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Functional analysis of RPS27 mutations and expression in melanoma.
Pigment Cell & Melanoma Research ( IF 4.3 ) Pub Date : 2019-11-22 , DOI: 10.1111/pcmr.12841
Alfredo Floristán 1, 2 , Leah Morales 2, 3 , Douglas Hanniford 1, 2 , Carlos Martinez 2, 3 , Elena Castellano-Sanz 1, 2 , Igor Dolgalev 4 , Alejandro Ulloa-Morales 1, 2 , Eleazar Vega-Saenz de Miera 2, 5, 6 , Una Moran 2, 6 , Farbod Darvishian 1, 2 , Iman Osman 2, 5, 6 , Tomas Kirchhoff 2, 3 , Eva Hernando 1, 2
Affiliation  

Next-generation sequencing has enabled genetic and genomic characterization of melanoma to an unprecedent depth. However, the high mutational background plus the limited depth of coverage of whole-genome sequencing performed on cutaneous melanoma samples make the identification of novel driver mutations difficult. We sought to explore the somatic mutation portfolio in exonic and gene regulatory regions in human melanoma samples, for which we performed targeted sequencing of tumors and matched germline DNA samples from 89 melanoma patients, identifying known and novel recurrent mutations. Two recurrent mutations found in the RPS27 promoter associated with decreased RPS27 mRNA levels in vitro. Data mining and IHC analyses revealed a bimodal pattern of RPS27 expression in melanoma, with RPS27-low patients displaying worse prognosis. In vitro characterization of RPS27-high and RPS27-low melanoma cell lines, as well as loss-of-function experiments, demonstrated that high RPS27 status provides increased proliferative and invasive capacities, while low RPS27 confers survival advantage in low attachment and resistance to therapy. Additionally, we demonstrate that 10 other cancer types harbor bimodal RPS27 expression, and in those, similarly to melanoma, RPS27-low expression associates with worse clinical outcomes. RPS27 promoter mutation could thus represent a mechanism of gene expression modulation in melanoma patients, which may have prognostic and predictive implications.

中文翻译:

RPS27突变和在黑色素瘤中表达的功能分析。

下一代测序已使黑素瘤的遗传和基因组表征达到前所未有的深度。然而,高突变背景加上对皮肤黑色素瘤样品进行的全基因组测序的覆盖深度有限,使得鉴定新的驱动子突变变得困难。我们试图探索人类黑素瘤样本中外显子和基因调控区域的体细胞突变组合,为此我们对89位黑素瘤患者的肿瘤和匹配的种系DNA样本进行了靶向测序,从而确定了已知的和新型的复发性突变。在RPS27启动子中发现了两个与RPS27 mRNA体外水平降低相关的复发突变。数据挖掘和IHC分析显示,RPS27在黑色素瘤中呈双峰表达,低RPS27的患者预后较差。高RPS27和低RPS27黑色素瘤细胞系的体外表征以及功能丧失实验表明,高RPS27状态可提供增强的增殖和侵袭能力,而低RPS27可在低依从性和抗药性方面赋予生存优势。此外,我们证明了10种其他癌症类型具有双峰RPS27表达,并且在那些中,与黑素瘤相似,RPS27低表达与较差的临床结果相关。因此,RPS27启动子突变可能代表黑色素瘤患者基因表达调控的机制,这可能具有预后和预测意义。低RPS27赋予低依恋度和对治疗的抵抗力的生存优势。此外,我们证明了10种其他癌症类型具有双峰RPS27表达,并且在那些中,与黑素瘤相似,RPS27低表达与较差的临床结果相关。因此,RPS27启动子突变可能代表黑色素瘤患者基因表达调控的机制,这可能具有预后和预测意义。低RPS27在低依从性和对治疗的抵抗力方面赋予生存优势。此外,我们证明了10种其他癌症类型具有双峰RPS27表达,并且在那些中,与黑素瘤相似,RPS27低表达与较差的临床结果相关。因此,RPS27启动子突变可能代表黑色素瘤患者基因表达调控的机制,这可能具有预后和预测意义。
更新日期:2019-11-22
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