Dynamic Effects of CYP2D6 Genetic Variants in a Set of Poor Metaboliser Patients with Infiltrating Ductal Cancer Under Treatment with Tamoxifen.

Breast cancer is a group of multigenic diseases. It is the most common cancer diagnosed among women worldwide and is often treated with tamoxifen. Tamoxifen is catalysed by cytochrome P450 2D6 (CYP2D6), and inter-individual variations in the enzyme due to single nucleotide polymorphisms (SNPs) could alter enzyme activity. We evaluated SNPs in patients from Colombia in South America who were receiving tamoxifen treatment for breast cancer. Allelic diversity in the CYP2D6 gene was found in the studied population, with two patients displaying the poor-metaboliser phenotype. Molecular dynamics and trajectory analyses were performed for CYP2D6 from these two patients, comparing it with the common allelic form (CYP2D6*1). Although we found no significant structural change in the protein, its dynamics differ significantly from those of CYP2D6*1, the effect of such differential dynamics resulting in an inefficient enzyme with serious implications for tamoxifen-treated patients, increasing the risk of disease relapse and ineffective treatment.

Frequency of 14 genetic variants associated with breast cancer risk and treatment in a Colombian population / Frecuencia de 14 variantes genéticas asociadas con el riesgo y el tratamiento del cáncer de mama en una población colombiana

SUMMARY Introduction: Genetic variations have been related to risk and treatment efficacy. Many polymorphisms in breast cancer are known to influence susceptibility, breast cancer risk and treatment outcome. Polymorphisms vary among populations; therefore, local studies are necessary. Objective: To establish the frequency of polymorphisms associated to breast cancer risk and treatment pharmacogenomics in a group of Colombian individuals. Methods: Data from microarray profiles including gene polymorphisms associated with breast cancer treatment were retrospectively collected (Pathway Genomics®). The frequency of marker CYP2D6 rs3892097 and a breast cancer panel (CAS8 rs1045485, CHEK21100delC, ESR1 rs2046210, FGFR2 rs1219648, intergenic_2q35rs13387042, intergenic_8q24 rs13281615, MSRP30 rs10941679, TNRC9 rs3803662, AKAP9 rs6964587, LSP1 rs3817198, MAP3K1rs889312, PALBS1592 delT, ESR1 rs3020314) were studied. Results: Microarray data from 68 men and 92 women were analyzed. All polymorphisms were in Hardy-Weinberg equilibrium. Genotypic frequencies of CYP2D6 rs3892097 C/T, CAS8 rs1045485 G/C, and those of genes included in a breast cancer panel (CAS8 rs1045485, CHEK21100delC, FGFR2rs1219648, intergenic_2q35rs13387042, intergenic_8q24 rs13281615, MSRP30 rs10941679, TNRC9 rs3803662, LSP1 rs3817198, MAP3K1rs889312, PALBS1592 del T, ESR1rs3020314) did not significantly differ from previously published data. ESR1 rs2046210, with allele frequencies of C=0.04 and T=0.02, and AKAP9 rs6964587, with a frequency of A=0.005, were determined as rare. Conclusions: The population studied was not significantly different in allele distribution from previously reported data at HapMap. Genotypes in Colombian population are similar to other previously studied groups of healthy subjects. Extended use of genotyping pharmacogenetic polymorphisms will prevent toxicity and adverse effects in tamoxifen treatment (for example in CYP2D6 rs3892097). Therefore, therapeutic alternatives should be evaluated based on individual pharmacogenetic studies.

RESUMEN Introducción: las variaciones genéticas se han relacionado con el riesgo y la eicacia del tratamiento. Es sabido que muchos polimorfismos en cáncer de mama influyen en la susceptibilidad, el riesgo de cáncer y el resultado del tratamiento. Los polimorfismos varían entre las poblaciones, y por tanto, es necesario realizar estudios locales. Objetivo: establecer la frecuencia de polimorismos asociados al riesgo de cáncer de mama y la farmacogenómica del tratamiento en un grupo de individuos colombianos. Métodos: los datos de los perfiles de microarreglos, incluidos los polimorismos genéticos asociados con el tratamiento del cáncer de mama, se obtuvieron de forma retrospectiva (Pathway Genomics®). Se estudiaron la frecuencia del marcador CYP2D6 rs3892097 y un panel de cáncer de mama (CAS8 rs1045485, CHEK21100delC, ESR1 rs2046210,FGFR2 rs1219648, intergenic_2q35rs13387042, intergenic_8q24 rs13281615, MSRP30 rs10941679, TNRC9 rs3803662, AKAP9 rs6964587, LSP1 rs3817198, MAP3K1rs889312, PALBS1592 delT, ESR1 rs3020314). Resultados: se analizaron los datos de microarreglos de 68 hombres y 92 mujeres. Todos los polimorfismos siguieron el equilibrio Hardy-Weinberg. Las frecuencias fenotípicas de CYP2D6 rs3892097 C/T, CAS8 rs1045485 G/C, y aquellas de los genes incluidos en un panel de cáncer de mama (CAS8 rs1045485, CHEK21100delC, FGFR2rs1219648, intergenic_2q35rs13387042, intergenic_8q24 rs13281615, MSRP30 rs10941679, TNRC9 rs3803662, LSP1 rs3817198, MAP3K1rs889312, PALBS1592 del T, ESR1rs3020314) no difirieron significativamente de los datos publicados previamente. ESR1 rs2046210, con frecuencias alélicas de C = 0,04 y T = 0,02, y AKAP9 rs6964587, con una frecuencia de A = 0,005, se determinaron como raras.

Diabetes-Related Neurological Implications and Pharmacogenomics.

Diabetes mellitus (DM) is the most commonly occurring cause of neuropathy around the world and is beginning to grow in countries where there is a risk of obesity. DM Type II, (T2DM) is a common age-related disease and is a major health concern, particularly in developed countries in Europe where the population is aging. T2DM is a chronic disease which is characterised by hyperglycemia, hyperinsulinemia and insulin resistance, together with the body's inability to use glucose as energy. Such metabolic disorder produces a chronic inflammatory state, as well as changes in lipid metabolism leading to hypertriglyceridemia, thereby producing chronic deterioration of the organs and premature morbidity and mortality. The pathology's effects increase cerebral damage, leading to the rapid onset of neurodegenerative diseases. Hyperglycemia causes oxidative stress in tissues which are susceptible to the complications involved in diabetes, including peripheral nerves. Other additional mechanisms include activation of polyol aldose reductase signalling accompanied by protein kinase C (PKC)-ß activation, poly(ADP ribose) polymerase activation, cyclooxygenase (COX) 2 activation, endothelial dysfunction, altered Na+/K+ ATPase pump function, dyslipidaemia and perturbation of calcium balance. All the forgoing has an impact on neuron activity, mitochondrial function, membrane permeability and endothelial function. These biochemical processes directly affect the neurons and endothelial tissue, thereby accelerating cerebral aging by means of peroxidation of the polyunsaturated fatty acids and thus injuring cell membrane integrity and inducing apoptosis in the glial cells. The Central Nervous System (CNS) includes two types de glial cells: microglia and macroglia (astrocytes, oligodendrocytes and radial cells which include Bergmann cells and Müller cells). Glial cells constitute more than 90% of the CNS cell population. Human studies have shown that some oral antidiabetic drugs can improve cognition in patients suffering mild cognitive impairment (MCI) and dementia [1, 2]. While it is still unclear whether diabetes management will reduce MCI and Alzheimer's disease (AD), incidence, emerging evidence suggests that diabetes therapies may improve cognitive function. This review focuses three aspects: the clinical manifestation of diabetes regarding glial and neuronal cells, the association between neurodegeneration and diabetes and summarises some of the pharmacogenomic data obtained from studies of T2DM treatment, focusing on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly-prescribed oral anti-diabetic drugs (OADs).

Tratamiento de cáncer de seno y farmacogenética / Treatment of breast cancer and pharmacogenetics

El cáncer de seno es un grupo de enfermedades con gran impacto a nivel mundial dado que es una de las patologías con mayor prevalencia en mujeres y el cáncer con mayor tasa de mortalidad en varios países (GLOBOCAN 2012). El uso de la farmacogenética y farmacogenómica, en pacientes con cáncer de seno tiene como fin, generar una salud personalizada que permita tratar a cada paciente como individuo y no como enfermedad, pues cada paciente tiene necesidades particulares a la hora de suministrarle un tratamiento. El propósito de esta revisión es identificar las variantes genéticas reportadas en la literatura científica, donde se evalúan diferentes poblaciones y su posible uso como herramienta para medicina de precisión. En población colombiana es poca la caracterización poblacional que existe y por tanto estudios poblacionales son necesarios para definir los perfiles genéticos que deberán implementarse en nuestra población.

Breast cancer is one of the most prevalent diseases in women with increasing mortality in several countries (GLOBOCAN 2012). The use of pharmacogenetics and pharmacogenomics in patients with breast cancer allows generating personalized health for treating each patient as an individual, as each patient has unique needs when supplying a treatment. The purpose of this review is to identify genetic variants reported in the scientific literature, where different populations are evaluated and for possible use as a tool for medical precision. Colombian population is unique and therefore population studies are needed to define the genetic profiles to be implemented.

Rol biológico y aplicaciones de los miRNAs en cáncer de seno / Biological role and applications of miRNAs in breast cancer

Los miRNAs son pequeños RNAs que participan en diversos procesos de regulación génica, mediante ribointerferencia y juegan un papel clave en diversos procesos biológicos, tales como proliferación celular, diferenciación y apoptosis. En consecuencia, la expresión alterada de miRNAs contribuye a la enfermedad humana, incluyendo cáncer. En esta revisión, nos centraremos en los recientes hallazgos de miRNAs que inciden en el desarrollo de cáncer y particularmente en cáncer de seno, simultáneamente evaluaremos sus mecanismos de regulación, su clasificación, su uso como marcadores de invasión tumoral, de sensibilidad a fármacos y adicionalmente exploraremos la utilidad de los miRNAs en el diagnóstico, seguimiento y tratamiento individualizo. Finalmente encontramos que los miRNAs representan una gran alternativa para entender las bases moleculares de los procesos tumorales implícitos en cáncer de seno y una vez se conozcan todas sus dianas, será posible dilucidar al menos en parte este proceso complejo y multigénico, ayudado mediante herramientas como la generación de bases de datos, para reportan la expresión diferencial de miRNAs, elementos que nos permitirá realizar medicina preventiva y mejorar la calidad de vida de los pacientes y sus familias.

MiRNAs are small RNAs that are involved in various processes of gene regulation by RNAi and play a key role in various biological, such as cell proliferation, differentiation and apoptosis processes. Consequently, the altered expression of miRNAs contribute to human disease, including cancer. In this review, we will focus on the recent findings of miRNAs that affect the development of cancer, particularly breast cancer, simultaneously evaluate their regulatory mechanisms , their classification , their use as markers of tumor invasion, drug susceptibility and further explore the utility of miRNAs in the diagnosis, monitoring and individualize treatment. Finally found that miRNAs represent a great alternative for understanding the molecular basis of implicit tumor processes in breast cancer and once all targets are known, it will be possible to elucidate at least in part this complex and multigenic process, aided by tools such as generation of databases, to report the differential expression of miRNAs, elements that allow us to preventive medicine and improve the quality of life of patients and their families.