Gene promoter methylation in colorectal cancer and healthy adjacent mucosa specimens: correlation with physiological and pathological characteristics, and with biomarkers of one-carbon metabolism.
We evaluated the promoter methylation levels of the APC, MGMT, hMLH1, RASSF1A and CDKN2A genes in 107 colorectal cancer (CRC) samples and 80 healthy adjacent tissues. We searched for correlation with both physical and pathological features, polymorphisms of folate metabolism pathway genes (MTHFR, MTRR, MTR, RFC1, TYMS, and DNMT3B), and data on circulating folate, vitamin B12 and homocysteine, which were available in a subgroup of the CRC patients. An increased number of methylated samples were found in CRC respect to adjacent healthy tissues, with the exception of APC, which was also frequently methylated in healthy colonic mucosa. Statistically significant associations were found between RASSF1A promoter methylation and tumor stage, and between hMLH1 promoter methylation and tumor location. Increasing age positively correlated with both hMLH1 and MGMT methylation levels in CRC tissues, and with APC methylation levels in the adjacent healthy mucosa. Concerning gender, females showed higher hMLH1 promoter methylation levels with respect to males. In CRC samples, the MTR 2756AG genotype correlated with higher methylation levels of RASSF1A, and the TYMS 1494 6bp ins/del polymorphism correlated with the methylation levels of both APC and hMLH1. In adjacent healthy tissues, MTR 2756AG and TYMS 1494 6bp del/del genotypes correlated with APC and MGMT promoter methylation, respectively. Low folate levels were associated with hMLH1 hypermethylation. Present results support the hypothesis that DNA methylation in CRC depends from both physiological and environmental factors, with one-carbon metabolism largely involved in this process.
Department of Translational Research and New Technologies in Medicine and Surgery; Division of Medical Genetics; University of Pisa; Pisa, Italy; Istituto Toscano Tumori (ITT); Florence, Italy; Research Center Nutraceuticals and Food for Health-Nutrafood; University of Pisa; Pisa, Italy.
Fabio
F
Coppedè
Department of Translational Research and New Technologies in Medicine and Surgery; Division of Medical Genetics; University of Pisa; Pisa, Italy; Istituto Toscano Tumori (ITT); Florence, Italy.
Francesca
F
Migheli
Department of Translational Research and New Technologies in Medicine and Surgery; Division of Medical Genetics; University of Pisa; Pisa, Italy; Doctoral School in Genetics, Oncology, and Clinical Medicine; University of Siena; Siena, Italy.
Angela
A
Lopomo
Istituto Toscano Tumori (ITT); Florence, Italy; Department of Clinical and Experimental Medicine; University of Pisa; Pisa, Italy.
Alessandra
A
Failli
Department of Clinical and Experimental Medicine; University of Pisa; Pisa, Italy.
Annalisa
A
Legitimo
Department of Clinical and Experimental Medicine; University of Pisa; Pisa, Italy.
Rita
R
Consolini
Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy.
Gabriella
G
Fontanini
Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy.
Elisa
E
Sensi
Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy.
Adele
A
Servadio
Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy.
Massimo
M
Seccia
Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy.
Giuseppe
G
Zocco
Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy.
Massimo
M
Chiarugi
Department of Surgery, Medical, Molecular, and Critical Area Pathology; University of Pisa; Pisa, Italy.
Roberto
R
Spisni
Department of Translational Research and New Technologies in Medicine and Surgery; Division of Medical Genetics; University of Pisa; Pisa, Italy; Istituto Toscano Tumori (ITT); Florence, Italy; Research Center Nutraceuticals and Food for Health-Nutrafood; University of Pisa; Pisa, Italy.
Lucia
L
Migliore
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012007:Rectum / Q000378:metabolism* / Q000473:pathology; D014805:Vitamin B 12 / Q000097:blood
D015415:Biomarkers; D006710:Homocysteine; D005492:Folic Acid; D014805:Vitamin B 12
APC; CDKN2A; Colorectal Cancer; DNA methylation; MGMT; RASSF1A; epigenetics; folate metabolism; hMLH1; polymorphisms