中文摘要
　　鼻咽癌(nasopharyngeal carcinoma, NPC)是一個鱗狀細胞癌，對於全世界大部分族群來說是一個較罕見疾病，可是卻在中國南方如台灣、香港、新加坡、廣東、福建有較高的發盛行率。鼻咽癌被認為與一些危險因子有關：如EBV感染、遺傳因子、飲食習慣和抽煙。Simons等人(1974)第一個指出遺傳因子可能會使個人具有罹患鼻咽癌的傾向，而他們指出與HLA-A2是有相關的。繼起的遺傳連鎖分析在染病同胞兄弟配對也支持HLA基因座是會增加罹患鼻咽癌的危險率想法。先前研究指出有一個NPC易感受基因座(susceptible locus)位在HLA-A區域。最近有人研究HLA區域內的基因與NPC的關連性，有關一個延伸MHC 半套體(extended MHC haplotype)與NPC的遺傳區域易感受性有關，這個研究引起到底有多少個NPC-易感受基因位於HLA中。為了調查這個議題，我們有系統地分析HLA-A, -B, -C與NPC的關係。為了增加樣本大小的統計檢力，將病人增加為93人，健康人對照組93人。本篇指出HLA-A2、-B38、-Cw7與NPC有密切相關(OR=2.64, p=0.00096; OR=5.77, p= 0.0025;OR=2.13, p= 0.0087)。兩基因座分析(Two-locus analysis)可以看出個體具有A2, B38, Cw7中任何兩個比單獨具有一個基因更易罹患鼻咽癌，而且這種現象不是因為遺傳連鎖導致。多變項邏輯斯回歸分析指出當個體帶有A2, B38, Cw7時期罹患NPC的機率最高(OR=37.7)。從半倍體分析證實NPC族群中帶有A2 , B38 , Cw7頻率比正常人來得高(OR=15.62, p=0.007)。這個結果也使人聯想可能有三個NPC易感受基因座在HLA區域，位在HLA-B, -C區域的微粒星體標竿也檢測了這個可能性。相關分析(association analysis)和基因型差異性分析(genotytpic differentiation)也指出有兩個重疊區域在HLA-B和HLA-C區域，一個位在HLA-B附近的C1_2_E 和 C1_2_BB之間，另一個位在HLA-C附近的C1_4_3 和 C1_3_2；另外，相關分析也指出C1_4_3_431對偶基因與NPC有相關性(p=0.004, pc=0.048)。藉助生物資訊資料庫協助在此區域我們發現三個候選基因，分別是OTF3、SC1與HCR基因。DNA序列也顯示有一些SNPs和缺失的突變在一些病人上。藉由PCR-SSP基因型分析指出一個SC1對偶基因在胺基酸210位置改變(Val210Met)及在3’ flanking region有變異(g.4353_4354TT>AA; 4356delC)與NPC具有統計顯著相關(p=0.013)。以上結果，顯示可能有三個NPC易感受基因座在HLA區域。而在HLA-C區域至少有一個基因即SC1為鼻咽癌易感基因，其變異種(Val210Met; g.4353_4354TT>AA; 4356delC)與NPC有統計上顯著相關。此外目前發現的變異是如何促成NPC的形成仍需要探討，至於這些變異如何改變SC1基因功能，仍須用功能性分析才能得知。

Abstract
　　Nasopharyngeal carcinoma (NPC) is a squamouse cell carcinoma that is rare in most populations in the world. But it is highly prevalent in southern Chinese, including people residing in Taiwan, Hong-Kong, Singapore, Guangdong, Fukine. NPC was though to be associated with several risk factors: EBV infection, genetic components, dietary factors and smoking. The first indication that there may be genetic factors that predispose individuals susceptible to NPC comes from the study of Simons et al (1974). Their studies indicate that HLA-A2 was associated with NPC. Subsequent genetic linkage study based on affected sib pairs also supports the notion that HLA region was associated with increased risk of NPC. Previous study has shown that one NPC susceptible locus is located within the HLA-A region. Recently, an extended MHC haplotype was associated with inherited susceptibility to NPC in Taiwanese. This study also raises the issue of how many NPC-susceptible genes are located within the HLA region. To investigate this issue, we have systemically re-examined the association of HLA-A, -B and –C with NPC. To increase the power of resolution the sample size has been increased to 93 cases and 93 controls. Here we show that HLA-A2, HLA-B38 and HLA-Cw7 are closely associated with NPC (OR=2.64, p=0.00096; OR=5.77, p= 0.0025;OR=2.13, p= 0.0087, respectively). The two-locus analysis indicates that individuals with any two of A2, B38 and Cw7 genes are at greater risk of NPC than with either one alone. The increased susceptibility to NPC is not due the genetic linkage. Multiple logistic regression analysis indicates individuals with A2, B38 and Cw7 has a highest risk of NPC (OR= 37.7). In support of this conclusion, haplotype analysis demonstrates that the frequency of A2(+), B38(+) and Cw7(+) haplotype was significantly higher in NPC than in controls(OR=15.62, p=0.007). These results also suggest that there may be three NPC-susceptible loci within HLA region. To examine this possibility, microsatellite markers spans HLA-B, -C region were employed. Association analysis and genotypic differentiation analysis indicated that there are two overlapping region. One is located between C1_2_E and C1_2_BB adjacent to HLA-B region and the another is within a segment of DNA between C1_4_3 and C1_3_2 nearby HLA-C region. This conclusion is further supported by association analysis demonstrating that one allele of C1_4_3, ie, C1_4_3_431 was significantly associated with NPC(p=0.004, pc=0.048, OR=2.4). Bioinformatics-assisted database search has identified two candidate genes within these region, OTF3 and SC1 gene. DNA sequence analysis has revealed several SNPs and deletion mutations within two genes. Genotyping by PCR-SSP demonstrated that one SC1 allele with amino acid substitution (Val210M) and mutation in 3’flanking region (g.4353_4354TT>AA;4356delC) was statistically significant associated with NPC (p= 0.013). In conjunction with previous study demonstrating one NPC-susceptible locus within the HLA-A, taken together, these results suggest that there are at least three NPC-susceptible loci within the HLA region. Furthermore, these results also identified one SC1 variant (Val210M ;g.4353_4354TT>AA;4356delC) is associated with genetic susceptible to NPC. The biological and functional significance of this variant relating to the development of NPC remains to be analyzed.

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