Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey Piscataway, NJ, USA.
Front Genet. 2013 Jan 25;3:330. doi: 10.3389/fgene.2012.00330. eCollection 2012.
Genomic variation is a trend observed in various human diseases including cancer. Genetic studies have set out to understand how and why these variations result in cancer, why some populations are pre-disposed to the disease, and also how genetics affect drug responses. The melanoma incidence has been increasing at an alarming rate worldwide. The burden posed by melanoma has made it a necessity to understand the fundamental signaling pathways involved in this deadly disease. Signaling cascades such as mitogen-activated protein kinase and PI3K/AKT have been shown to be crucial in the regulation of processes that are commonly dysregulated during cancer development such as aberrant proliferation, loss of cell cycle control, impaired apoptosis, and altered drug metabolism. Understanding how these and other oncogenic pathways are regulated has been integral in our challenge to develop potent anti-melanoma drugs. With advances in technology and especially in next generation sequencing, we have been able to explore melanoma genomes and exomes leading to the identification of previously unknown genes with functions in melanomagenesis such as GRIN2A and PREX2. The therapeutic potential of these novel candidate genes is actively being pursued with some presenting as druggable targets while others serve as indicators of therapeutic responses. In addition, the analysis of the mutational signatures of melanoma tumors continues to cement the causative role of UV exposure in melanoma pathogenesis. It has become distinctly clear that melanomas from sun-exposed skin areas have distinct mutational signatures including C to T transitions indicative of UV-induced damage. It is thus necessary to continue spreading awareness on how to decrease the risk factors of developing the disease while at the same time working for a cure. Given the large amount of information gained from these sequencing studies, it is likely that in the future, treatment of melanoma will follow a highly personalized route that takes into account the differential mutational signatures of each individual's cancer.
基因组变异是各种人类疾病（包括癌症）中观察到的一种趋势。遗传研究旨在了解这些变异如何以及为何导致癌症，为什么某些人群易患该疾病，以及遗传如何影响药物反应。全球范围内黑色素瘤的发病率一直在以惊人的速度增长。黑色素瘤所带来的负担使得我们有必要了解参与这种致命疾病的基本信号通路。丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）等信号级联已被证明在调节癌症发展过程中经常失调的过程中至关重要，例如异常增殖、细胞周期失控、凋亡受损和药物代谢改变。了解这些和其他致癌途径如何被调节，对于我们开发有效的抗黑色素瘤药物的挑战至关重要。随着技术的进步，尤其是下一代测序技术的进步，我们已经能够探索黑色素瘤的基因组和外显子，从而鉴定出以前未知的与黑色素瘤发生有关的基因，如 GRIN2A 和 PREX2。这些新候选基因的治疗潜力正在积极探索中，其中一些作为可药物靶点，而另一些则作为治疗反应的指标。此外，对黑色素瘤肿瘤突变特征的分析继续巩固了紫外线暴露在黑色素瘤发病机制中的因果作用。显然，来自暴露于阳光的皮肤区域的黑色素瘤具有独特的突变特征，包括 C 到 T 的转换，提示紫外线诱导的损伤。因此，有必要继续提高人们对如何降低患这种疾病的风险因素的认识，同时努力寻找治疗方法。鉴于从这些测序研究中获得的大量信息，未来黑色素瘤的治疗可能会遵循一种高度个性化的途径，考虑到每个个体癌症的差异突变特征。
