Modes of silencing of p16 in development of esophageal squamous cell carcinoma.
To clarify modes of silencing of p16 and their concerns to the development and progression of esophageal squamous cell carcinomas (ESCCs), we examined immunoreactivity of p16, loss of heterozygosity (LOH) at six microsatellite loci in 9p13-22, and the methylation status of the p16 promoter in 42 cases of the ESCC at various stages. The samples taken from step sections in and around the tumors were examined to map heterogeneity of those changes. Thereby at least one focus of dysplasia was detected in each case. No immunoexpression of p16 was detected in the ESCCs of 38 cases (90.5%) and in dysplasias of 34 cases (81%), whereas the histologically normal epithelia adjacent to the ESCC showed the p16 expression even in the presence of p16 methylation. Of the ESCCs/dysplasias without p16 expression (38/34), 16/0 showed both p16 methylation and LOH at the near-p16 loci (+/+), 14/30 did only methylation (+/-) and 8/4 did only LOH (-/+). The presence of LOH with/without homozygous deletion (HD) at the near-p16 loci correlated with the advanced tumor stages (P < 0.001). The mapping of +/+ cases indicated that the +/+ carcinomas were included in the +/- carcinomas, which were, in turn, surrounded by the +/- dysplasias and/or by the +/- normal-looking epithelia, whereas the -/+ dysplasias were always accompanied by the -/+ carcinomas. These results suggest that the mode of p16 silencing either through methylation or through LOH and possible mutation is determined in each patient before the occurrence of ESCCs and dysplasia. The mapping of HD and p16 expression suggest that the HD is a later event than the p16 silencing.
First Department of Pathology, Shiga University of Medical Science, Ohtsu, 520-2192 Japan.
Tomoki
T
Tokugawa
Hiroyuki
H
Sugihara
Tohru
T
Tani
Takanori
T
Hattori
D000368:Aged; D000483:Alleles; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D019942:Genes, p16; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D019938:Cyclin D1