The Association of p53 Gene Mutation and Human Papillomavirus Infection in Tissues from Cervical Cancer

「人類乳突瘤病毒感染」與「子宮頸癌」密切有關，持久(persistent)感染高危險型別的人類乳突瘤病毒，在子宮頸多重癌化步驟過程中，是必要的先決條件之一。我們過去已經發表：在四十三例子宮頸癌組織（包括：四十例鱗狀上皮癌，二例鱗狀上皮癌與腺癌混合型、一例腺癌）樣本中，發現三十一例（約佔72%）被人類乳突瘤病毒感染。本實驗為延續性質，我們利用「聚合酵素連鎖反應－單鏈核酸型態多型性」(PCR-SSCP)方式，檢視前述實驗剩餘並被保留的國人四十三例子宮頸癌症組織中，p53基因突變情形。p53是體內重要的腫瘤抑制基因，一旦突變，身體反而易於發生各種腫瘤。這類突變，大多屬於「點突變」，造成轉譯為單個錯義(missense)胺基酸，突變後的p53蛋白質，經常具有致癌特性。p53在「子宮頸」的癌化過程所扮演的角色，與其他器官部位的腫瘤生成機轉並不相同。根據文獻：檢測子宮頸癌組織內的p53，大多並沒有發現「錯義」或其它形式的突變，仍舊維持原始的野生型(wild type)序列。子宮頸上皮通常是先被人類乳突瘤病毒感染，病毒產生的特殊癌化蛋白（如：E6），會與宿主細胞的腫瘤抑制蛋白結合（如：p53），造成後者(p53)功能喪失。這種特殊的p53去活化(inactivation)機轉，與其它腫瘤生成的機轉有所差異。我們的實驗，在四十三例子宮頸癌組織中，均未發生任何p53錯義突變。由於本實驗腫瘤取樣純化DNA時，無法剔除其它非腫瘤成分，因此可能影響檢測「結果」，並降低「敏感度」。其他類似研究文獻報告，也僅找到極少數的突變案例。雖然大家只針對幾個特定的p53基因突變點好發部位(hotspots)所在基因片段做檢測，並沒有分析完整p53基因有意義的序列，但歸納出來的共識為：在子宮頸癌症的生成過程機轉中，「p53序列突變」並沒有扮演關鍵性的角色。結論：子宮頸癌症組織中，發現p53突變的案例機率極為稀少，本國人亦不例外；在子宮頸癌症生成的過程中，「p53突變與否」與「人類乳突瘤病毒感染與否」也沒有關聯性。未來將結合「顯微解剖技術」與更為精確的「分子檢測技術」，對這些組織樣本做進一步分析，會是我們考量重點與努力的方向。

關鍵字

p53:腫瘤抑制基因之一； HPV human papillomavirus:人類乳突瘤病毒； PCR-SSCP polymerase chain reaction-single strand conformational polymorphism:聚合酵素連鎖反應－單鏈核酸型態多型性； missense mutation:錯義突變

並列摘要

Cervical cancer is strongly linked to infection by high-risk human papillomavirus (HPV) types. HPV-induced cervical cancer is a multi-step process and HPV persistence is an important prerequisite for the evolution and maintenance of cervical cancer. We have already reported that 31 (72%) of 43 cervical carcinomas, with 40 squamous cell carcinomas (SCC), 2 cervical adenosquamous cell carcinomas, and 1 adenocarcinoma, were HPV positive. We designed this extension study, to investigate the status of p53 gene mutation by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) for those samples reserved in Professor Chen SL's tissue bank. It is well known that loss of the function of the wild-type p53 gene product will result from the binding of the E6 oncoprotein. This unique mode of p53 inactivation in cervical cancer is different from other tumors. In our series, neither mutations nor changes of the p53 gene were observed by SSCP analysis. Due to the inherent heterogeneity of our samplings with an admixture of various reactive cell populations, this may have caused our results to have relatively low sensitivity. Several other independent studies have also shown that the p53 gene is mutated in a very small percentage of cervical tumors. Although the entire p53 coding region has not been fully analyzed, all these observations suggest that p53 mutation might not play a critical role in cervical carcinogenesis. In conclusion, the frequency of p53 mutation in primary cervical cancer is very low. However, this event appears to be unassociated with the status of HPV infection and the nature of cervical carcinogenesis. We hope to reconsider the microdissection techniques in combination with other more sensitive molecular analytical methods (such as heteroduplex analysis, etc.) for further evaluation and assessment of these remaining samples in the near future.

並列關鍵字

p53 a tumor suppressor gene ； HPV human papillomavirus ； SCC squamous cell carcinomas ； PCR polymerase chain reaction ； SSCP single strand conformational polymorphism ； RFLP restriction fragments length polymor

國際替代計量

The Association of p53 Gene Mutation and Human Papillomavirus Infection in Tissues from Cervical Cancer

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