Frequent involvement of ras-signalling pathways in both polypoid-type and flat-type early-stage colorectal cancers.
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.
Noda
H
H
Department of Molecular Diagnosis, Japanese Foundation for Cancer Research, Tokyo, Japan.
Kato
Y
Y
Yoshikawa
H
H
Arai
M
M
Togashi
K
K
Nagai
H
H
Konishi
F
F
Miki
Y
Y
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008198:Lymph Nodes; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D011123:Polyploidy; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C411762:RASSF1 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf