Abstract
The cause of multiple myeloma (MM) remains largely unknown. Several pieces of evidence support the involvement of genetic and multiple environmental factors (i.e., chemical agents) in MM onset. The inter-individual variability in the bioactivation, detoxification, and clearance of chemical carcinogens such as asbestos, benzene, and pesticides might increase the MM risk. This inter-individual variability can be explained by the presence of polymorphic variants in absorption, distribution, metabolism, and excretion (ADME) genes. Despite the high relevance of this issue, few studies have focused on the inter-individual variability in ADME genes in MM risk. To identify new MM susceptibility loci, we performed an extended candidate gene approach by comparing high-throughput genotyping data of 1936 markers in 231 ADME genes on 64 MM patients and 59 controls from the CEU population. Differences in genotype and allele frequencies were validated using an internal control group of 35 non-cancer samples from the same geographic area as the patient group. We detected an association between MM risk and ADH1B rs1229984 (OR = 3.78; 95% CI, 1.18–12.13; p = 0.0282), PPARD rs6937483 (OR = 3.27; 95% CI, 1.01–10.56; p = 0.0479), SLC28A1 rs8187737 (OR = 11.33; 95% CI, 1.43–89.59; p = 0.005), SLC28A2 rs1060896 (OR = 6.58; 95% CI, 1.42–30.43; p = 0.0072), SLC29A1 rs8187630 (OR = 3.27; 95% CI, 1.01–10.56; p = 0.0479), and ALDH3A2 rs72547554 (OR = 2.46; 95% CI, 0.64–9.40; p = 0.0293). The prognostic value of these genes in MM was investigated in two public datasets showing that shorter overall survival was associated with low expression of ADH1B and SLC28A1. In conclusion, our proof-of-concept findings provide novel insights into the genetic bases of MM susceptibility.
Highlights
Multiple myeloma (MM) accounts for approximately 1% of all cancers and 10% of all hematologic malignancies
We identified an association between MM risk and the SLC28A2 rs1060896 (p = 0.0125) while we found that the Minor Allele Frequency (MAF) for seven variant alleles in seven genes was undetectable in the CEU control group and over-represented in the MM group
Products of endobiotic/xenobiotic metabolism can impact the onset and progression of cancer by the activation of DNA damage can impact thefactor onsetsignaling and progression of cancer by the activation of DNA
Summary
Multiple myeloma (MM) accounts for approximately 1% of all cancers and 10% of all hematologic malignancies. In 2020, based on the GLOBOCAN database (https://gco.iarc.fr/today, accessed on 10 November 2021 ), the estimated number of new cases diagnosed yearly in Europe was over 50,000, and almost 32,000 patients die of the disease. There is strong evidence that obesity, systemic inflammation, oxidative stress, and exposure to radiation or environmental chemical agents might increase the risk of MM [2]. It has been reported that inherited genetic variants significantly contribute to MM onset, accounting for approximately 16% of cases [3]. Environmental exposure to chemicals such as dioxin, asbestos, benzene, and pesticides are causally connected to MM transition from the two stages of Monoclonal Gammopathy of Uncertain Significance (MGUS) and Smouldering Multiple Myeloma [4]. The metabolism of chemical carcinogens relies on key processes such as bioactivation by phase
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