肺癌p53 exon4基因多形性與p53 exon 5-8突變類型

P53 Exon 4 Polymorphism and the Pattern of p53 Exon 5-8 Mutation in Lung Cancer

肺癌在台灣為男性癌症死亡中，為僅次於肝癌之第二大癌症死因，在女性癌症死亡則居第一位。我們先前分析了多種宿主因素，發現在p53 exon 4 （codon 72）arginine/proline多型性為肺癌的危險因子，具有pro/pro基因型之個體有較高的罹患上皮細胞癌之危險，其危險性（odds ratio）為arg/arg之4.48倍。藉著p53基因之突變分析，我們想了解不同組織型態的肺癌之發生與吸菸及p53多型性之關係。本研究收集67位肺癌病患，包含37位腺癌30位上皮細胞癌的肺腫瘤組織，使用PCR-SSCP、DNA序列分析來進行p53 exon5-8突變之分析。結果顯示，p53基因在非小細胞癌中突變率為（10.4%）。這些突變以腺癌居多，且大多發生於exon 8。突變型態以G to T倒位居多。p53基因突變與吸菸、性別、肺癌組織型態在統計上皆無差異，但與p53 exon 4多型性在統計上有差異（p=0.0478），尤其是在腺癌（p=0.0136），以arg/pro基因型之突變率顯著低於具有pro/pro基因型與arg/arg基因型者。因此，pro/pro基因型在腺癌並非是顯著的危險因子，此與先前的研究結果相同。在上皮細胞癌因為突變人數太少，無法看出p53突變與p53 exon 4多型性之間的相關性。因此，本研究無法解釋為何p53之pro/pro基因型對於肺癌會是一個危險因子。至於pro/pro基因型在人體內生理上扮演的角色仍須進一步探討。

Lung cancer has been the second leading cause of cancer deaths among males, and the first among females. In previous study, a polymorphism at codon 72 of the p53 gene, encoding either arginine or proline, was implicated in lung cancer risk. The Pro/Pro genotype of p53 contributed a higher risk to squamous cell carcinoma as compared to Arg/Arg genotype (OR=4.88). Here we studied the relationship between histological types of lung cancer and p53 mutation patterns, linkage between p53 exon 4 polymorphism and p53 mutations. Genomic DNA was extracted from 67 surgical resected lung tumor and 67 normal lung tissue, including 37 adenocarcinoma and 30 squamous cell carcinoma. PCR-SSCP and DNA sequencing was used to investigate point mutation in exons 5-8. The mutation rate was 10.4% in this series of cancer tissues. Five of seven mutations occurred in adenocarcinoma, and were most often found in exon 8. The most frequent mutation patterns was G to T transversion. P53 mutation was not significantly associated with smoking status, sex, or histology. An association was found between p53 mutation and exon 8 polymorphism (p=0.0478), especially in adenocarcinoma (p=0.0136), with arg/pro genotype having the lowest mutation rate. This study did not elucidate the relationship between pro/pro genotype and the increased risk for lung cancers. The functional significance of pro/pro genotype remains to be investigated.