Department of Urology, The University of Texas Health Science Center San Antonio, San Antonio, Texas.
Eastern Virginia Medical School, Pathology, Microbiology and Molecular Biology, Norfolk, Virginia.
Urol Oncol. 2020 Dec;38(12):932.e1-932.e7. doi: 10.1016/j.urolonc.2020.06.015. Epub 2020 Jul 12.
Most prostate cancers (CaPs) grow slowly and remain indolent, yet some become aggressive and metastasize. Clinical decision-making requires prognostic markers that can be utilized at the time of diagnosis to identify aggressive tumors. Previous studies have shown a correlation between genomic alterations on the long arm of chromosome 18 (18q) and metastatic CaP.
The goal of this study was to comprehensively profile copy number alterations found on 18q in prostate tumors with varying outcomes to identify putative biomarkers associated with more aggressive disease METHODS: A custom comparative genomic hybridization array was created composed of high-density tiling of 18q sequences. Primary prostate tumor tissues were gathered from men who underwent radical prostatectomy and were categorized based on the patient's long-term clinical outcome as either metastatic disease (MET) or no evidence of disease (NED). DNA was isolated from formalin-fixed, paraffin-embedded prostatectomy tumor tissues, and analyzed for copy number variations (CNVs). Protein levels of genes found within the region of CNVs were analyzed using immunohistochemistry.
Thirty-Four primary prostate tumors were analyzed: 17 NEDs and 17 METs. Two significant regions of copy number gains were found on 18q associated with outcome. One gain located at 18q11.2 was found exclusively in NED outcome tumors while another gain, located at 18q21.31, was found exclusively in MET outcome tumors (P -value< 0.0076). Immunohistochemistry analysis of protein levels showed more protein associated with copy number gain in the MET samples vs. those without the gain as indicated by H-scores of 184.7 and 121.0 respectively.
The latter of these CNVs represent a putative biomarker for aggressive disease and highlights a putative metastasis promoting gene. Further study of known connections to CaP suggests that the paracaspase MALT1 is the most likely target of the copy number gain and represents a potential therapeutic target. Future studies would be of interest to determine MALT1's role in aggressive CaP and the ability of this CNV region to differentiate CaP that will eventually metastasize.
大多数前列腺癌（CaP）生长缓慢且呈惰性，但有些则具有侵袭性并发生转移。临床决策需要能够在诊断时识别侵袭性肿瘤的预后标志物。先前的研究表明，染色体 18 长臂（18q）上的基因组改变与转移性 CaP 之间存在相关性。
本研究的目的是全面分析不同结局的前列腺肿瘤中 18q 上的拷贝数改变，以确定与更具侵袭性疾病相关的潜在生物标志物。
创建了由 18q 序列高密度平铺组成的定制比较基因组杂交阵列。从接受根治性前列腺切除术的男性中采集原发性前列腺肿瘤组织，并根据患者的长期临床结局将其分为转移性疾病（MET）或无疾病证据（NED）。从福尔马林固定、石蜡包埋的前列腺切除术肿瘤组织中分离 DNA，并分析拷贝数变异（CNV）。使用免疫组织化学分析位于 CNV 区域内的基因的蛋白水平。
分析了 34 例原发性前列腺肿瘤：17 例 NED 和 17 例 MET。发现与结局相关的 18q 上有两个显著的拷贝数增益区域。位于 18q11.2 的一个增益仅在 NED 结局肿瘤中发现，而另一个位于 18q21.31 的增益仅在 MET 结局肿瘤中发现（P 值<0.0076）。蛋白水平的免疫组织化学分析显示，与无增益的 MET 样本相比，与拷贝数增益相关的蛋白更多，H 评分分别为 184.7 和 121.0。
这些 CNV 中的后者代表侵袭性疾病的潜在生物标志物，并突出了潜在的促进转移的基因。对与 CaP 的已知联系的进一步研究表明，副半胱氨酸天冬氨酸蛋白酶 MALT1 是拷贝数增加的最可能靶点，代表了潜在的治疗靶点。未来的研究将有助于确定 MALT1 在侵袭性 CaP 中的作用以及该 CNV 区域区分最终转移的 CaP 的能力。
