The urinary arsenic metabolites may vary among individuals and the genetic factors have been reported to explain part of the variation. We assessed the influence of polymorphic variants of Arsenic-3-methyl-transferase and Glutathione-S-transferase on urinary arsenic metabolites. Twenty-two groundwater wells for human consumption from municipalities of Colombia were analyzed for assessed the exposure by lifetime average daily dose (LADD) (µg/kg bw/day). Surveys on 151 participants aged between 18 and 81 years old were applied to collect demographic information and other factors. In addition, genetic polymorphisms (GSTO2-rs156697, GSTP1-rs1695, As3MT-rs3740400, GSTT1 and GSTM1) were evaluated by real time and/or conventional PCR. Arsenic metabolites: As^III, As^V, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were measured using HPLC-HG-AFS. The influence of polymorphic variants, LADD and other factors were tested using multivariate analyses. The median of total arsenic concentration in groundwater was of 33.3 μg/L and the median of LADD for the high exposure dose was 0.33 µg/kg bw/day. Univariate analyses among arsenic metabolites and genetic polymorphisms showed MMA concentrations higher in heterozygous and/or homozygous genotypes of As3MT compared to the wild-type genotype. Besides, DMA concentrations were lower in heterozygous and/or homozygous genotypes of GSTP1 compared to the wild-type genotype. Both DMA and MMA concentrations were higher in GSTM1-null genotypes compared to the active genotype. Multivariate analyses showed statistically significant association among interactions gene-gene and gene-covariates to modify the MMA and DMA excretion. Interactions between polymorphic variants As3MT*GSTM1 and GSTO2*GSTP1 could be potential modifiers of urinary excretion of arsenic and covariates as age, LADD, and alcohol consumption contribute to largely vary the arsenic individual metabolic capacity in exposed people.

Prognostic markers for cancer can assist in the evaluation of survival probability of patients and help clinicians to assess the available treatment modalities. Gallbladder cancer (GBC) is a rare tumor that causes 165 087 deaths in the world annually. It is the most common cancer of the biliary tract and has a particularly high incidence in Chile, Japan, and northern India. Currently, there is no accurate diagnosis test or effective molecular markers for GBC identification. Several studies have focused on the discovery of genetic alterations in important genes associated with GBC to propose novel diagnosis pathways and to create prognostic profiles. To achieve this, we performed data-mining of GBC in public repositories, harboring 133 samples of GBC, allowing us to describe relevant somatic mutations in important genes and to propose a genetic alteration atlas for GBC. In our results, we reported the 14 most altered genes in GBC: arid1a, arid2, atm, ctnnb1, erbb2, erbb3, kmt2c, kmt2d, kras, pik3ca, smad4, tert, tp53, and znf521 in samples from Japan, the United States, Chile, and China. Missense mutations are common among these genes. The annotations of many mutations revealed their importance in cancer development. The observed annotations mentioned that several mutations found in this repository are probably oncogenic, with a putative loss-of-function. In addition, they are hotspot mutations and are probably linked to poor prognosis in other cancers. We identified another 11 genes, which presented a copy number alteration in gallbladder database samples, which are ccnd1, ccnd3, ccne1, cdk12, cdkn2a, cdkn2b, erbb2, erbb3, kras, mdm2, and myc. The findings reported here can help to detect GBC cancer through the development of systems based on genetic alterations, for example, the development of a mutation panel specifically for GBC diagnosis, as well as the creation of prognostic profiles to accomplish the development of GBC and its prevalence.

Testicular cancer is one of the most commonly occurring malignant tumors in young men with fourfold higher rate of incidence and threefold higher mortality rates in Chile than the average global rates. Surgery is the initial line of treatment for testicular cancers, and is generally followed by chemotherapy, usually with combinations of bleomycin, etoposide, and cisplatin (BEP). However, the adverse effects of chemotherapy vary significantly among individuals; therefore, the present study explored the association of functionally significant allelic variations in genes related to the pharmacokinetics/pharmacodynamics of BEP and DNA repair enzymes with chemotherapy-induced toxicity in BEP-treated testicular cancer patients. We prospectively recruited 119 patients diagnosed with testicular cancer from 2010 to 2017. Genetic polymorphisms were analyzed using PCR and/or qPCR with TaqMan^®probes. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, v4.03. After univariate analyses to define more relevant genetic variants (p < 0.2) and clinical conditions in relation to severe (III–IV) adverse drug reactions (ADRs), stepwise forward multivariate logistic regression analyses were performed. As expected, the main severe ADRs associated with the non-genetic variables were hematological (neutropenia and leukopenia). Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1-null genotype could develop lymphocytopenia (III–IV). Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia. The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p < 0.05). Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia. Grades III–IV vomiting, nausea, and alopecia could be partly explained by the presence of specific ERCC1/2, MDR1, GSTP1, and BLMH genotypes (p < 0.05). Hence, we provide evidence for the usefulness of pharmacogenetics as a tool for predicting severe ADRs in testicular cancer patients treated with BEP chemotherapy.

Introducción. El citocromo CYP2C9 metaboliza, aproximadamente, el 15 % de los fármacos prescritos. Su gen presenta alelos cuyas frecuencias difieren entre grupos étnicos y poblaciones. Los alelos CYP2C9*2 y CYP2C9*3 dan cuenta de una enzima con actividad disminuida cuya frecuencia no ha sido determinada en la población mestiza peruana.Objetivo. Caracterizar la frecuencia de las variantes *2 (rs1799853) y *3 (rs1057910) del gen CYP2C9 en muestras de población mestiza peruana provenientes de Lima, Tacna y Junín.Materiales y métodos. Se hizo un estudio descriptivo, observacional y prospectivo, con muestreo no probabilístico, por conveniencia e incidental. Se incluyeron 218 sujetos según los criterios de inclusión y exclusión; todos los participantes otorgaron su consentimiento informado. El ADN genómico se obtuvo mediante hisopado de mucosa oral, y la detección de los genotipos para los alelos CYP2C9*2 y CYP2C9*3 se hizo mediante reacción en cadena de la polimerasa (PCR) en tiempo real, utilizando sondas TaqMan™.Resultados. Las variantes de CYP2C9*2 y CYP2C9*3 están presentes en la población mestiza peruana con frecuencias de 0,046 y 0,062, respectivamente. El análisis de las frecuencias genotípicas observadas permitió predecir que la frecuencia de fenotipos metabolismo intermedio sería del 15,13 % (CYP2C9*1/*2: 5,96 %; CYP2C9*1/*3: 9,17 %), y la de fenotipos de metabolismo lento, del 3,22 % (CYP2C9*2/*2: 1,38 %; CYP2C9*3/*3: 1,38 %; CYP2C9*2/*3: 0,46 %).Conclusiones. Se lograron determinar las frecuencias genotípicas y alélicas para las variantes *2 y *3 del gen CYP2C9 en una muestra no probabilística de población mestiza peruana.

Epilepsy is the most common neurological disorder with a worldwide incidence of 20% and a treatment failure rate of 25–30%. The fluctuation in serum levels, efficacy and safety of antiepileptic drugs can be attributed to single nucleotide polymorphisms of genes encoding their respective proteins involved in drug metabolism. The present study attempted to evaluate the pharmacogenetic variants of CYP2C9 and CYP2C19 associated with adverse reactions induced by antiepileptic drugs used in Peru. Few studies were found to significantly associate the CYP2C9*2, CYP2C9*3, CYP2C19*2, and CYP2C19*3 single nucleotide polymorphisms with elevated serum levels of valproic acid and carbamazepine, and valproic acid induction of hyperammonemia, and adverse reactions cutaneous for carbamazepine. There is further evidence of a significant association of CYP2C9*2/CYP2C9*3 with severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and epidermal necrolysis (TEN) phenytoin-induced. CYP2C9*3 may be a pharmacogenetic biomarker for such a drug. It is proposed to reduce the dose of drugs for intermediate and poor metabolizers. No pharmacogenetic studies were found in patients with epilepsy in Peruvian populations. It is concluded that this review could help physicians in the prediction and prevention of adverse reactions induced by antiepileptic drugs, as well as to improve their pharmacotherapeutic results. It could also be used as scientific evidence to carry out pharmacogenetic and precision medicine studies in Peruvian patients with epilepsy, due to their tricontinental and Latin American ancestry.