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Abstract
BackgroundColorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect.Methodology/Principal FindingsWe examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals) and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2), RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008) and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047) as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006). Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17), SFRP1 (r = 0.83, 0.06), HPP1 (r = 0.64, p = 0.17), 3OST2 (r = 0.83, p = 0.06) and GATA4 (r = 0.6, p = 0.24). Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant difference in any evaluated gene.ConclusionsThese results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity. This underlying epigenetic defect may have noteworthy implications in the prevention of patients with sporadic CRC.
Highlights
Colorectal cancer (CRC) is a relevant public health problem since it represents the second most common malignant tumor and the second leading cause of cancer death in Western countries
These results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity
The aim of this study was to evaluate methylation patterns of genes involved in colorectal carcinogenesis through this mechanism in both tumor tissue and normal appearing colorectal mucosa samples of patients with multiple and solitary CRC, as a proof-of-concept of a putative underlying epigenetic defect associated with tumor multiplicity
Summary
Colorectal cancer (CRC) is a relevant public health problem since it represents the second most common malignant tumor and the second leading cause of cancer death in Western countries. Inheritance constitutes the underlying cause in up to one third of all CRC cases, with highly penetrant and well-defined hereditary disorders, i.e. adenomatous and hamartomatous polyposis and Lynch syndrome, representing 3–5% of the total CRC burden [1]. In such conditions, presence of a germline mutation in the causative gene (i.e. APC, MYH, LKB1, SMAD4, BMPR1A, PTEN, MLH1, MSH2, MSH6 and PMS2) [1,2], predisposes these individuals to the development of multiple colorectal neoplasms. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect
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