新疆维吾尔族及汉族恶性黑色素瘤致病基因的研究

Malignant melanoma is a typically malignant tumor which is origined from epidermal melanocytes.It has the clinical features of high Metastatic rate,rapid development, poor prognosis and high mortality rate.The incidence of malignant melanoma was found to be closely related to the hereditary factors. Malignant melanoma has long been known that activation of the RAS-RAF-MEK-ERK-MAPK pathway plays an important role in cutaneous melanoma development. BRAF and NRAS are two important molecules belonging to the mitogen-activated protein kinase (MAPK) signal transduction pathway, which regulates cell growth, survival, and invasion.. BRAF is a serine/threonine kinase that transduces regulatory signals from RAS through MEK to MAPK in the RAS-RAF-MEK-ERK-MAPK signalling cascade.A high frequency of an activating BRAF mutation more than 60% in melanoma cell lines and human tumour samples. The most frequent mutation, the V600E amino acid substitution in BRAF exon 15. .Mutations in the upstream gene NRAS which occur in about 15% of cutaneous melanomas. NRAS exon 2 have been identified with high frequency in Maligant melanoma..Genetic alterations were associated with differences in clinical phenotypes clinicopathologic subtypes, and clinical stages.Previous studies had shown that the incidence of BRAF mutation in superficial spreading malignant melanomas is more than other subtypes. There is general agreement that pure in situ melanomas carry a low prevalence of NRAS and BRAF mutations compared with rates seen in other progression phases. .Other distinct subgroups of melanoma have been shown to harbor oncogenic mutations in the receptor tyrosine kinase C-KIT. Recent study has show that KIT mutations are more common among acral and mucosal melanomas than among cutaneous..Previously studies of DNA copy number alterations in melanoma have indirectly demonstrated unique gains and losses associated with sporadic cases (where mutations of BRAF are most prevalent).Furthermore, C-KIT mutations are accompanied by an increase in gene copy number and genomic amplification.DNA copy number instability has been coupled with the deregulation of several key oncogenic pathways. This change occurs asecondary result of some oncogenic activation through either genetic (gene mutation, copy number various)..Xinjiang uygur Autonomous Region lies in the north-west of China and is a multinational area.There is rich in genetic resources which still have not been researched.One hundred and ninety Malignant melanoma were examined for Mutations ,expression and copy number various of BRAF,NRAS,and C-KIT gene to explore genomic alterations that might affect the development and progression of Uyghur and Han groups' melanoma in Xinjiang.??.

恶性黑色素瘤(MM)是起源于表皮黑素细胞的高度恶性肿瘤，转移性强，发展迅速，愈后差，死亡率高。MM的发病与遗传因素密切相关，位于RAS-MEK-ERK途径的BRAF、NRAS基因是突变率最高的基因，尤以BRAF基因V600E突变显著。此外C-KIT基因变异也在MM的发生中起重要作用。目前BRAF基因V600E突变及C-KIT基因突变成为分子靶向治疗热点。新疆MM临床发病情况及致病基因的研究目前尚未见报道。本研究拟对收集的190例新疆地区维吾尔族及汉族MM临床资料整理分析，从蛋白表达和基因突变、基因拷贝数变异揭示维、汉民族恶性黑色素瘤BRAF、NRAS及C-KIT致病基因变异情况，构建基因突变谱，明确BRAF、NRAS及C-KIT基因变异在MM不同临床表型、临床病理分型及分期的差异，比较不同民族间基因型及表型的差异，为MM生长及预后判断提供新的指标，为新疆MM患者的分子靶向治疗提供理论依据。

恶性黑素瘤是起源于表皮黑素细胞的高度恶性肿瘤，转移性强，发展迅速，愈后差，死亡率高。其发病与遗传因素密切相关，位于RAS-MEK-ERK 途径的BRAF 基因是突变率最高的基因，尤以BRAF 基因V600E 突变显著。在亚洲人和有色人种，最常见类型为肢端型和黏膜型。C-KIT基因在肢端型和黏膜型恶性黑素瘤中突变率较高，对肿瘤生长及预后判断具有重要作用。本项目建立了恶性黑素瘤临床病例数据库,初步分析探讨新疆地区恶性黑素瘤临床发病情况及进行生存分析,并对相关致病基因BRAF、C-KIT基因进行基因突变筛查，分别从mRNA和蛋白水平检测新疆地区恶性黑素瘤BRAF、C-KIT基因表达水平。研究发现新疆地区恶性黑素瘤以中老年人多见。同时肢端型黑素瘤是本地区恶性黑素瘤的主要类型。恶性黑素瘤不同类型热点突变基因不同，其中BRAF基因突变主要发生于非肢端部位，而C-KIT基因多见于肢端型。BRAF基因突变以15外显子V600E突变为主，C-KIT基因突变以11外显子L576P突变为主。本项目填补了新疆地区维吾尔族及汉族恶性黑素瘤研究的空白，通过对新疆地区恶性黑素瘤热点基因的突变研究及表达分析，为恶性黑素瘤发病及预后判断提供新指标，并为针对BRAF、C-KIT基因突变的靶向药物的应用提供理论依据。