Traditional serrated adenoma (TSA) consists of glands with tall cells and short cells. Two kinds of cells alternate to give a unique serrated configuration. The aim of this study was to identify the relationship between the alterations of both Wnt and serrated pathways and the unique morphology of TSAs. The tall and short cells in 28 TSAs were separated by microdissection. Semi-nested polymerase chain reaction was performed to detect the mutations of BRAF, β-catenin, APC, and KRAS. BRAF mutations were observed in 22 of 28 (78.6%) TSAs, and all mutations occurred at the tall cells. In conclusion, BRAF mutation is associated with the serrated morphology of TSAs. Genetic alterations in both the serrated pathway and the Wnt signaling pathway may both contribute to TSAs.
BurgessAWFauxMCLaytonMJRamsayRG. Wnt signaling and colon tumorigenesis—a view from the periphery. Exp Cell Res. 2011;317:2748-2758.
2.
NoffsingerAE. Serrated polyps and colorectal cancer: new pathway to malignancy. Annu Rev Pathol. 2009;4:343-364.
3.
SnoverDC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol. 2011;42:1-10.
4.
VogelsteinBFearonERKernSE. Allelotype of colorectal carcinomas. Science. 1989;244:207-211.
5.
IinoHJassJRSimmsLA. DNA microsatellite instability in hyperplastic polyps, serrated adenoma, and mixed polyps: a mild mutator pathway for colorectal cancer?J Clin Pathol. 1999;52:5-9.
6.
HuangCSO’BrienMJYangSFarrayeFA. Hyperplastic polyps, serrated adenomas, and the serrated polyp neoplasia pathway. Am J Gastroenterol. 2004;99:2242-2255.
7.
KambaraTSimmsLAWhitehallVL. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004;53:1137-1144.
8.
LeeSChoNYChoiMYooEJKimJHKangGH. Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation. Pathol Int. 2008;58:104-113.
9.
EnglishDRYoungJPSimpsonJA. Ethnicity and risk for colorectal cancers showing somatic BRAF V600E mutation or CpG island methylator phenotype. Cancer Epidemiol Biomarkers Prev. 2008;17:1774-1780.
10.
SawyerEJCerarAHanbyAM. Molecular characteristics of serrated adenomas of the colorectum. Gut. 2002;51:200-206.
11.
O’BrienMJYangSMackC. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol. 2006;30:1491-1501.
12.
NashGMGimbelMCohenAM. KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer. Ann Surg Oncol. 2010;17:416-424.
13.
MatsumotoTIidaMKoboriY. Serrated adenoma in familial adenomatous polyposis: relation to germline APC gene mutation. Gut. 2002;50:402-404.
14.
JiaoYFNakamuraSSugaiTYamadaNHabanoW. Serrated adenoma of the colorectum undergoes a proliferation versus differentiation process: new conceptual interpretation of morphogenesis. Oncology. 2008;74:127-134.
15.
YachidaSMudaliSMartinSAMontgomeryEAIacobuzio-DonahueCA. Beta-catenin nuclear labeling is a common feature of sessile serrated adenomas and correlates with early neoplastic progression after BRAF activation. Am J Surg Pathol. 2009;33:1823-1832.
16.
WuJMMontgomeryEAIacobuzio-DonahueCA. Frequent β-catenin nuclear labeling in sessile serrated polyps of the colorectum with neoplastic potential. Am J Clin Pathol. 2008;129:416-423.
17.
BosmanFTCarneiroFHrubanRHTheiseND, eds. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.
18.
TateyamaHLiWTakahashiEMiuraYSugiuraHEimotoT. Apoptosis index and apoptosis-related antigen expression on serrated adenoma of the colorectum: the saw-tooth structure may be related to inhibition of apoptosis. Am J Surg Pathol. 2002;26:249-256.
19.
StefaniusKYlitaloLTuomistoA. Frequent mutations of KRAS in addition to BRAF in colorectal serrated adenocarcinoma. Histopathology. 2011;58:679-692.
20.
KimYHKakarSCunLDengGKimYS. Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polyps. Int J Cancer. 2008;123:2587-2593.
21.
CarrNJMahajanHTanKLHawkinsNJWardRL. Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma. J Clin Pathol. 2009;62:516-518.
22.
VelhoSMoutinhoCCirnesL. BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: primary or secondary genetic events in colorectal carcinogenesis?BMC Cancer. 2008;8:255.
CarragherLASnellKRGiblettSM. V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a. EMBO Mol Med. 2010;2:458-471.
25.
van de WeteringMSanchoEVerweijC. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell. 2002;111:241-250.
26.
ChiangJMChouYHChenTCNgKFLinJL. Nuclear beta-catenin expression is closely related to ulcerative growth of colorectal carcinoma. Br J Cancer. 2002;86:1124-1129.
27.
HamiltonSR. The adenoma-adenocarcinoma sequence in the large bowel: variations on a theme. J Cell Biochem Suppl. 1992;16G:41-46.
28.
YamamotoTKonishiKYamochiT. No major tumorigenic role for β-catenin in serrated as opposed to conventional colorectal adenomas. Br J Cancer. 2003;89:152-157.
UchidaHAndoHMaruyamaK. Genetic alterations of mixed hyperplastic adenomatous polyps in the colon and rectum. Jpn J Cancer Res. 1998;89:299-306.
31.
FuXLiJLiKTianXXZhangY. Hypermethylation of APC promoter 1A is associated with moderate activation of Wnt signaling pathway in a subset of colorectal serrated adenomas. Histopathology. 2009;55:554-563.
32.
KinzlerKWNilbertMCSuLK. Identification of FAP locus genes from chromosome 5q21. Science. 1991;253:661-665.
33.
ChanTLZhaoWLeungSYYuenST; Cancer Genome Project. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 2003;63:4878-4881.
34.
AjiokaYWatanabeHJassJRYokotaYKobayashiMNishikuraK. Infrequent K-ras codon 12 mutation in serrated adenomas of human colorectum. Gut. 1998;42:680-684.
