Role of methylation of the hMLH1 gene promoter in the development of gastric and colorectal carcinoma in the elderly.
The occurrence of malignant neoplasms increases with advancing age. Although aging and carcinogenesis are basically different processes, they share phenomena such as the accumulation of DNA damage and abnormal proteins. Recent advances in molecular biology have shown an accumulation of genetic and epigenetic changes in both aging and carcinogenesis, as well as the alteration of metabolism, immunosenescence and shortened telomeres. DNA methylation is a representative epigenetic phenomenon and is frequently involved in controlling gene functions during development and tumorigenesis. We herein focused on methylation of genes in the development of gastrointestinal carcinomas in the elderly. The proportion of gastric and colorectal carcinomas with hypermethylation of the hMLH1 promoter increases with age, reaching 25-30% of all carcinomas of the stomach and large intestine in elderly patients. These tumors have clinicopathological and molecular characteristics such as loss of hMLH1 expression, microsatellite instability, poorly differentiated histology, peritumoral inflammatory cell infiltration, low incidence of lymph node metastasis and favorable prognosis. However, methylation-related carcinogenesis accounts for up to approximately one-third of tumors, and other mechanisms; for example chromosomal instability as a result of telomere dysfunction, are responsible for the development of most carcinomas in the elderly.
Arai
Tomio
T
Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan. arai@tmig.or.jp
Kasahara
Ichiro
I
Sawabe
Motoji
M
Honma
Naoko
N
Aida
Junko
J
Tabubo
Kaiyo
K
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000502:physiology; D006801:Humans; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000737:chemistry*; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1