Dutton-Regester Ken, Gartner Jared J, Emmanuel Rafi, Qutob Nouar, Davies Michael A, Gershenwald Jeffrey E, Robinson William, Robinson Steven, Rosenberg Steven A, Scolyer Richard A, Mann Graham J, Thompson John F, Hayward Nicholas K, Samuels Yardena
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
National Cancer Institute, NIH, MD, USA.
Oncotarget. 2014 May 30;5(10):2912-7. doi: 10.18632/oncotarget.2048.
The incidence of melanoma continues to rise globally and is increasing at a rate greater than any other cancer. To systematically search for new genes involved in melanomagenesis, we collated exome sequencing data from independent melanoma cohort datasets, including those in the public domain. We identified recurrent mutations that may drive melanoma growth, survival or metastasis, and which may hold promise for the design of novel therapies to treat melanoma. These included a frequent recurrent (i.e. hotspot) mutation in the 5' untranslated region of RPS27 in ~10% of samples. We show that the mutation expands the 5'TOP element, a motif known to regulate the expression of most of the ribosomal protein family, to which RPS27 belongs, and thus might sensitize the mutated transcript to growth-mediated regulation. This finding highlights not only the important role of non-protein coding genetic aberrations in cancer development but also their potential as novel therapeutic targets.
黑色素瘤的发病率在全球范围内持续上升，且增长速度超过其他任何癌症。为了系统地寻找参与黑色素瘤发生的新基因，我们整理了来自独立黑色素瘤队列数据集（包括公共领域的数据集）的外显子组测序数据。我们鉴定出了可能驱动黑色素瘤生长、存活或转移的复发性突变，这些突变可能为设计治疗黑色素瘤的新疗法带来希望。其中包括在约10%的样本中，核糖体蛋白S27（RPS27）的5'非翻译区出现频繁的复发性（即热点）突变。我们发现，该突变扩展了5'TOP元件，这是一种已知可调节大多数核糖体蛋白家族（RPS27所属家族）表达的基序，因此可能使突变转录本对生长介导的调节敏感。这一发现不仅突出了非蛋白质编码基因畸变在癌症发展中的重要作用，也凸显了它们作为新型治疗靶点的潜力。
