人類的第二型胰島素生長因子接受器基因(IGF2R)，可產生多功能的蛋白質，參與溶脢體酵素的運輸、胎兒器官型成、轉形生長因子-β活化(TGF-β)，及毒殺T細胞(cytotoxic T cell)引發的細胞計劃性死亡。第二型胰島素生長因子接受器基因包含48個外顯子，共137000個鹼基，位於6號染色體長臂上25-27的位置。先前研究推斷第二型胰島素生長因子接受器基因可能扮演著抑癌基因的角色，而且在60 % 的肝細胞不正常增生及肝癌病患中發現突變點，也與乳癌早期發展有關。甚者，基因上一段連續多鳥糞瞟呤(poly-G)的區域常在直腸癌、胃癌、子宮內膜癌等患者中發現突變，而造成基因錯誤配對修補缺陷及微衛星序列不穩定。第二型胰島素生長因子接受器基因在有袋目、齧齒目及偶蹄目動物中是屬於遺傳印記的基因，只表現母方的對偶基因。然而，在人類中第二型胰島素生長因子接受器基因的遺傳印記的情形還不清楚，而它對於人類癌症的評估及演化有很高的生化意義。在我們實驗室的先前研究中，已經將可能包含鼻腔區NK/T細胞淋巴癌抑癌基因的區域，定位至6號染色體長臂上25的位置。在這個區域中，第二型胰島素生長因子是一個很好的候選基因，值得我們再深入研究。另外，第二型胰島素生長因子是第一個在老鼠找到的遺傳印記基因，遺傳印記的機制改變後，常常導致基因表現不正常而產生疾病。本篇研究的目的即在於釐清人類第二型胰島素生長因子接受器基因的遺傳現象及研究它在鼻腔區NK/T細胞淋巴癌是否扮演著抑癌基因的角色。我們從NCBI資料庫中選出五個位於第二型胰島素生長因子接受器基因譯碼區的單核甘酸多型性標識(cSNPs)，其中有兩個在台灣族群中有較高多形性的標識被用來評估基因表現的形式。在五十個分析的對象中，第二型胰島素生長因子接受器基因都是兩個對偶基因表現。為研究在第二型胰島素生長因子接受器基因上的序列變異是否會導致鼻腔區NK/T細胞淋巴癌生成，我們定序了鼻腔區NK/T細胞淋巴癌病患的癌化及正常組織的基因。此研究結果將有助於了解人類的第二型胰島素生長因子接受器基因在癌症形成中扮演的角色。在十個包含突變率高的外顯子區域中，有一個突變點和幾個核甘酸多型性被找到。這個點突變在外顯子38上，會導致氨基酸從半胱氨酸轉變成酪胺酸。在癌化的過程中，此突變會造成怎樣的功能上的影響，正在從鼻腔區NK/T細胞淋巴癌上著手研究。

The human mannose 6-phosphate / insulin-like growth factor 2 receptor (M6P/IGF2R) gene encodes a multifunctional protein involved in lysosomal enzyme trafficking, fetal organogenesis, latent TGF-β activation, and cytotoxic T cell-induced apoptosis. IGF2R gene contains 48 exons and spans 137 kb genomic region on chromosome 6q25-27. Previous studies suggested that IGF2R acts as a tumor suppressor gene and sequence mutations have been identified in 60 % of dysplastic liver lesions and HCCs, also in the early stage of breast cancer development. Furthermore, a poly-G region was commonly mutated in colon, gastric and endometrial tumors with mismatch repair deficiencies and microsatellite instability. IGF2R is imprinted and expressed only maternal allele in Rodentia, Marsupialia and Artidactyla. The imprinting status in the human remains unclear but it is critically impacted upon biological impact ranging from human cancer predisposition to evolution. Study in our laboratory has previously mapped potential tumor suppressor gene containing region of nasal NK/T cell lymphoma to chromosome 6q25. IGF2R is a good candidate gene within this region thus it merits further investigation. Besides, Igf2r is the first imprinted gene to be identified in mice and the imprinting status changes often lead to abnormal gene expression thus it may cause diseases. The aims of this study are to clarify the imprinting status of the human IGF2R gene and to study the role of IGF2R as a tumor suppressor gene in human nasal NK/T cell lymphoma. Five coding region single nucleotide polymorphisms (cSNPs) on IGF2R were selected from NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/SNP/). Two polymorphic cSNPs were used to examine the gene expression pattern. Up to 50 individuals being analyzed, IGF2R gene exhibits biallelic expression in all examined samples. To investigate if sequence variant of IGF2R gene plays a role in tumorigenesis for human nasal NK/T cell lymphoma, we sequence DNA from tumor and normal tissues of patients with the nasal NK/T cell lymphoma. Ten exons reported as mutation hot spots were selected for mutation screening and one point mutation and few polymorphisms have been identified. The point mutation is in exon38 G5716A that leads to amino acid change from cysteine to tyrosine. On tumorigenesis, functional impact of the G5716A mutatin is currently under investigation of nasal NK/T cell lymphoma.

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