Polymorphisms of Arsenic (+3 Oxidation State) Methyltransferase and Arsenic Methylation Capacity Affect the Risk of Bladder Cancer

Abstract

The mechanisms underlying how arsenic methylation capacity affects bladder cancer (BC) are still unclear. The objective of this study was to explore the effects of polymorphisms of arsenic (+3 oxidation state) methyltransferase (AS3MT) on BC risk. We conducted a hospital-based study and enrolled 216 BC and 648 healthy controls from 2007 to 2011. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generation-atomic absorption spectrometry. The gene polymorphisms of AS3MT were identified using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Inefficient arsenic methylation capacity (high monomethylarsonic acid percentage [MMA%] and low dimethylarsinic acid percentage [DMA%]) was associated with increased risk of BC in a dose-response relationship. AS3MT rs11191438 (C > G) G/G genotype, AS3MT rs10748835 (A > G) G/G genotype, and AS3MT rs1046778 (C > T) T/T genotype were found to be related to BC risk, where the odds ratio (OR) (95% CI) was 0.50 (0.31-0.82), 0.49 (0.30-0.79), and 0.54 (0.36-0.80), respectively. The combination of AS3MT haplotype 2 (AS3MT rs11191453, rs11191454, rs10748835, and rs1046778)'s high-risk haplotype (C-G-A-C, T-A-A-C, and T-G-G-T) was significantly associated with increased risk of BC. Among controls, only 3 of the 9 candidate genotypes evaluated, rs1119438 C/C, rs10748835 A/A and rs1046778 C/C, were associated with significantly higher MMA% compared with the other genotypes. No other genotypes or haplotypes were related to arsenic methylation capacity. High MMA%, low DMA% and AS3MT rs1046778 C/C + C/T genotype predicted a significantly higher risk of BC according to stepwise multiple logistic regression analyses. AS3MT gene polymorphisms and arsenic methylation capacity appeared to affect BC risk independently.

Inorganic arsenic‐mediated upregulation of AS3MT promotes proliferation of nonsmall cell lung cancer cells by regulating cell cycle genes

“…To our knowledge, this has not been reported in any studies. Generally speaking, AS3MT impact the risk of cancer by affecting arsenic metabolism 11,13,14 . But, it is unclear whether overexpression of AS3MT by arsenic exposure could directly act on the cell and affect the progression of NSCLC.…”

“…AS3MT, an enzyme that is encoded by the AS3MT gene in humans, which catalyzes the transfer of a methyl group from S‐adenosy‐L‐methionine (SAM) to trivalent arsenical 12 . It has been demonstrated that polymorphisms of AS3MT rs11191438 and AS3MT rs1046778 were associated with the risk of bladder cancer and upper tract urothelial carcinoma by affecting arsenic methylation capacity 13,14 . Similarly, AS3MT polymorphisms also impact the risk of lung cancer 11 .…”

“…12 It has been demonstrated that polymorphisms of AS3MT rs11191438 and AS3MT rs1046778 were associated with the risk of bladder cancer and upper tract urothelial carcinoma by affecting arsenic methylation capacity. 13,14 Similarly, AS3MT polymorphisms also impact the risk of lung cancer. 11 Furthermore, AS3MT has been found to be upregulated and negatively correlated with antioncogene mir-548c-3p in arsenic-exposed population.…”

As3MT and GST Polymorphisms Influencing Arsenic Metabolism in Human Exposure to Drinking Groundwater

“…The focus of these differences may be the direct or indirect relationship that these genes have with the degree of methylation of urinary arsenic species. One of the current hypothesis of the arsenic methylation efficiency in the toxicity of arsenic supposes that a lower excretion of DMA is the result of a decreasing in the degree of methylation of the inorganic forms, generating a minor individual metabolic capacity of arsenic [34,47]. Methylated species of arsenic are recognized to be less toxic than inorganic ones, the methylation has been considered to be a detoxification mechanism for arsenic in the mammals [12].…”

“…Nevertheless, its effects are minors [2,31]. Conversely, As3MT and GSTO are polymorphisms that have the most evidence associated with the capacities to metabolize arsenic, through the increasing in the expression of the enzymatic activity responsible for the methylation of inorganic arsenic [32][33][34][35]. Genetic polymorphisms in these enzymes have been shown to have differences in frequencies (genotypic and allelic) worldwide, depending on ethnicity/race [36,37].…”