Effects of Arsenic (+3 Oxidation State) Methyltransferase Gene Polymorphisms and Risk of Bladder Cancer

Bladder cancer ranks as the ninth most common malignant tumor worldwide. Cigarette smoking is among factors known to be associated with increased risk — with smokers exhibiting 3-fold higher risk of developing bladder cancer than nonsmokers. In addition, chronic exposure to chemicals in the environment, more specifically occupational exposure (e.g. workers in the dye industry) is another factor that might increase bladder cancer risk. Inorganic arsenic (As) is a known human carcinogen, commonly ingested by human populations in contaminated water and food, as well as inhalation of particulate matter in polluted air (such as that seen in recent wildfires in the US). In humans, As is reduced to arsenite (AsIII); after methylation by S-adenosylmethionine, AsIII is converted to monomethylated arsenate (MMA) and dimethylated arsenate (DMA), both of which are excreted in urine. Compared with As, MMA and DMA are far more chemically reactive (and therefore more toxic) and more likely to result in bladder cancer.

Heritable differences in the AS3MT gene encoding the arsenic (+3 oxidation state) methyltransferase enzyme (AS3MT) exist in human populations; this could be an additional parameter, when considering risk of AS-induced bladder cancer. Several studies have assessed the possible association of AS3MT polymorphisms with high vs low enzyme activity. To this end, eight single-nucleotide variants (SNVs) have been extensively studied [rs1046778, rs11191439, rs3740393, rs11191438, rs10748835, rs3740391, rs3740392, and rs11191454; see attached article for more details]; authors therefore queried whether AS3MT expression might influence the clinicopathologic characteristics, risk, and prognosis of bladder cancer.

Authors reviewed “eligible” case-control studies of AS3MT polymorphisms and bladder cancer by meta-analysis. They also conducted a series of analyses, based on The Cancer Genome Atlas (TGCA) dataset. Five articles were recruited; authors state that the “pooled results demonstrated that rs3740393 and rs11191438 polymorphisms are related to bladder cancer risk in the overall population (P <0.05) and that GG and GC genotypes in rs3740393, and GG genotype in rs11191438, might be susceptibility genotypes for bladder cancer.” Authors also state that “results, based on 168 bladder cancer samples from TGCA, indicated that patients with higher AS3MT expression had poorer overall survival time (i.e. AS3MT expression is an independent indicator for bladder cancer prognosis).” However, these kinds of “P <0.05 studies” very often are identifying false positives, due to the >3 billion nucleotides in the haploid genome of each individual, thereby requiring a P-value of <5.0 x 10–8 (also denoted as <5.0e–08) in order to reach statistical significance. The title of this [attached] paper was exciting — which was the reason these GEITP pages chose to highlight it. Sadly, however, this “meta-analysis paper” was improperly reviewed and should never have been accepted for publication. Alternatively, authors might have concluded from their meta-analysis that “no statistically significant association was found.” The sizes of the cohorts were likely far too small to reach statistical significance (i.e. perhaps statistical significance of <5.0e-08 could be achieved — assigning AS3MT as a small-effect gene contributing to bladder cancer risk — if one had 100,000 cases of bladder cancer, compared with 100,000 controls?). * * * * * * * * * * In comparison, consider a genome-wide association study (GWAS) of 1,313 As-exposed Bangladeshi individuals, in which five highly significant SNVs in and near the AS3MT gene showed independent associations with As-induced toxicity at a significance level of P <5.0e–08, with five SNVs showing independent associations. Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individuals’ lymphocyte RNA also suggested that several of these identified SNVs represent cis-eQTLs for AS3MT (P = 1.0e-12) and for neighboring gene C10orf32 (P = 10e-44), which is involved in C10orf32-AS3MT read-through transcription [PLoS Genet 2012; 8: e1002522].This paper is commendable 😊, especially compared to the [attached] article. ☹ DwN Toxicol Sci Sept 2020; 77: 27-40 COMMENT: I think this is interesting. Arsenic is known to induce bladder cancer, so it makes sense that the AS3MT gene encoding As3MT is likely to be associated with this increased risk of bladder cancer. So, they simply need a larger cohort to prove this. It is also interesting that this gene was demonstrated in 2012 to be associated with arsenic-induced toxicity. Sooner or later, a GWAS will show an association between SNVs in and near the AS3MT gene and arsenic-induced skin cancer. In the past we discovered aquaporin-9 (AQP9) transports arsenic. However, I don’t see yet any GWAS results to show an association between the AQP9 gene and arsenic-related diseases...

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