Variantes genéticas y actividad enzimática de la citidin desaminasa: relación con la toxicidad a la capecitabina y recomendación de ajuste de las dosis / Genetic variants and enzyme activity in citidin deaminase: Relationship with capecitabine toxicity and recommendation for dose adjustment

Objetivo: la capecitabina es un fármaco antineoplásico utilizado en el tratamiento del cáncer de mama y de colon que puede dar lugar a una toxicidad grave, llegando a ser mortal en algunos pacientes. La variabilidad interindividual de esta toxicidad es debida en gran medida a las variaciones genéticas en los genes diana y las enzimas de metabolismo de este fármaco, como la timidilato sintasa y la dihidropirimidina deshidrogenasa. La enzima citidin desaminasa (CDA), imprescindible en la activación de la capecitabina, también presenta diversas variantes asociadas con un mayor riesgo de toxicidad al tratamiento, aunque su papel como biomarcador aún no está claramente definido. Por ello, nuestro objetivo principal es estudiar la asociación entre la presencia de las variantes genéticas en el gen CDA, su actividad enzimática y el desarrollo de la toxicidad grave en los pacientes tratados con capecitabina, cuya dosis inicial se haya ajustado con base en el perfil genético del gen de la dihidropirimidina deshidrogenasa (DPYD). Método: estudio de cohortes observacional multicéntrico prospectivo, centrado en el análisis de la asociación genotipo-fenotipo de la enzima CDA. Tras la fase experimental, se desarrollará un algoritmo que permita determinar el ajuste necesario de las dosis para disminuir el riesgo de toxicidad del tratamiento en función del genotipo CDA, elaborando una guía clínica para la dosificación de la capecitabina en función de las variantes genéticas en DPYD y CDA. Con base en esta guía, se creará una herramienta bioinformática que genere el informe farmacoterapéutico de manera automática, facilitando la implementación del consejo farmacogenético en la práctica clínica. Esta herramienta proporcionará un gran respaldo en la toma de decisiones farmacoterapéuticas basadas en el perfil genético del paciente, incorporando la medicina de precisión en la rutina clínica. ... (AU)

Objective: Capecitabine, an antineoplastic drug used in the treatment of breast and colon cancer, can cause severe, even fatal toxicity in some patients. The interindividual variability of this toxicity is largely due to genetic variations in target genes and enzymes of metabolism of this drug, such as thymidylate synthase and dihydropyrimidine dehydrogenase. The enzyme cytidine deaminase (CDA), involved in the activation of capecitabine, also has several variants associated with an increased risk of toxicity to treatment, although its role as a biomarker is not yet clearly defined.Therefore, our main objective is to study the association between the presence of genetic variants in CDA gen, CDA enzymatic activity and the development of severe toxicity in patients treated with capecitabine whose initial dose was adjusted based on the genetic profile of the dihydropyrimidine dehydrogenase gen (DPYD). Method: Prospective multicenter observational cohort study, focused on the analysis of the genotype-phenotype association of the CDA enzyme.After the experimental phase, an algorithm will be developed to determine the dose adjustment needed to reduce the risk of treatment toxicity according to CDA genotype, developing a clinical guide for capecitabine dosing according to genetic variants in DPYD and CDA. Based on this guide, a Bioinformatics Tool will be created to generate the pharmacotherapeutic report automatically, facilitating the implementation of pharmacogenetic advice in clinical practice. This tool will be a great support in making pharmacotherapeutic decisions based on the patient's genetic profile, incorporating precision medicine into clinical routine. Once the usefulness of this tool has been validated, it will be offered free of charge to facilitate the implementation of pharmacogenetics in hospital centers and equitably benefit all patients on capecitabine treatment. (AU)

[Translated article] Genetic variants and enzyme activity in citidin deaminase: Relationship with capecitabine toxicity and recommendation for dose adjustment.

OBJECTIVE: Capecitabine, an antineoplastic drug used in the treatment of breast and colon cancer, can cause severe, even fatal toxicity in some patients. The interindividual variability of this toxicity is largely due to genetic variations in target genes and enzymes of metabolism of this drug, such as Thymidylate Synthase (TS) and Dihydropyrimidine Dehydrogenase (DPD). The enzyme Cytidine Deaminase (CDA), involved in the activation of capecitabine, also has several variants associated with an increased risk of toxicity to treatment, although its role as a biomarker is not yet clearly defined. Therefore, our main objective is to study the association between the presence of genetic variants in CDA gen, CDA enzymatic activity and the development of severe toxicity in patients treated with capecitabine whose initial dose was adjusted based on the genetic profile of the DPD gen (DPYD). METHOD: Prospective multicenter observational cohort study, focused on the analysis of the genotype-phenotype association of the CDA enzyme. After the experimental phase, an algorithm will be developed to determine the dose adjustment needed to reduce the risk of treatment toxicity according to CDA genotype, developing a Clinical Guide for capecitabine dosing according to genetic variants in DPYD and CDA. Based on this guide, a Bioinformatics Tool will be created to generate the pharmacotherapeutic report automatically, facilitating the implementation of pharmacogenetic advice in clinical practice. This tool will be a great support in making pharmacotherapeutic decisions based on the patient's genetic profile, incorporating precision medicine into clinical routine. Once the usefulness of this tool has been validated, it will be offered free of charge to facilitate the implementation of pharmacogenetics in hospital centers and equitably benefit all patients on capecitabine treatment.

Genetic variants and enzyme activity in citidin deaminase: Relationship with capecitabine toxicity and recommendation for dose adjustment. / Variantes genéticas y actividad enzimática de la citidin desaminasa: relación con la toxicidad a la capecitabina y recomendación de ajuste de las dosis.

OBJECTIVE: Capecitabine, an antineoplastic drug used in the treatment of breast and colon cancer, can cause severe, even fatal toxicity in some patients. The interindividual variability of this toxicity is largely due to genetic variations in target genes and enzymes of metabolism of this drug, such as thymidylate synthase and dihydropyrimidine dehydrogenase. The enzyme cytidine deaminase (CDA), involved in the activation of capecitabine, also has several variants associated with an increased risk of toxicity to treatment, although its role as a biomarker is not yet clearly defined. Therefore, our main objective is to study the association between the presence of genetic variants in CDA gen, CDA enzymatic activity and the development of severe toxicity in patients treated with capecitabine whose initial dose was adjusted based on the genetic profile of the dihydropyrimidine dehydrogenase gen (DPYD). METHOD: Prospective multicenter observational cohort study, focused on the analysis of the genotype-phenotype association of the CDA enzyme. After the experimental phase, an algorithm will be developed to determine the dose adjustment needed to reduce the risk of treatment toxicity according to CDA genotype, developing a clinical guide for capecitabine dosing according to genetic variants in DPYD and CDA. Based on this guide, a Bioinformatics Tool will be created to generate the pharmacotherapeutic report automatically, facilitating the implementation of pharmacogenetic advice in clinical practice. This tool will be a great support in making pharmacotherapeutic decisions based on the patient's genetic profile, incorporating precision medicine into clinical routine. Once the usefulness of this tool has been validated, it will be offered free of charge to facilitate the implementation of pharmacogenetics in hospital centers and equitably benefit all patients on capecitabine treatment.

DPYD variant testing in candidates for fluoropyrimidine treatment: A study protocol.

OBJECTIVE: The main purpose of this study is to evaluate the potential clinical impact of pharmacogenetic testing on the reduction of the toxicity in patients treated with fluoropyrimidines. This will be achieved by  comparing the frequency of adverse events and the incidence of toxicity of two groups of patients that will differ from each other only in that one  will receive pharmacogenetic counseling. The hypothesis is that availability of a pharmacogenetic report prior to treatment initiation has a positive  effect. One of the main secondary goals is to analyze allele frequencies  and the association of polymorphisms rs895819 (miR27A) and rs1801160  (DPYD*6) with toxicity by conducting an observational study to determine  their clinical relevance and standardize a dose adjustment  recommendation. METHOD: The study has an single-center ambispective, quasi-experimental design and is based on a multidisciplinary protocol involving  implementation and standardization of DPYD*2A; DPYD*13; c.2846A>T;  and HapB3 measurements. Following these measurements,  pharmacogenetic counseling will be carried out and its clinical impact will  be evaluated. The primary endpoint of the study is severe toxicity and/or  mortality. The toxicity observed in two groups with similar epidemiological  characteristics will be compared: the intervention group (candidates for  treatment with fluoropyrimidines who will be subjected to the protocol)  and the control group (retrospective cohort). Additionally, rs895819  (MIR27A) and rs1801160 (DPYD*6) will be determined. Testing for these  variants is not part of the hospital's daily practice, nor are they included in  clinical guidelines. However, according to recently published studies, the  activity of dihydropyrimidine dehydrogenase might be affected by these  variants, as they may be associated with toxicity. The results of the  measurements of these two variants will not be incorporated to  pharmacogenetics counseling until their association with toxicity is  determined by means of the observational study to be conducted. The  project, as well as the patient information sheet and the informed consent  form, were approved by the Ethics Committee of the participating center  (code 20/006).

Objetivo: El objetivo principal es evaluar el impacto clínico de la implementación de la farmacogenética en la reducción de toxicidad en pacientes tratados con fluoropirimidinas, comparando frecuencia y  grado de toxicidad con una población de las mismas características, pero  sin orientación farmacogenética, y demostrando que la disponibilidad de  un informe farmacogenético previo al inicio del tratamiento tiene influencia positiva. Uno de los principales objetivos secundarios es analizar la frecuencia y la asociación del polimorfismo con toxicidad de rs895819 en MIR27A y DPYD*6, mediante un estudio observacional, para determinar su relevancia clínica y poder estandarizar una recomendación  de ajuste de dosis.Método: Estudio con diseño ambispectivo, cuasi-experimental, nicéntrico, llevado a cabo mediante un protocolo de actuación  multidisciplinar, a través del cual se implantará la determinación de  PYD*2A, DPYD*13, c.2846A>T, HapB3, se estandarizará y se realizará el  consejo farmacogenético y posteriormente se evaluará su impacto clínico.  La variable principal es la toxicidad severa y/o mortalidad. Se compararán  dos grupos con características epidemiológicas similares, grupo  intervención (pacientes candidatos a tratamiento con fluoropirimidinas y  sobre los que se implantará el protocolo) y grupo control (cohorte  retrospectiva). Por otra parte, se determinará rs895819 en MIR27A y  DPYD*6, estas variantes no forman parte de la práctica diaria del hospital  ni están contempladas en guías clínicas, pero según estudios publicados  recientemente, pueden afectar a la actividad de la enzima y estar  asociados con toxicidad. Los resultados de estas dos variantes no  intervendrán en el consejo farmacogenético hasta determinar su  asociación con la toxicidad, precisamente mediante el estudio  observacional que se llevará a cabo. Tanto el proyecto como la hoja de  información al paciente y el consentimiento informado han sido aprobados  por el Comité Ético del centro participante, código: 20/006.

Genotype of Null Polymorphisms in Genes GSTM1, GSTT1, CYP1A1, and CYP1A1*2A (rs4646903 T>C)/CYP1A1*2C (rs1048943 A>G) in Patients with Larynx Cancer in Southeast Spain.

BACKGROUND: some types of cancer have been associated with the presence of single nucleotide polymorphisms (SNPs) of some genes that encode enzymes: glutathione-S transferase (GST), whose alteration leads to loss of function and a lower capacity to eliminate toxic GSTM1 and GSTT1 null genotypes; SNPs causing loss of function of CYP1A1 or CYP1A1-2 cytochrome P450 enzymes related with a lower capacity to deactivate hydrocarbons related to smoking, which involves a higher risk of developing some smoking-dependent cancers including larynx cancer. OBJECTIVE: to compare the presence of null SNPs in genes GSTM1, GSTT1, and CYP1A1 rs 4646903 T>C, and CYP1A1-2 RS1048943 A>G in patients with hypopharyngeal and larynx cancer with a healthy control group. MATERIALS AND METHOD: The study included a total of 80 patients with hypopharyngeal and laryngeal cancer and 23 healthy subjects. Genomic DNA was obtained from saliva samples, determining genotype GSTM1 (present +, or null -), GSTT1 (present + or null -). Polymorphisms (SNP) in CYP1A1 T>C (present + CC, or absent - TC/TT), and CYP1A1-2 A>G (present + GG, or absent - AG/AA). RESULTS: the mean age of patients with larynx cancer was 62 years and of control subjects 63 years. Of the total sample, over 95% were men, and over 90% were smokers. The presence of null genotypes for GTM1 was 50% in patients with larynx cancer (p = 0.042), while GSTT1 was 88.75% (p = 0.002). CYP1A1 rs4646903 T>C polymorphisms were detected in 100% of cases of larynx cancer and 17.39% of healthy subjects (p > 0.001). CONCLUSIONS: patients with larynx cancer present more gene GSTM1 and GSTT1 null polymorphisms, and CYP1A1 rs4646903 T>C polymorphisms.

Genotyping of the C>T allele of rs16906252, predictor of O16-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, in erosive atrophic lesions of oral lichen planus.

BACKGROUND: DNA promoter methylation is usually an early stage in carcinogenesis process, including oral cancer. The purpose of this study was to investigate the association between T allele of specific single nucleotide polymorphism (SNP) C>T rs 16906252 and O16-methylguanine-DNA methyltransferase (MGMT) methylation as prospective biomarkers of malignant transformation in oral lichen planus (OLP), a chronic autoimmune mucocutaneous disease. METHODS: This research is an observational, analytical case-control study where a total of 85 subjects (43 control individuals and 42 OLP patients) participated. The samples (mouthwashes) from all volunteers were analyzed, and DNA extraction was carried out. The genotyping of the rs 16906252 SNP in the MGMT gene was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Statistical analyses of Student t test and multiple logistic regressions were used. RESULTS: C>T genotype in the control and OLP groups was detected in 2.3% and 19.0%, respectively. The presence of this genotype was associated with methylation of the MGMT gene. In fact, taking into account age and gender, subjects with C>T genotype were 10.5 (95% CI 1.03-106; P = 0.047) times more likely to methylate promoter region of the MGMT gene. CONCLUSIONS: These findings indicate that C>T allele of rs 16906252, predictor of MGMT promoter methylation status, may be an important feature in the clinical prognosis of premalignant lesions of OLP, although this finding requires further clinical and laboratory investigation.

La enseñanza de Farmacogenética/Farmacogenómica y Genética en las facultades de Farmacia de España, las causas del atraso / Teaching of Pharmacogenetics, Pharmacogenomics and Genetics in Spanish Pharmacy Faculties; causes of delay

La asignatura de Farmacogenética/Farmacogenómica (FG) se imparte en el 26,1% de las facultades de Farmacia (FF), siendo su porcentaje en las privadas del 40% y en las públicas 15,3%, y la de Genética en un 30,4%, homogéneo en ambas. Hace 6 años, en el 2010, y referido a la FG, este porcentaje era más de 3 veces superior (89,3%) en las FF de Estados Unidos. El mayor porcentaje de aquellas en las que no se imparte ninguna de las 2 asignaturas se da en las facultades que concentran la mayor oferta de plazas. En aquellas que las imparten, el carácter es mayoritariamente obligatorio. A la asignatura de Genética se le dedican 6 ECTS y a la de FG 3 ECTS. Ambas tienen un marcado carácter teórico, con una escasa o nula formación en el ámbito experimental, analítico, clínico o sanitario. Las desigualdades formativas de estas materias en nuestro país, cuando los conocimientos son universales, sientan las bases para una desigual aplicación de los avances científicos y condicionan el principio de universalidad de nuestra sanidad. Esta falta de conocimientos impide hoy una dispensación segura y eficaz en un buen número de fármacos siguiendo las recomendaciones de agencias reguladoras, como la Agencia Europea de Medicamentos o la Food and Drug Administration

The subject of Pharmacogenetics/Pharmacogenomics (PG) is provided in the 26.1% of the Spanish Pharmacy faculties, with the percentage being higher in private faculties (40%) than in the public ones (15.3%), and similar in Genetics (30.4%, in both). Six years ago in 2010, the teaching of PG was three times higher (89.3%) in American faculties. The higher percentage of those who do not provide/teach either of these two subjects relates to faculties that offer a higher number of places. In those where it is provided, it is mainly a mandatory subject. The subject of Genetics subject consists of 6 ECTS (European credit transfer and accumulation system), and the PG course 3 ECTS. Both have a high theoretical content, with a partial or total absence of practical, analytical, or health-related training. As knowledge is universal, these inequalities in the area of education of those subjects in our country lays the foundation for an unequal application of scientific advances and influences the principal of universality in our health. This lack of knowledge prevents having a safe and effective dispensation of drugs, following the recommendations of Regulatory Agencies like European Medicines Agency and Food and Drug Administration