Jung MoonSun, Russell Amanda J, Kennedy Catherine, Gifford Andrew J, Mallitt Kylie-Ann, Sivarajasingam Siva, Bowtell David D, DeFazio Anna, Haber Michelle, Norris Murray D, Henderson Michelle J
Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, Kensington, NSW, Australia.
Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
JNCI Cancer Spectr. 2018 Nov 16;2(3):pky047. doi: 10.1093/jncics/pky047. eCollection 2018 Jul.
The Myc oncogene family has been implicated in many human malignancies and is often associated with particularly aggressive disease, suggesting Myc as an attractive prognostic marker and therapeutic target. However, for epithelial ovarian cancer (EOC), there is little consensus on the incidence and clinical relevance of Myc aberrations. Here we comprehensively investigated alterations in gene copy number, expression, and activity for Myc and evaluated their clinical significance in EOC.
To address inconsistencies in the literature regarding the definition of copy number variations, we developed a novel approach using quantitative polymerase chain reaction (qPCR) coupled with a statistical algorithm to estimate objective thresholds for detecting Myc gain/amplification in large cohorts of serous (n = 150) and endometrioid (n = 80) EOC. , , and mRNA expression and Myc activity score for each case were examined by qPCR. Kaplan-Meier and Cox-regression analyses were conducted to assess clinical significance of Myc aberrations.
Using a large panel of cancer cell lines (n = 34), we validated the statistical algorithm for determining clear thresholds for Myc gain/amplification. was the most predominantly amplified of the Myc oncogene family members, and high mRNA expression levels were associated with amplification in EOC. However, there was no association between prognosis and increased copy number or gene expression of or with a pan-Myc transcriptional activity score, in EOC, although amplification was associated with late stage and high grade in endometrioid EOC.
A systematic and comprehensive analysis of Myc genes, transcripts, and activity levels using qPCR revealed that although such aberrations commonly occur in EOC, overall they have limited impact on outcome, suggesting that the biological relevance of Myc oncogene family members is limited to certain subsets of this disease.
Myc癌基因家族与多种人类恶性肿瘤相关，且常与侵袭性特别强的疾病相关，这表明Myc是一个有吸引力的预后标志物和治疗靶点。然而，对于上皮性卵巢癌（EOC），关于Myc基因异常的发生率和临床相关性几乎没有共识。在此，我们全面研究了Myc基因的拷贝数、表达和活性变化，并评估了它们在EOC中的临床意义。
为解决文献中关于拷贝数变异定义的不一致问题，我们开发了一种新方法，即使用定量聚合酶链反应（qPCR）结合统计算法来估计在大量浆液性（n = 150）和子宫内膜样（n = 80）EOC队列中检测Myc基因增益/扩增的客观阈值。通过qPCR检测每个病例的、和mRNA表达以及Myc活性评分。进行Kaplan-Meier和Cox回归分析以评估Myc基因异常的临床意义。
使用大量癌细胞系（n = 34），我们验证了用于确定Myc基因增益/扩增明确阈值的统计算法。是Myc癌基因家族成员中扩增最主要的基因，EOC中高mRNA表达水平与扩增相关。然而，在EOC中，预后与或的拷贝数增加、基因表达增加或泛Myc转录活性评分之间没有关联，尽管在子宫内膜样EOC中扩增与晚期和高级别相关。
使用qPCR对Myc基因、转录本和活性水平进行系统全面的分析表明，虽然这些异常在EOC中普遍存在，但总体上它们对预后的影响有限，这表明Myc癌基因家族成员的生物学相关性仅限于该疾病的某些亚组。
