染色体16q、17p遗传学不稳定与乳腺癌发生的关系

发布时间：2018-04-09 16:05

本文选题：乳腺肿瘤　切入点：微卫星不稳定(MSI)　出处：《贵州医科大学》2017年硕士论文

【摘要】：目的:通过检测乳腺导管上皮普通型增生(usual ductal hyperplasia,UDH)、乳腺导管非典型增生(atypical ductal hyperplasia,ADH),乳腺导管原位癌(ductal carcinoma in situ,DCIS)及乳腺浸润性导管癌(invasive ductal carcinoma,IDC)中染色体16q、17p微卫星不稳定(microsatellite instability,MSI)与杂合性缺失(loss of heterozygosity,LOH)的发生频率及p53、CDH13基因启动子的异常甲基化,尝试发现从UDH发展为IDC的重要分子生物学标志。方法:通过PCR-SSCP方法来检测101例乳腺病变(其中UDH 31例,ADH 10例,DCIS32例,IDC 28例)中染色体16q、17p上13个微卫星位点的LOH/MSI发生情况;甲基化特异性PCR(MS-PCR)及琼脂糖凝胶电泳法来检测其p53、CDH13基因启动子的异常甲基化发生情况。结果:101例标本中所有位点均有一定程度的LOH/MSI发生,且DCIS及IDC中的发生频率要高于UDH组(P0.05)。染色体16q23区域的D16S515、D16S507、D16S422,17p12及17p13区域的D17S261、D17S654,LOH/MSI发生总频率分别为31.7%、21.8%、30.7%、25.7%、22.8%(P0.05),进一步两两比较后可知在D16S507和D16S515上UDH组的LOH/MSI的发生频率明显低于ADH组、DCIS组和IDC组(P0.05);D17S654和D16S422上UDH组的LOH/MSI的发生频率明显低于DCIS组和IDC组(P0.05);D17S261上UDH组的LOH/MSI的发生频率明显低于IDC组(P0.05)。在IDC组中,16q与17p染色体上的MS发生LOH/MSI频率改变显著相关。在UDH中p53和CDH13基因的启动子区域的CpG岛异常甲基化发生率较低,并且p53基因启动子异常甲基化在乳腺癌患者中其发生频率明显高于UDH组和ADH组(P0.05);CDH13基因启动子异常甲基化的发生频率在乳腺癌患者中明显高于UDH组(P0.05)。在UDH组和IDC组中,染色体发生LOH/MSI与p53基因启动子甲基化成正相关性(P0.05);在UDH组与IDC组中染色体发生LOH/MSI与CDH13基因启动子甲基化显著相关(P0.05)。p53、CDH13基因启动子的异常甲基化发生时,四组乳腺病变中LOH/MSI发生频率的比较差异无统计学意义(P0.05)。结论:位点D16S515、D16S507、D16S422和D17S654、D17S261发生LOH/MSI的改变可能在UDH发展为IDC中起到关键作用,是乳腺癌发生早期分子事件。抑癌基因p53的启动子异常甲基化发生可能是参与UDH及ADH发展为IDC的早期分子事件。抑癌基因CDH13的启动子异常甲基化发生可能成为UDH发展为IDC的重要分子生物学标志之一。
[Abstract]:The frequency of loss of heterozygosity of heterozygosity and abnormal methylation of p53 CDH13 promoter.An important molecular biological marker from UDH to IDC was found.Methods: 13 microsatellite loci on chromosome 16qS17p were detected by PCR-SSCP method in 101 cases of breast lesions (including 31 cases of UDH and 10 cases of DCIS 32 cases of IDC).Methylation specific PCRS-PCR) and agarose gel electrophoresis were used to detect the abnormal methylation of p53 CDH13 gene promoter.Results there was a certain degree of occurrence of LOH/MSI at all loci in 10 ~ 1 samples, and the frequency of occurrence in DCIS and IDC was higher than that in UDH group (P 0.05).The incidence rate of LOH/MSI in UDH group was significantly lower than that in DCIS group and IDC group (P 0.05 P 17S261). The frequency of LOH/MSI in UDH group was significantly lower than that in IDC group (P 0.05).In IDC group, there was a significant correlation between the frequency of LOH/MSI and the frequency of LOH/MSI on chromosome 17p.The incidence of abnormal CpG island methylation in the promoter region of p53 and CDH13 genes in UDH was lower.The frequency of abnormal methylation of p53 promoter in breast cancer patients was significantly higher than that in UDH group and ADH group. The frequency of abnormal methylation of p53 promoter was significantly higher in breast cancer patients than that in UDH group.In UDH group and IDC group, there was a positive correlation between LOH/MSI and p53 promoter methylation, and in UDH group and IDC group, there was a significant correlation between LOH/MSI and CDH13 promoter methylation.There was no significant difference in the frequency of LOH/MSI among the four groups (P 0.05).Conclusion: the changes of LOH/MSI in D16S515D16S507, D16S422 and D17S654D17S261 may play a key role in the development of UDH into IDC, and may be an early molecular event in the development of breast cancer.The abnormal methylation of p53 promoter may be an early molecular event involved in the development of UDH and ADH into IDC.The abnormal methylation of CDH13 promoter may be one of the important molecular biological markers for the development of UDH into IDC.
【学位授予单位】：贵州医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R737.9

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