Mutational analysis of the BRAF gene in colorectal mucinous carcinoma in association with histological configuration.
Genetic alterations and their association with clinicopathological features in colorectal mucinous carcinoma (MC) remain unknown. In particular, little is known about the mutational status of the BRAF gene, which is activated by oncogenic Ras. This study aimed to evaluate the status of BRAF together with K-ras, p53 and mismatch-repair deficiency to clarify their association with tumorigenesis of colorectal MC. BRAF and K-ras mutations were determined in 43 colorectal MCs by direct sequencing. p53 alteration was investigated immunohistochemically. The status of mismatch-repair deficiency was assessed by microsatellite analyses and immunohistochemistry for hMLH1. We also examined the association between these molecular alterations and clinicopathological features including histological configuration. BRAF mutation was detected in 4 (9.3%) tumors and was located at codon 599 of exon 15 in all cases. K-ras mutation was detected in 13 tumors (30.2%). No BRAF and K-ras mutations were identified simultaneously in the same tumor. The incidence of mismatch-repair deficiency tended to be higher in MC with BRAF mutation than without. In terms of histological configuration, we classified the cases according to growth type by tumor edge morphology. All MCs with BRAF mutation and 9 of 13 MCs (69.2%) with K-ras mutation were classified as polypoid type. BRAF and K-ras mutation did not affect patient prognosis, but non polypoid type was significantly more aggressive than polypoid type. Our findings indicate that BRAF mutation plays an important role in the tumorigenesis of colorectal MC and in tumor edge morphology, similar to K-ras mutation.
Yoshitake
Naoto
N
Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan.
Fujii
Shigehiko
S
Mukawa
Kenichiroh
K
Tominaga
Keiichi
K
Fukui
Hirokazu
H
Ichikawa
Kazuhito
K
Tomita
Shigeki
S
Ono
Yuko
Y
Imai
Yasuo
Y
Terano
Akira
A
Hiraishi
Hideyuki
H
Fujimori
Takahiro
T
D048868:Adaptor Proteins, Signal Transducing; D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1