Inactivation of p16INK4a by CpG hypermethylation is not a frequent event in colorectal cancer.
OBJECTIVE
Gene promoter hypermethylation is common in colorectal cancer and is associated with transcriptional silencing. However, the clinicopathological significance of p16(INK4a) gene silencing with hypermethylation is unknown. Therefore, the aim of this study was to analyze loss of p16 expression and its relationship to hypermethylation in sporadic colorectal cancer.


METHODS
Tissue from 426 colorectal cancers underwent histological analysis. Immunohistochemistry was performed for p16 expression. Fresh tumor DNA was analyzed for microsatellite instability (MSI) and the presence of K-ras mutations. In addition, DNA was bisulphite-modified and analyzed for p16(INK4a) promoter methylation by methylation-specific PCR.


RESULTS
There were 25% of tumors with p16(INK4a) promoter hypermethylation. These tumors were associated with older patients, right-sidedness, MSI and were poorly differentiated, mucinous, and had intraepithelial and peritumoral lymphocytes and a Crohn's-type lymphocytic reaction (P < 0.05). However, only right-sidedness was significant on multivariate analysis (P < 0.001). Only 8.1% of tumors did not express p16, and this was associated with hypermethylation (P < 0.05).


CONCLUSIONS
p16(INK4a) promoter methylation, although common in colorectal cancer, does not result in a clinicopathologically distinct subgroup of tumors and infrequently results in transcriptional silencing. This suggests that p16(INK4a) gene inactivation does not have an important role in the pathogenesis of sporadic colorectal cancer.
Norrie
Mark W A
MW
Department of Medical Oncology, Schools of Medicine and Medical Science, St Vincent's Hospital, Darlinghurst, Australia.
Hawkins
Nicholas J
NJ
Todd
Alison V
AV
Meagher
Alan P
AP
O'Connor
Terence W
TW
Ward
Robyn L
RL
D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D019942:Genes, p16; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm