One-carbon genetic variants and the role of MTHFD1 1958G>A in liver and colon cancer risk according to global DNA methylation.

Sara Moruzzi,Oliviero Olivieri,Silvia Udali,Nicola Martinelli,Patrizia Pattini,Simonetta Friso,Sang-Woon Choi,Alfredo Guglielmi,Patrizia Guarini,Stephanie A Tammen,Andrea Ruzzenente,Simone Conci,Lorenzo Chiariotti

doi:10.1371/journal.pone.0185792

Sara Moruzzi, Oliviero Olivieri + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0185792

Copy DOI

Journal: PloS one	Publication Date: Oct 2, 2017
Citations: 22	License type: CC BY 4.0

Affiliation: University of Verona, Tufts University, CHA University

Abstract

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation.The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation.

Highlights

One-carbon metabolism is a complex pathway involved both in the nucleotide synthesis and biological methylation reactions [1, 2]
This study demonstrates that the MTHFD1 1958GG genotype shows a higher frequency among cancer patients and it is associated, in all the study subjects, to peripheral blood mononuclear cells (PBMCs) DNA hypomethylation as compared to the A allele carriers
The MTHFD1 1958G>A variants have been mainly studied in relation to neural tube defects and embryonic development [31, 33, 35], but it has been described as associated to cancer disease, with not univocal results [3, 36, 37]

Summary

Introduction

One-carbon metabolism is a complex pathway involved both in the nucleotide synthesis and biological methylation reactions [1, 2]. The molecular mechanisms underlying such association are, not clearly defined yet, while it is known that one-carbon metabolism modulates a major epigenetic mechanism as DNA methylation [7, 8] that is strongly linked to cancer [6]. DNA methylation is a heritable and reversible phenomenon with potential implications for the understanding of molecular mechanisms and disease prevention strategies in complex diseases such as cancer [6]. Both global and gene-specific DNA methylation show altered patterns in cancer disease and, in particular, a global DNA hypomethylation has been described as an almost universal finding in cancer cells [10]. The worldwide mortality rate of liver cancer is 14.6% in males and 5.7% in females, and the mortality of colon cancer is 9.7% in males and 7.0% in females [14]

Methods

Results

Conclusion