Konishi Noboru, Nakamura Mitsutoshi, Kishi Munehiro, Nishimine Masayoshi, Ishida Eiwa, Shimada Keiji
Second Department of Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan.
Jpn J Cancer Res. 2002 Jul;93(7):767-73. doi: 10.1111/j.1349-7006.2002.tb01318.x.
Multiple genetic mutations and epigenetic methylation are believed to be involved in prostate carcinogenesis, but it is not known whether these events are independent or correlated in some fashion. We therefore studied 32 prostate adenocarcinomas not only for deletions and / or mutations of multiple suspect genes, but also for aberrant DNA methylation using methylation-specific PCR (MSP). Of those genes examined, p16(INK4a), O(6)-MGMT, and GST-P were found to be the most frequently methylated (66%, 25% and 75% of cases, respectively), while methylations of p14(ARF), RB1, p21(Waf1), and p27(Kip1) were far less common (3%, 6%, 6% and 6% of cases, respectively). Methylation of O(6)-MGMT and GST-P genes was defective in about 19% of the cases and there were occasional simultaneous deletions and methylations of p14(ARF) and p16(INK4a) genes (13% and 3% of cases, respectively). In p16(INK4a), methylation occurred in the promoter region in 9% of samples and in exon 2 in 66% of tumors. Hypermethylation of O(6)-MGMT with concurrent p53 and ras gene mutations were found in 6% and 13% of specimens, respectively; among those tumors with high Gleason scores were 2 carcinomas showing hypermethylated O(6)-MGMT with G-to-A transitions in K-ras. Our results demonstrate that multiple genes of a subset common in prostate carcinomas are methylated and not infrequently show concurrent deletions. Further, there is a suggestion that specific combinations of hypermethylation and mutation correlate to tumor malignancy.
多种基因突变和表观遗传甲基化被认为与前列腺癌发生有关，但尚不清楚这些事件是独立的还是以某种方式相关联。因此，我们研究了32例前列腺腺癌，不仅检测多个可疑基因的缺失和/或突变，还使用甲基化特异性PCR（MSP）检测异常DNA甲基化。在所检测的基因中，发现p16(INK4a)、O(6)-MGMT和GST-P是最常发生甲基化的基因（分别为66%、25%和75%的病例），而p14(ARF)、RB1、p21(Waf1)和p27(Kip1)的甲基化则少见得多（分别为3%、6%、6%和6%的病例）。约19%的病例中O(6)-MGMT和GST-P基因甲基化存在缺陷，偶尔会同时出现p14(ARF)和p16(INK4a)基因的缺失和甲基化（分别为13%和3%的病例）。在p16(INK4a)基因中，9%的样本启动子区域发生甲基化，66%的肿瘤外显子2发生甲基化。分别在6%和13%的标本中发现O(6)-MGMT高甲基化同时伴有p53和ras基因突变；在那些高Gleason评分的肿瘤中，有2例癌显示O(6)-MGMT高甲基化且K-ras发生G到A的转变。我们的结果表明，前列腺癌中常见的一部分基因发生甲基化，且常伴有缺失。此外，有迹象表明高甲基化和突变的特定组合与肿瘤恶性程度相关。
