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.

Mutational spectrum in breast cancer associated BRCA1 and BRCA2 genes in Colombia / Espectro de mutaciones en los genes BRCA1 y BRCA2 asociados a cáncer de mama en Colombia

Abstract Introduction: The risk of developing breast and ovarian cancer is higher in families that carry mutations in BRCA1 or BRCA2 genes, and timely mutation detection is critical. Objective: To identify the presence of mutations in the Colombian population and evaluate two testing strategies. Methods: From a total universe of 853 individual blood samples referred for BRCA1 and BRCA2 typing, 256 cases were analyzed by complete direct sequencing of both genes in Myriad Genetics, and the remaining 597 cases were studied by partial sequencing based on founder mutations in a PCR test designed by ourselves ("Profile Colombia"). Results: We found 107 patients carrying deleterious mutations in this group of patients, 69 (64.5%) located in BRCA1, and 38 (35.5%) in BRCA2. Overall, we detected 39 previously unreported mutations in Colombia (22 in BRCA1 and 17 in BRCA2) and only 4 out of the 6 previously reported founder mutations. Sixty four out of 597 patients (10.7%) studied by "Profile Colombia" showed mutations in BRCA1 or BRCA2, and 41/256 patients (16%) showed mutations by complete BRCA1-BRCA2 sequencing. Conclusions: The spectrum of 44 different mutations in Colombia as detected in our study is broader than the one previously reported for this country. "Profile Colombia" is a useful screening test to establish both founder and new mutations (detection rate of 10.7%) in cases with family history of breast cancer. Complete sequencing shows a detection rate of 16.0%, and should complement the study of the genetic basis of this disease.

Resumen Introducción: El riesgo de desarrollar cáncer de mama y cáncer de ovario puede transmitirse en familias que porten mutaciones en los genes BRCA1 o BRCA2. La detección de estas mutaciones permite tomar decisiones oportunas en el ámbito de la medicina preventiva. Objetivo: Estudiar el espectro de mutaciones en la población colombiana y evaluar dos estrategias de detección. Metodos: Se incluyeron en total 853 pacientes con diagnóstico de cáncer de mama y con solicitud de análisis de los genes BRCA1 y BRCA2. Un total de 256 pruebas se analizaron mediante secuencia directa completa de estos genes en Myriad Genetics, y las restantes 597 se estudiaron mediante secuencia parcial basada en mutaciones fundadoras a través de la prueba "Perfil Colombia", implementada por nosotros. Resultados: Se detectaron 107 pacientes portadores de mutaciones en pacientes colombianos, 69 de las cuales estaban localizadas en BRCA1 y 38 en BRCA2. De estas 39 mutaciones son nuevas (22 en BRCA1 y 17 en BRCA2) y solo se hallaron 4 de las 6 mutaciones reportadas previamente como fundadoras en Colombia. En 64/597 pacientes analizados mediante el "Perfil Colombia" se detectaron mutaciones en BRCA1 o BRCA2, así como en 41/256 pacientes que solicitaron la secuenciación completa de los genes BRCA1 y BRCA2. Conclusiones: El espectro de mutaciones fundadoras en Colombia es más amplio que el reportado anteriormente para este país. El "Perfil Colombia" es una prueba que revela a la vez mutaciones fundadoras y mutaciones nuevas, con una tasa de detección del 10.7%. La secuenciación completa presenta una tasa de detección del 16.0% y puede complementar el diagnóstico de la base genética de esta enfermedad.

Variantes de hemoglobina en una población con impresión diagnóstica positiva para hemoglobinopatías en Colombia / Hemoglobin variants in Colombian patients referred to discard hemoglobinopathies

Background: Oxygen transport is altered in hemoglobinopathies. Aim: To study the distribution of hemoglobinopathies in Andean subjects without African ancestry. Material and Methods: We analyzed blood samples of 1,407 subjects aged 18 to 59 years (58% females), living in the central Andean region of Colombia, referred to discard hemoglobinopathies. The frequency and type of hemoglobinopathy was established by capillary and agarose gel electrophoresis. Results: The frequency of hemoglobinopathies was 34.5% and higher among females. The structural variants found were: AS-heterozygous hemoglobin (8.1%), homozygous SS (3.7%), heterozygous SC (2.2%), AC heterozygotes (0.5%) and heterozygous AE (0.3%). Quantitative variants found were Hb A-Beta thalassemia (13.91%) and Hb H (0.06%), Beta-thalassemia heterozygotes C (0.88%), S-Beta thalassemia heterozygotes (6.07%) and compound heterozygous SC/Beta thalassemia (0.25%), with a persistence of fetal hemoglobin 0. Composite thalassemia was also found in 31%. All techniques showed good correlation and capillary electrophoresis demonstrated a greater detection of hemoglobin variants. Conclusions: The frequency of hemoglobin variants in the analyzed population was high, which is an important public health indicator. The most common hemoglobin variant was HbA/Increased structural Hb A2 and the mos frequent structural hemoglobinopathy was sickle cell trait. Capillary electrophoresis can discern any Hb variants present in the population.

C677t (rs1801133) MTFHR gene polymorphism frequency in a colombian population / Frecuencia del polimorfismo c677t (rs1801133) del gen MTFHR en individuos colombianos

Introduction: Abnormal levels of the enzyme methylenetetrahydrofolate reductase (MTHFR) are associated with an increased risk of both cardiovascular and cerebrovascular disease and higher concentrations of homocysteine. Abnormal levels are also related to birth defects, pregnancy complications, cancer and toxicity to methotrexate (MTX). Polymorphisms of MTHFR affect the activity of the enzyme. Genetic associations have been related to treatment efficacy. Objective: To establish the frequency of the C>T polymorphism at nucleotide 677 of the MTHFR gene in a group of Colombian individuals. Methods: Data from pharmacogenetic microarrays that include MTX sensibility-associated polymorphisms were retrospectively collected (Pathway Genomics©). The frequency of the C>T MTHFR rs1801133 marker polymorphism was analyzed. Results: Microarray data from 68 men and 84 women were analyzed. Comparisons of genotype C/C vs. C/T and T/T were statistically significantly different (p= 0.00, p= 0.026, respectively), as were C/T and T/T (p= 0.0001). Conclusions: Results for the C/C and C/T genotypes in a Colombian population are similar to other previously studied groups of healthy subjects. Subjects from our population might be at risk of developing diseases associated with MTHFR polymorphisms and might present toxicity and adverse effects if treated with MTX, which suggests the need to evaluate therapeutic alternatives based on individual pharmacogenetic studies.

Introducción: Las alteraciones de la enzima metilen-tetrahidrofolato reductasa (MTHFR) se asocian con riesgo cardiovascular y cerebrovascular y con presencia de concentraciones altas de homocisteína. Se relacionan también con defectos congénitos, complicaciones en embarazo, cáncer y toxicidad del Metotrexato (MTX). Los polimorfismos del gen MTHFR afectan la actividad de la enzima. Se han descrito asociaciones genéticas con la eficacia del tratamiento con MTX. Objetivo: Establecer la frecuencia del polimorfismo C>T en el nucleótido 677 del gen MTHFR en un grupo de individuos Colombianos. Métodos: Estudio descriptivo de corte transversal. Se recolectaron retrospectivamente resultados de microarreglos farmacogenéticos que incluyen polimorfismos asociados con la sensibilidad al MTX (PathwayGenomics©). Se analizó la frecuencia del polimorfismo C>T del polimorfismo rs1801133 del gen MTHFR. Resultados: Se analizaron microarreglos de 68 hombres y 84 mujeres. Las comparaciones del genotipo C/C frente a C/T y a T/T fueron estadísticamente significativas (p= 0.001 y p= 0.026 respectivamente) tanto como la comparación entre C/T y T/T (p= 0.0001). Conclusiones: Los genotipos C/C y C/T en Colombia son tan variables como en otros grupos sanos en otras poblaciones. Los sujetos de nuestra población podrían tener riesgo para el desarrollo de enfermedades asociadas al polimorfismo del gen MTHFR y con genotipos de riesgo de presentar toxicidad y efectos adversos del MTX, lo cual sugiere la necesidad de evaluar alternativas terapéuticas con estudios farmacogenéticos.