Li Yuanyuan, Umbach David M, Li Leping
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA.
Melanoma Res. 2017 Dec;27(6):527-535. doi: 10.1097/CMR.0000000000000388.
Approximately 50% of all cutaneous melanomas harbor activating BRAF V600 mutations; among, these 10-30% carry the V600K mutation. Clinically, patients with V600K tumors experience distant metastases sooner and have an increased risk of relapse and shorter survival than patients with V600E tumors. Despite the clinical and other histopathological differences between these BRAF tumor subtypes, little is known about them at the genomic level. Herein, we systematically compared BRAF V600E and V600K skin cutaneous melanoma (SKCM) samples from the Cancer Genome Atlas (TCGA) for differential protein, gene, and microRNA expression genome-wide using the Mann-Whitney U-test. Our analyses showed that elements of energy-metabolism and protein-translation pathways were upregulated and that proapoptotic pathways were downregulated in V600K tumors compared with V600E tumors. We found that c-Kit protein and KIT gene expressions were significantly higher in V600K tumors than in V600E tumors, concurrent with significant downregulation of several KIT-targeting microRNAs (mir) including mir-222 in V600K tumors, suggesting KIT and mir-222 might be key genomic contributors toward the clinical differences observed. The relationship that we uncovered among KIT/c-Kit expression, mir-222 expression, and growth and prosurvival signals in V600 tumors is intriguing. We believe that the observed clinical aggressiveness of V600K tumors compared to V600E tumors may be attributable to the increased energy metabolism, protein translation and prosurvival signals compared with V600E tumors. If confirmed using larger numbers of V600K tumors, our results may prove useful for designing clinical management and targeted chemotherapeutical interventions for BRAF V600K-positive melanomas. Finally, the small sample size in V600K tumors is a major limitation of our study.
所有皮肤黑色素瘤中约50%存在激活型BRAF V600突变；其中，10%-30%携带V600K突变。临床上，与V600E肿瘤患者相比，V600K肿瘤患者远处转移更早，复发风险增加，生存期更短。尽管这些BRAF肿瘤亚型在临床和其他组织病理学方面存在差异，但在基因组水平上对它们的了解甚少。在此，我们使用曼-惠特尼U检验，对来自癌症基因组图谱（TCGA）的BRAF V600E和V600K皮肤黑色素瘤（SKCM）样本进行全基因组差异蛋白质、基因和微小RNA表达的系统比较。我们的分析表明，与V600E肿瘤相比，V600K肿瘤中能量代谢和蛋白质翻译途径的元件上调，促凋亡途径下调。我们发现，V600K肿瘤中c-Kit蛋白和KIT基因表达显著高于V600E肿瘤，同时V600K肿瘤中包括mir-222在内的几种靶向KIT的微小RNA（mir）显著下调，提示KIT和mir-222可能是观察到的临床差异的关键基因组因素。我们在V600肿瘤中发现的KIT/c-Kit表达、mir-222表达与生长和生存信号之间的关系很有趣。我们认为，与V600E肿瘤相比，V600K肿瘤观察到的临床侵袭性可能归因于与V600E肿瘤相比能量代谢、蛋白质翻译和生存信号增加。如果使用更多数量的V600K肿瘤得到证实，我们的结果可能对设计BRAF V600K阳性黑色素瘤的临床管理和靶向化疗干预有用。最后，V600K肿瘤样本量小是我们研究的一个主要局限。
