Raspin Kelsie, Marthick James R, Donovan Shaun, Blizzard Leigh, Malley Roslyn C, Jung Chol-Hee, Banks Annette, Redwig Frank, Skala Marketa, Dickinson Joanne L, FitzGerald Liesel M
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Diagnostic Services, Sonic Healthcare, Hobart, Tasmania, Australia.
Genes Chromosomes Cancer. 2023 May;62(5):247-255. doi: 10.1002/gcc.23117. Epub 2022 Dec 23.
Recurrent tumor copy number variations (CNVs) in prostate cancer (PrCa) have predominantly been discovered in sporadic tumor cohorts. Here, we examined familial prostate tumors for novel CNVs as prior studies suggest these harbor distinct CNVs. Array comparative genomic hybridization of 12 tumors from an Australian PrCa family, PcTas9, highlighted multiple recurrent CNVs, including amplification of EEF2 (19p13.3) in 100% of tumors. The EEF2 CNV was examined in a further 26 familial and seven sporadic tumors from the Australian cohort and in 494 tumors unselected for family history from The Cancer Genome Atlas (TCGA). EEF2 overexpression was observed in seven PcTas9 tumors, in addition to seven other predominantly familial tumors (n = 34%). EEF2 amplification was only observed in 1.4% of TCGA tumors, however 7.5% harbored an EEF2 deletion. Analysis of genes co-expressed with EEF2 revealed significant upregulation of two genes, ZNF74 and ADSL, and downregulation of PLSCR1 in both EEF2 amplified familial tumors and EEF2 deleted TCGA tumors. Furthermore, in TCGA tumors, EEF2 amplification and deletion were significantly associated with a higher Gleason score. In summary, we identified a novel PrCa CNV that was predominantly amplified in familial tumors and deleted in unselected tumors. Our results provide further evidence that familial tumors harbor distinct CNVs, potentially due to an inherited predisposition, but also suggest that regardless of how EEF2 is dysregulated, a similar set of genes involved in key cancer pathways are impacted. Given the current lack of gene-based biomarkers and clinical targets in PrCa, further investigation of EEF2 is warranted.
前列腺癌（PrCa）中的复发性肿瘤拷贝数变异（CNV）主要是在散发性肿瘤队列中发现的。在此，我们检查了家族性前列腺肿瘤中的新型CNV，因为先前的研究表明这些肿瘤具有独特的CNV。对来自澳大利亚一个PrCa家族（PcTas9）的12个肿瘤进行的阵列比较基因组杂交突出显示了多个复发性CNV，包括100%的肿瘤中EEF2（19p13.3）的扩增。在来自澳大利亚队列的另外26个家族性肿瘤和7个散发性肿瘤以及来自癌症基因组图谱（TCGA）的494个未根据家族史选择的肿瘤中检查了EEF2 CNV。除了其他7个主要为家族性的肿瘤（n = 34%）外，在7个PcTas9肿瘤中观察到EEF2过表达。仅在1.4%的TCGA肿瘤中观察到EEF2扩增，然而7.5%的肿瘤存在EEF2缺失。对与EEF2共表达的基因进行分析发现，在EEF2扩增的家族性肿瘤和EEF2缺失的TCGA肿瘤中，两个基因ZNF74和ADSL显著上调，而PLSCR1下调。此外，在TCGA肿瘤中，EEF2扩增和缺失与更高的Gleason评分显著相关。总之，我们鉴定出一种新型的PrCa CNV，其在家族性肿瘤中主要扩增，而在未选择的肿瘤中缺失。我们的结果提供了进一步的证据，表明家族性肿瘤具有独特的CNV，这可能是由于遗传易感性，但也表明无论EEF2如何失调，一组参与关键癌症途径的相似基因都会受到影响。鉴于目前PrCa中缺乏基于基因的生物标志物和临床靶点，有必要对EEF2进行进一步研究。
