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题名: 台灣地區影響乳癌發生之相關因素之研究---探討X染色體不隨機不活化現象及Xq25區域發生LOH與乳癌發生的關聯性
The Study of Related Factors that Influence the Development of Breast Cancer in Taiwan---The Association of Non-random X Chromosome Inactivation as Well as LOH at Xq25 with Breast Cancer
作者: 簡一治
贡献者: 生物學系
关键词: 乳癌;X 染色體非隨機不活化
LOH
日期: 2004
上传时间: 2013-02-05T03:07:38Z
出版者: 行政院國家科學委員會
摘要: 早期認定遺傳性乳癌的發生和BRCA1 和BRCA2 的突變有關但越來越多的證據顯示「用來解釋家族性乳癌的起因，不應該只是侷限於兩個主要的基因BRCA1、BRCA2」；所以對於找尋其他相關的breast cancer susceptibility gene 是目前相當重要的目標之一。正常的人類女性細胞都有兩條X 染色體，而大部分的女性其中一條X 染色體不活化的現象是屬於隨機的方式，不過仍然有少部分的女性屬於非隨機的X 染色體不活化現象。目前X 染色體非隨機的不活化現象廣泛地被研究，並且指出與X-linked 的隱性疾病以及某些癌症的發生有關，所以本研究的目的之一主要是探討X 染色體非隨機的不活化現象與乳癌發生的相關性以及是否會影響乳癌腫瘤的形成，實驗方法則是根據 HUMARA 基因是否有甲基化的情形並且計算Modified allelic cleavage ratio (CR) 以判斷個體X 染色體不活化的模式是屬於隨機的還是非隨機的方式，並進一步以卡方考驗分析或費雪正確機率考驗(當期望次數小於5)比較實驗組與對照組是否有顯著差異。根據Kundson 提出的假設，癌症必須符合二次衝擊理論，針對遺傳性的癌症看來，第一次衝擊是可能遺傳到父親或母親突變的腫瘤抑制基因，而第二次就是相對的正常基因發生突變或有LOH 也就是基因的缺失。初發性癌症第一次可能是腫瘤抑制基因有LOH 現象或發生突變，而第二次就是相對的正常基因發生突變，兩次衝擊發生順序也可顛倒，所以必須兩個對偶基因完全喪失功能。至於屬於X 染色體非隨機不活化現象的婦女，可以說組織中幾乎所有的細胞活化的X 染色體均來自於父親或母親，所以被認為與LOH 具有相等的意義與功能；不管就遺傳性或初髮型的癌症來看，屬於X 染色體非隨機不活化現象的婦女，等於是已經有了一次的癌化衝擊，至於另外一次的衝擊在遺傳性的癌症可能是活化的X 染色體上遺傳自父親或母親突變的腫瘤抑制基因，而在初髮型的癌症，則是在活化的X 染色體上的腫瘤抑制基因有LOH 的現象或是發生突變。因此，若屬於X 染色體非隨機不活化現象的婦女，在其活化的 X 染色體上的腫瘤抑制基因又有LOH 的現象，則此婦女發生婦女專有的癌症的機率會大大的增加。而有報導指出國外的乳癌患者在Xq25 區域有高頻率的L OH, 且暗示Xq25 此處可能存有腫瘤抑制基因。而其功能可能與腫瘤的轉移及增生有關。所以，本研究的另一目的是偵察國人乳癌病患Xq25 上DXS8098 或附近區域其腫瘤LOH 的頻率，進而分析此LOH 與X 染色體非隨機的不活化現象及之前本實驗室研究的PlasmaLOH(PLOH)的相關性。
A significant proportion of breast cancers cannot be explained by mutations in the BRCA1 and BRCA2 genes. Various approaches have been applied to search for other possible genetic variations (such as LOH of tumor suppressor genes), which may account for the initiation of either sporadic or familial breast cancers. Normal human female cells contain two X-chromosomes, and one of which is inactivated randomly. However, nonrandom X-chromosome inactivation (NXI) may occur in a subset of females. Recently, a few studies reported that NXI might be a risk factor for the development of some cancers and X-linked diseases. One of the purposes of this study is to find the relationship between NXI and the development of breast cancers as well as tumorgenesis of breast cancer. X inactivation analysis was performed using HhaI predigestion of DNA followed by PCR of the CAG repeat of the androgen receptor gene (HUMARA), which amplifies the undigested inactive X chromosome only. The Chi-square test or Fisher』s exact probability test (if expected frequency <5) was applied to determine if there was a significant difference in ratios of NXI between experimental and control samples. According to Knodson』s hypothesis, development of tumor has to fit what is called 「two-hit theory」. For the familial cancers, the first hit could be the inheritance of one of the parent』s mutated tumor suppressor genes (TSGs); the second hit could the mutation or LOH of the counterpart genes. For the primary cancers, the first hit could be the mutations or loss of a normal TSG; while the second hit could be mutations of the counterpart normal TSG. A woman with the phenomenon of NXI, whose activated X chromosome was derived from either father or mother, is supposed to have received a first tumorgenic hit in the first place. Her second hit might be easily arrived if she inherited a mutated TSG or mutations or LOH occurred after birth. Therefore, a woman with NXI has greater chance to develop female-specific cancers than the other. It has been reported that high incidence of LOH occurred at Xq25 in breast cancer patients, and further implied that there were TSGs, which might be associated with progression and metastasis of tumor, in this district of X chromosome. The other purpose of the study is to investigate the frequency of LOH at Xq25 of breast cancer patients in Taiwan, and further analyze the association of the LOH at Xq25 with the phenomenon of NXI and PLOH, which has been investigated by our lab previously.
關聯: 國科會計畫, 計畫編號: NSC93-2320-B018-002; 研究期間: 9308-9407
显示于类别:[生物學系] 國科會計畫

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