5%的病例中检测到CHD1基因缺失，5.9%的病例存在SPOP突变。CHD1缺失与SPOP突变密切相关（p = 0.003），并且显示出与ERG野生型癌症相关的趋势（p = 0.08）。SPOP蛋白缺失（p = 0.01）以及PTEN和SPOP蛋白缺失的联合（p = 0.002）在5级癌症中在统计学上更为常见，患病率分别为60%和37.5%。此外，SPOP缺失/PTEN缺失和SPOP野生型/PTEN缺失表型与前列腺外神经周围浸润密切相关（p = 0.007）。在单变量分析中，强烈的CHD1缺失与PSA复发时间缩短相关（p = 0.04），并且在多变量分析中显示出与PSA复发风险相关的趋势（p = 0.058）。
本研究结果表明，SPOP蛋白表达缺失，无论是单独出现还是与PTEN缺失共同出现，以及另一方面CHD1基因的显著缺失，都是PCa中非常有前景的预后生物标志物。
