Shiomori Kenji, Shimada Shinya, Marutsuka Takashi, Hatayama Ichiro, Ogawa Michio
Department of Surgery II, Kumamoto University School of Medicine, Kumamoto, Japan.
Int J Oncol. 2003 Jan;22(1):65-74.
'De novo' carcinogenesis has been advocated besides 'adenoma carcinoma sequence' as another dominant pathway leading to the colorectal carcinoma. Our previous study demonstrated that brain (fetal)-type glycogen phosphorylase (BGP) positive foci in the transitional mucosa (BGP foci) have frequent p53 mutations and that the distribution of BGP foci has a close relationship with the location of 'de novo' carcinoma. The aims of the present study were to investigate further genetic alterations in the BGP foci and to clarify the mechanism of 'de novo' carcinogenesis. Twenty-eight colorectal carcinomas with invasion into submucosa or superficial muscularis propria without any adenoma component expressing immunoreactive p53 protein were selected from 168 resected specimens. Investigations of the p53, K-ras and APC mutations was performed in the BGP foci, BGP negative colorectal mucosa and 'de novo' carcinoma using PCR-SSCP and DNA squencing. In all 28 cases, immunoreactive BGP was positive in the carcinomas and the BGP foci were observed sporadically in the mucosa adjacent to the carcinoma. No K-ras mutation was observed in either carcinoma or BGP foci in any of the cases. Mutations of p53 and APC were 14 (50.0%) and 9 (32.1%) in 'de novo' carcinomas, and 11 (39.3%) and 1 (3.6%) in BGP foci, respectively. Both p53 and APC mutations were detected in 8 and 1, p53 mutation alone in 6 and 10, APC mutation alone in 1 and 0 out of 28 carcinomas and BGP positive foci, respectively. These results suggest that the BGP foci may play a very important role in the 'de novo' colorectal carcinogenesis from the frequent genetic alterations of p53, and that there may be two major pathways, i.e., the p53-APC pathway and the p53 alone pathway, from the chain of genetic alterations between BGP foci and 'de novo' carcinoma.
除了“腺瘤 - 癌序列”外，“新发”致癌作用被认为是导致结直肠癌的另一条主要途径。我们之前的研究表明，移行黏膜中的脑（胎儿）型糖原磷酸化酶（BGP）阳性灶（BGP 灶）常有 p53 突变，且 BGP 灶的分布与“新发”癌的位置密切相关。本研究的目的是进一步研究 BGP 灶中的基因改变，并阐明“新发”致癌作用的机制。从 168 例切除标本中选取 28 例侵犯黏膜下层或浅肌层且无任何表达免疫反应性 p53 蛋白的腺瘤成分的结直肠癌。使用 PCR - SSCP 和 DNA 测序技术对 BGP 灶、BGP 阴性的结直肠黏膜和“新发”癌进行 p53、K - ras 和 APC 突变检测。在所有 28 例病例中，癌组织中免疫反应性 BGP 呈阳性，且在癌旁黏膜中散在观察到 BGP 灶。所有病例的癌组织和 BGP 灶中均未观察到 K - ras 突变。“新发”癌中 p53 和 APC 突变分别为 占 14 例（50.0%）和 9 例（32.1%），BGP 灶中分别为 11 例（39.3%）和 1 例（3.6%）。在 28 例癌组织和 BGP 阳性灶中，分别有 8 例和 1 例同时检测到 p53 和 APC 突变，6 例和 10 例仅检测到 p53 突变，1 例和 0 例仅检测到 APC 突变。这些结果表明，由于 p53 频繁发生基因改变，BGP 灶可能在“新发”结直肠癌发生过程中起非常重要的作用，并且从 BGP 灶与“新发”癌之间的基因改变链来看，可能存在两条主要途径，即 p53 - APC 途径和单独的 p53 途径。
