Noda H, Kato Y, Yoshikawa H, Arai M, Togashi K, Nagai H, Konishi F, Miki Y
Department of Molecular Diagnosis, Japanese Foundation for Cancer Research, Tokyo, Japan.
J Exp Clin Cancer Res. 2006 Jun;25(2):235-42.
The development of colorectal neoplasms proceeds mainly via the adenoma-carcinoma sequence. BRAF and RASSF1A are members of Ras-signaling pathways, but the roles of their aberrations in colorectal carcinogenesis remain unclear. The authors studied mutations of the BRAF and K-ras genes, RASSF1A promoter methylation, and p53 overexpression in 43 polypoid-type and 30 flat-type early-stage colorectal cancers. No tumor simultaneously showed any combination of K-ras mutations, BRAF mutations, and RASSF1A promoter methylation. Three of the 73 tumors (4.1%) had BRAF mutations. All BRAF mutation-positive tumors were flat-type cancers, not associated with coexisting adenoma or p53 overexpression. RASSF1A promoter methylation was detected in 12 out of 73 tumors (16.4%), and the proportion of positive cases was similar in polypoid-type and flat-type cancers. BRAF mutations, K-ras mutations, and RASSF1A promoter methylation independently participate in early-stage colorectal carcinogenesis. BRAF mutations are involved only in flat-type cancers, whereas RASSF1A promoter methylation is involved in both polypoid-type and flat-type cancers. Thus, BRAF mutations most likely participate in de novo colorectal carcinogenesis, K-ras mutations in the adenoma-carcinoma sequence of colorectal carcinogenesis, and RASSF1A promoter methylation in both cascades.
结直肠肿瘤的发展主要通过腺瘤-癌序列进行。BRAF和RASSF1A是Ras信号通路的成员，但它们的畸变在结直肠癌发生中的作用仍不清楚。作者研究了43例息肉样型和30例平坦型早期结直肠癌中BRAF和K-ras基因的突变、RASSF1A启动子甲基化以及p53过表达情况。没有肿瘤同时出现K-ras突变、BRAF突变和RASSF1A启动子甲基化的任何组合。73例肿瘤中有3例（4.1%）发生BRAF突变。所有BRAF突变阳性肿瘤均为平坦型癌，与共存腺瘤或p53过表达无关。73例肿瘤中有12例（16.4%）检测到RASSF1A启动子甲基化，息肉样型和平坦型癌的阳性病例比例相似。BRAF突变、K-ras突变和RASSF1A启动子甲基化独立参与早期结直肠癌的发生。BRAF突变仅参与平坦型癌的发生，而RASSF1A启动子甲基化则参与息肉样型和平坦型癌的发生。因此，BRAF突变很可能参与结直肠癌的原发致癌过程，K-ras突变参与结直肠癌发生的腺瘤-癌序列过程，而RASSF1A启动子甲基化则参与这两个过程。
