Poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum show higher rates of loss of heterozygosity and loss of E-cadherin expression due to methylation of promoter region.
Previous studies have reported that poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum (Por & Muc) show a low incidence and poor prognosis. However, genetic alterations and tumourigenesis of Por & Muc remain unclear. In our study, we analyzed the genetic and epigenetic alterations of Por & Muc to clarify the difference from those of well-differentiated adenocarcinoma (WD). First, we evaluated the loss of heterozygosity (LOH) on 4 chromosomes (2p, 5q, 17p, 18q) frequently observed in colorectal cancer. Second, to determine large-scale allelic losses, we performed wide-ranging allelotyping study. Using 27 microsatellite markers spanning every 10 cM on chromosome 17 and 18, we defined the LOH ratio as the proportion of markers that exhibit LOH out of 27 markers. Third, we evaluated the methylation of E-cadherin. With respect to LOH of 4 loci, higher rates of LOH were observed in Por & Muc and a statistical significance was found on the markers adjacent to MSH2 and SMAD4/DCC. Moreover, as the evidence of large-scale allelic imbalance, the average LOH ratio was higher in Por & Muc (0.70) than in WD (0.24) (p = 0.01). Methylation analysis showed that 54.5% of Por & Muc demonstrated hypermethylation of E-cadherin. In immunohistochemistry, 77.8% of Por & Muc exhibited abnormal expression of E-cadherin. Hypermethylation of E-cadherin correlated significantly with abnormal expression (p = 0.047). These results suggest that the higher rates of LOH contribute to Por & Muc tumourigenesis and most of Por & Muc lose normal E-cadherin expression, partly because of the methylation of promoter region.
Kanazawa
Takamitsu
T
Department of Surgical Oncology, Graduate School of Medical Sciences, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. t.kanazawa@helen.ocn.ne.jp
Watanabe
Toshiaki
T
Kazama
Shinsuke
S
Tada
Toshihiro
T
Koketsu
Shinichiro
S
Nagawa
Hirokazu
H
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D015820:Cadherins / Q000096:biosynthesis*; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism
D015820:Cadherins