Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

• Published in: Modern pathology Vol. 17; no. 2; pp. 172 - 179
• Main Authors: Arai, Tomio, Esaki, Yukiyoshi, Sawabe, Motoji, Honma, Naoko, Nakamura, Ken-ichi, Takubo, Kaiyo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2004; Elsevier Limited
• Subjects: Adaptor Proteins, Signal Transducing; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Aged; Aged, 80 and over; Carcinoma, Medullary - genetics; Carcinoma, Medullary - pathology; Carrier Proteins; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA Methylation; Female; hMLH1 gene promoter; hMLH1 protein; Humans; hypermethylation; Immunohistochemistry; large intestine; Male; medullary-type poorly differentiated adenocarcinoma; microsatellite instability and elderly; Microsatellite Repeats; MutL Protein Homolog 1; Neoplasm Proteins; Nuclear Proteins; Promoter Regions, Genetic; Sex Factors; hMLH1 protein; hMLH1 gene promoter; microsatellite instability and elderly; medullary-type poorly differentiated adenocarcinoma; large intestine; hypermethylation
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.3800018

To clarify the significance of hMLH1 promoter hypermethylation in the development of medullary-type poorly differentiated colorectal adenocarcinoma, we studied the status of promoter methylation and hMLH1 expression in 23 medullary-type and 12 pleomorphic-type carcinomas, as well as the pathology and microsatellite status. In medullary-type carcinomas, the percentages of cases with promoter methylation (83%) and an absence of hMLH1 expression (91%) were significantly higher than in pleomorphic-type carcinomas (14 and 17%), respectively. The rate of microsatellite instability in the medullary type was significantly higher than that of the pleomorphic type (87 vs 40%, P<0.01). Compared with pleomorphic-type carcinomas, medullary-type carcinomas were significantly associated with hMLH1 promoter methylation, absent expression of hMLH1 protein, microsatellite instability, as well as a proximal location, a Crohn's-like lymphoid reaction, a low incidence of lymph node metastasis, and a favorable outcome. Medullary-type carcinomas accumulated with advancing age, especially in the female. These results indicated that hMLH1 hypermethylation, concurrent with a lack of its protein expression, may play an important role in the development of medullary-type poorly differentiated colorectal adenocarcinomas in the elderly.