XRCC1之基因多形性與台灣肺癌發生與預後之相關性

The association of XRCC1 genetic polymorphisms and its prognostic value of lung cancer in Taiwan

林翠娟(Cuei-Jyuan Lin)

指導教授 ： 李輝 ； 鄭雅文

中山醫學大學/醫學院/醫學分子毒理學研究所/碩士(2007年)

https://doi.org/10.6834/CSMU.2007.00024

摘要

XRCC1是一種鹼基刪除DNA修補(base excision repair)基因。已知該基因有十七個基因多形性，其中位於促進子之T-77C、表現序列6 (Exon 6)之Arg194Trp及表現序列10 (Exon 10)之Arg399Gln等三個位置之基因多形性與人類癌症發生之相關性較常被研究。XRCC1之T-77C基因型中具有T/C 或C/C基因型者較T/T者有較低轉錄活性，會增加罹患肺癌之風險。XRCC1之Arg194Trp與Arg399Gln基因型主要影響與其他蛋白間之結合能力，進而影響XRCC1之DNA修補活性。已知Arg194Trp具有Arg/Trp + Trp/Trp者罹患肺癌之風險較Arg/Arg者為低，但是Arg399Gln基因多形性與罹患肺癌之風險，至今並沒有一致的結論。但已有研究指出具有Gln/Gln基因型者之p53發生突變之危險性較Arg/Arg基因型者為高。因此本研究擬以病例-對照研究探討XRCC1上述三種基因多形性是否與台灣肺癌之發生有關？是否是透過較易引起p53發生突變而形成肺癌？另外，本研究又在病例組探討這三種XRCC1基因多形性是否影響化療藥物的敏感性而影響肺癌患者之預後？
本研究共收集296位肺癌病患之腫瘤周邊正常肺組織與288位非癌症者之血液DNA，以PCR-RFLP方式分析T-77C、Arg194Trp及Arg399Gln之基因多形性，並利用邏輯式回歸分析不同基因型之XRCC1與肺癌發生之相關性。本研究又以Kaplan-Meier方法統計分析不同基因型之XRCC1與肺癌患者預後的相關性。結果僅發現在男性具有TC + CC同時為Arg/Trp + Trp/Trp基因型者，罹患肺癌之風險率是TT同時為Arg/Trp + Trp/Trp基因者的3.51倍(95% CI = 1.028-11.961，p = 0.045)，其餘不論何種分層分析皆沒有達到統計上的相關性。在基因多形性與p53突變的相關性分析得到的結果顯示，僅在女性可觀察到具有Gln/Gln基因型者，是Arg/Arg者的4.11倍(95% CI = 1.050-16.117，p = 0.042)，而男性僅在TC + CC基因型者p53基因突變之危險性是TT基因型者的1.99倍(95% CI = 0.906-4.353，p = 0.087)，但未達到統計上之顯著差異。本研究在分析基因多形性與肺癌患者預後之相關性時發現，具TC + CC基因型的肺癌患者之預後較TT基因型的患者為佳(p = 0.042)，因此未來需進一步探討XRCC1之T-77C基因多形性，是否可用來評估肺癌患者之預後。總之，本研究之結果顯示XRCC1之T-77C和Arg194Trp之基因型組合可能與台灣肺癌發生有關。同時分別於女性患者Arg399Gln及男性患者T-77C部分觀察到與p53突變有關，因此推測XRCC1基因多形性可能經由引起p53突變而與肺癌發生有關。

關鍵字

肺癌 ； p53 ； XRCC1

並列摘要

X-ray cross-complementing group 1 (XRCC1) is a base excision repair (BER) gene. There are 17 polymorphisms of XRCC1 been reported. Among these, the association of cancer risk of three polymorphisms of XRCC1 including 5’UTR T-77C, Exon 6 Arg194Trp and Exon 10 Arg399Gln has been extensively investigated. 5’UTR T-77C was association with increased lung cancer risk by reduced transcriptional activity of XRCC1. XRCC1 Arg194Trp and Arg399Gln could interact with some proteins involved in BER to decrease DNA repair activity. It has been shown that subjects with Arg/Trp + Trp/Trp at 194 codon had higher risk of lung cancer than those with Arg/Arg. However, no consistent result was obtained from previous reports regarding Arg399Gln polymorphism. Interestingly, subjects with Gln/Gln at 399 codon exhibited higher p53 mutation frequency than those with Arg/Arg genotype. Therefore, we will conduct a case-control study to understand whether the three genetic polymorphisms of XRCC1 were associated with lung cancer risk? Whether the lung cancer risk caused by these genetic polymorphisms was mediated through the increase of p53 mutation? Additionally, whether patient’s survival could be influenced by these genetic polymorphisms of XRCC1?
To answer those questions, 296 lung cancer cases and 288 non-cancer hospital controls were enrolled to determine the genotypes of XRCC1 by PCR-RFLP. Multiple logistic regression was performed to statistically analyzed understanding which genotype of XRCC1 was associated with lung cancer risk. The association of XRCC1 genotypes with patient’s survival was statistically analyzed by Kaplan-Meier method. Our data showed that male subjects with combination of TC + CC and Arg/Trp + Trp/Trp genotype had 3.51-fold lung cancer risk of those with the combination of TT and Arg/Trp + Trp/Trp genotype (95% CI = 1.028-11.961, p = 0.045). We also observed that female cases with Gln/Gln genotype exhibited a significantly higher p53 mutation frequency than those with Arg/Arg genotype (OR = 4.11, 95% CI = 1.050-16.117, p = 0.042). On the other hand, male cases with T/C + C/C genotype had more common to have p53 mutation than those with T/T genotype (OR = 1.99, 95% CI = 0.906-4.353, p = 0.087), but it did not reach statistically significant. Among the prognostic influence of XRCC1 polymorphisms, we only observed that patients with TC + CC genotype had longer survival time than those with T/T genotype (p = 0.042). Taken together, these results suggest that the combined T-77C and Arg194Trp genotype of XRCC1 could increase the risk of lung cancer in Taiwanese population. The association of XRCC1 genetic polymorphisms with lung cancer risk could partly mediate through the increase of p53 mutation.

並列關鍵字

Lung cancer ； p53 ； XRCC1

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