A comprehensive characterization of the spectrum of MUTYH germline pathogenic variants in Latin America.

MUTYH-Associated Polyposis (MAP) is caused by biallelic pathogenic germline variants in the MUTYH gene. However, individuals harboring monoallelic MUTYH pathogenic variants in the presence of a positive family history have been reported to have a twofold increased risk of colorectal cancer (CRC) and extra colonic cancers. Our aim was to characterize the spectrum of monoallelic and biallelic germline MUTYH pathogenic variants in Latin American patients and to describe their clinical and genetic characteristics. Patients were identified from eight high-risk genetic cancer centers of five Latin American countries. Statistical analysis was performed using the two-sided P test using the Vassarstats statistical tools. Statistical significance was set at a p value ≤ 0.05. Of the 105 unrelated patients with cancer or colorectal polyposis, 84.8% and 15.2% carried pathogenic monoallelic and biallelic MUTYH variants, respectively. The most common pathogenic variants were p.Gly396Asp and p.Tyr179Cys (55% and 23%, respectively). The mean age at first diagnosis was 48.29 years (range 31-71) and 49.90 years (range 27-87) in biallelic and monoallelic MUTYH patients, respectively. CRC was the only cancer diagnosed in patients with biallelic MUTYH pathogenic variants (75%), while breast cancer (46.1%) was more common than CRC (24.7%) in individuals with monoallelic MUTYH pathogenic variants. We reported a high frequency of European founder variants in our diverse population. Some phenotypic differences from current studies were identified, such as a higher breast cancer burden in monoallelic carriers and a complete absence of extra-colon tumors in biallelic patients.

Evaluación de parámetros inflamatorios, trombóticos y variantes genéticas en pacientes con ataque cerebrovascular isquémico que se asisten en un hospital de Uruguay

Introducción: El ataque cerebrovascular es la segunda causa de muerte en adultos en el mundo occidental y una de las principales causas de discapacidad permanente, aumentando su frecuencia con la edad, el 85 % es de tipo isquémico. Objetivos: Analizar parámetros trombofílicos, hipofibrinolíticos y genéticos en pacientes con ataque cerebrovascular isquémico y evaluar la posible asociación de estos con factores de riesgo cardiovascular. Metodología: Se utilizó un cuestionario para evaluar la presencia de factores de riesgo cardiovascular en 114 pacientes incluidos en el estudio con diagnóstico de ataque cerebrovascular isquémico. Proteína C y antitrombina fueron determinados mediante métodos cromogénicos, resistencia a la proteína C activada e inhibidor lúpico mediante métodos coagulométricos y proteína S libre, inhibidor del activador del plasminógeno-1, homocisteína y lipoproteína (a) por métodos inmunoquímicos. Fibrinógeno fue determinado por coagulometría y proteína C reactiva por inmunoturbidimetría, ambos contra un grupo control. Las variantes genéticas factor V Leiden, protrombina G20210A, rs1205 (gen PCR), rs1800779 (gen NOS3) y rs2257073 (gen ASB10) fueron analizadas mediante real-time PCR, comparando los últimos tres con una población de referencia. La alteración de las frecuencias de las variables fue determinada por análisis estadístico chi-cuadrado. Resultados: Tres de los cuatro pacientes jóvenes estudiados presentaron indicadores de trombofilia. El resto de los parámetros alterados fueron homocisteína 30.1% (22.4-39.1), lipoproteína (a) 32.1% (24.1-41.4), inhibidor del activador del plasminógeno-1 36.0% (27.8-45.1), fibrinógeno 12.3% (7.5-19.6) y proteína C reactiva 78.1% (69.6-84.7). Se encontró asociación (p < 0.05) entre ciertos factores de riesgo cardiovascular y los parámetros evaluados como hipertensión/proteína C reactiva, dislipemia/lipoproteína (a), arritmia/lipoproteína (a) y arritmia/fibrinógeno. Para pacientes con ataque cerebrovascular isquémico solo la variante rs1205 mostró una frecuencia más alta del alelo T. Conclusiones: Este estudio revela la importancia de analizar la trombofilia en pacientes jóvenes, especialmente en aquellos sin factores de riesgo cardiovascular, así como el rol de la hipofibrinolisis, inflamación y algunas variantes genéticas en el desarrollo de ataque cerebro vascular isquémico.

Introduction: Stroke is the second cause of death in adults in the Western world and one of the main causes of permanent disability, increasing in frequency with age; 85% are ischemic. Objectives: To analyze thrombophilic, hypofibrinolytic, inflammatory, and genetic parameters in patients with ischemic stroke and evaluate possible associations with vascular risk factors. Methodology: Questionnaires were used to evaluate vascular risk factors in 114 patients included in the study with ischemic stroke diagnosis. Protein C and Antithrombin were determined by chromogenic assays, Activated Protein C Resistance and Lupus Anticoagulant were determined with by coagulometry and Free Protein S, Plasminogen activator inhibitor-1, Homocysteine and Lipoprotein (a) by immunochemistry. Fibrinogen was assayed by coagulometry and C-reactive protein by immunoturbidimetry, both against a control group. Factor V Leiden, Prothrombin G20210A, rs1205 (CRP gene), rs1800779 (NOS3 gene) and rs2257073 (ASB10 gene) genetic variants were analyzed by Real-Time PCR, comparing the last three with a reference population. Alteration frequencies of the variables were determined by chi-square statistical analysis. Results: Three out of four of the young patients studied presented indicators of thrombophilia. The rest of the altered parameters were Homocysteine 30.1% (22.4-39.1), Lipoprotein (a) 32.1% (24.1-41.4), Plasminogen activator inhibitor-1 36.0% (27.8-45.1), Fibrinogen 12.3% (7.5-19.6) and C-reactive protein 78.1% (69.6-84.7). Associations were found (p<0.05) between certain vascular risk factors and parameters evaluated, namely hypertension/C-reactive protein, dyslipidemia/lipoprotein (a), arrhythmia/lipoprotein (a) and arrhythmia/fibrinogen. For ischemic stroke patients only the genetic variant rs1205 showed higher frequency of the T allele. Conclusions: This study reveals the importance of analyzing thrombophilia in young patients, especially those without vascular risk factors, as well as the role of hypofibrinolysis, inflammation and some genetic variants in the development of ischemic stroke.

Introdução: O AVC é a segunda causa de morte em adultos no mundo ocidental e uma das principais causas de incapacidade permanente, aumentando de frequência com a idade; 85% são isquémicos. Metas: Analisar os parâmetros trombofílicos, hipofibrinolíticos e genéticos em pacientes com acidente vascular cerebral isquêmico e avaliar a possível associação com fatores de risco cardiovascular. Metodologia: Um questionário foi utilizado para avaliar a presença de fatores de risco cardiovascular em 114 pacientes incluídos no estudo com diagnóstico de acidente vascular cerebral isquêmico. Proteína C e antitrombina foram determinadas por métodos cromogênicos, resistência à proteína C ativada e inibidor de lúpus por métodos coagulométricos e proteína S livre, inibidor do ativador do plasminogênio-1, homocisteína e lipoproteína (a) por métodos imunoquímicos. O fibrinogênio foi determinado por coagulometria e a proteína C-reativa por imunoturbidimetria, ambos contra um grupo controle. As variantes genéticas fator V Leiden, protrombina G20210A, rs1205 (gene PCR), rs1800779 (gene NOS3) e rs2257073 (gene ASB10) foram analisadas por PCR em tempo real, comparando as três últimas com uma população de referência. As frequências de alteração das variáveis ​​foram determinadas pela análise estatística qui-quadrado. Resultados: Três dos quatro pacientes jovens estudados apresentaram indicadores de trombofilia. O resto dos parâmetros alterados foram homocisteína 30,1% (22,4-39,1), lipoproteína (a) 32,1% (24,1-41,4), inibidor do ativador de plasminogênio-1 36,0% (27,8-45,1), fibrinogênio 12,3% (7,5-19,6) e proteína C reativa 78,1% (69,6-84,7). Foi encontrada associação (p<0,05) entre alguns fatores de risco cardiovascular e os parâmetros avaliados como hipertensão/proteína C reativa, dislipidemia/lipoproteína (a), arritmia/lipoproteína (a) e arritmia/fibrinogênio. Para pacientes com acidente vascular cerebral isquêmico apenas a variante rs1205 apresentou maior frequência do alelo T. Conclusões: Este estudo revela a importância de analisar a trombofilia em pacientes jovens, especialmente aqueles sem fatores de risco cardiovascular, bem como o papel da hipofibrinólise, inflamação e algumas variantes genéticas no desenvolvimento do acidente vascular cerebral isquêmico.

CYP2D6 genotyping and the clinical impact on outcomes in breast cancer tamoxifen-treated patients.

Aims: To report the distribution of allele frequencies of CYP2D6 gene and to evaluate their influence on the clinical outcomes of a group of breast cancer patients receiving adjuvant tamoxifen treatment from Uruguay. Patients & methods: 199 samples were genotyped through real-time polymerase chain reaction assays. Metabolization profiles were inferred from the genotypes. Correlations were evaluated using Pearson's χ2 test. Results: Phenotype frequencies were 0.65 normal (NM), 0.30 intermediate (IM) and 0.05 poor metabolizers (PM). Similar clinical outcomes between NM and (PM + IM) patient groups (odds ratio = 1.011, 95% CI = 0.2703-3.7826; p = 0.987) were found. Conclusion: CYP2D6 allele frequencies were analyzed for the first time in a cohort from Uruguay. Results did not support any impact of CYP2D6 gene polymorphisms on clinical outcomes.

Assessing Adherence to Adjuvant Hormone Therapy in Breast Cancer Patients in Routine Clinical Practice.

Background: Adjuvant hormone therapy (HT) in patients with hormone receptor-positive breast cancer (BC) increases overall survival (OS). A lack of adherence to adjuvant endocrine therapy is common, 31.0-73.0% of women discontinue endocrine treatment before 5 years. The aim of the study was to assess adherence to HT in routine clinical practice in patients assisted at the Clinical Oncology Department of the Hospital de Clinicas - Universidad de la Republica, Uruguay. Methods: Patients treated with HT for stage 0-III BC between 2017 and 2019 were included. The medication possession (MPR) rate was calculated using pharmacy records, and the Morisky-Green Scale was applied to assess adherence. Adherent patients were those with MPR ≥ 0.80 and who correctly answered the Morisky-Green treatment adherence questionnaire. The association of adherence with polypharmacy, treatment, and patient characteristics was assessed using simple logistic models. The associations between qualitative variables and adherence were assessed using simple logistic regression model or Fisher's exact test. The association between quantitative variables and adherence was assessed using the Student's t-test. The odds ratio (OR) for non-adherence to treatment and its 95% confidence interval were estimated. Results: Totally, 118 patients were included; 65.2% were treated with aromatase inhibitors (AIs), 36.0% presenting polypharmacy. The adherence rate at the end of 2 years was 81.0 %; and it was associated with age (P = 0.03, OR = 0.96 for non-adherence), with adherent and non-adherent patients having a mean age of 65.0 and 60.3 years, respectively; however, adherence was not associated with polypharmacy, territory of origin, marital status, living alone, level of education, occupation, or stage. The adherence profile was similar for both drugs, but homemakers and retired women showed greater adherence to AI. Conclusions: Adherence to HT was assessed in real life, with 19.0% of the patients not adhering to the treatment, despite the known benefit for OS, being a well-tolerated treatment, and being provided free of charge. Older patients were associated with being more adherent. The results show the need of the Pharmacy Service and Department of Clinical Oncology Medical Oncology combining efforts to develop coordinated strategies and interventions to increase adherence, given the impact that this may have on patients' OS.

Genetic and epigenetic characteristics of patients with colorectal cancer from Uruguay.

Colorectal cancer (CRC), the 3rd most frequent cancer worldwide, affects both men and women. This pathology arises from the progressive accumulation of genetic and epigenetic alterations. In this study, KRAS, NRAS, PIK3CA, and BRAF gene mutations, mismatch repair (MMR) genes methylation profile, microsatellite instability (MSI) and CpG Island Methylator Phenotype (CIMP) status were assessed. The associations of these molecular features with clinicopathological data were also investigated. A hundred and eight unselected CRC samples and their histological and clinical data, were gathered between 2017 and 2020. The prevalence of KRAS, NRAS and BRAF gene mutations was similar to that described in other populations. 28.7% of tumors were KRAS-mutated, mostly in men, distal location, with a CIMP-negative status. BRAFV600E frequency was 6.5% and associated with MSI (p = 0.048), MLH1-methylated (p < 0.001) and CIMP-High (p < 0.001) status. We also confirmed that BRAFV600E tumors were more prevalent in older women and proximal location. A striking different result was the lack of most common variants in the PIK3CA gene. A complete absence of PIK3CA-mutated tumors in a population has not been previously reported. Among MMR genes, the only with an aberrant methylation pattern was MLH1 gene. Its frequency was 9.25%, lower than previously reported. Methylated tumors were most frequent in patients older than 70 years old and proximal tumor location. Finally, CIMP-High status was mainly observed in moderately differentiated tumors with a rate of 15.7%. Our findings were consistent with previous reports in other populations, but also showed some features unique to our cohort. This study is the first to report the analysis of a large number molecular biomarkers of CRC in Uruguay and one of the few performed in Latin-America.

Tamizaje para cáncer de mama con resonancia magnética en mujeres portadoras de mutaciones BRCA y no-BRCA / Magnetic resonance imaging breast cancer screening in women who are carriers of BRCA and non-BRCA gene mutations / Rastreamento de câncer de mama com ressonância magnética em mulheres com mutações BRCA e não BRCA

Introducción: la predisposición hereditaria causada por mutaciones patogénicas de la línea germinal (MPG) explica hasta el 10% de los cánceres de mama. Para reducir su impacto en mujeres mutadas se han propuesto diferentes estrategias, tales como las cirugías reductoras de riesgo o el screening con resonancia magnética (RM) de mamas. Métodos: en este estudio observacional retrospectivo se analizaron los registros de mujeres portadoras de MPG para evaluar las diferentes acciones tomadas luego del test genético. A las pacientes no mastectomizadas se les recomendó ingresar a un programa anual de cribado con RM y se evaluó el porcentaje de adherencia al plan, el número de biopsias efectuadas y el número de cánceres de mama detectados. Resultados: se incluyeron 134 mujeres con MPG, con una distribución en tercios iguales de los genes BRCA1, BRCA2 y genes no-BRCA. Entre las mutadas con indicación de seguimiento, 64% ingresaron al programa de cribado con RM. Las razones que llevaron a las mujeres a no ingresar al programa de seguimiento fueron: la oposición del médico tratante (53%), oposición de la paciente (38%), y falta de recursos (9%). Se realizaron seis biopsias por hallazgos en la RM entre las cuales se detectó un cáncer de mama. La incidencia de cáncer fue de 11 cada 1.000 mujeres-años de riesgo. Conclusiones: nuestro programa de seguimiento con RM de pacientes mutadas logró captar un porcentaje alto de candidatas. Una proporción significativa de las mujeres no ingresó debido la desaprobación del médico tratante o de la propia paciente. La evidencia obtenida revela una necesidad imperiosa de reforzar los programas educativos que destaquen la importancia del seguimiento con RM de las pacientes de alto riesgo en nuestro país.

Summary: Introduction: genetic propensity caused by germline pathogenic mutations explain up to 10% of breast cancer cases. Different strategies have been proposed to reduce its impact on women who are carriers of mutations, such as risk-reducing surgeries or breast magnetic resonance screening. Method: observational, retrospective study analyzing the medical records of women who are carriers of germline pathogenic mutations to assess the different measures taken after the genetic test. Non-mastectomized patients were advised to join an annual MRI screening program and the percentage of adherence to plan was evaluated, along with biopsies performed and the number of breast cancer cases detected. Results: 134 women carriers of germline pathogenic mutations were included in the study, with equal distributions in thirds for BRCA1, BRCA2 and non-BRCA genes. 64% of carriers of mutations who were subject to follow-up checkups joined the RMI screening program. The reasons why women failed to join the follow-up program were: the treating physician objected to the program (53%), the patients opposed to program (38%) and lack of resources (9%). Six biopsies were performed as a consequence of findings in the RMI, and one case of breast cancer was detected. Cancer incidence was 11 out of 1000 women - risk years. Conclusions: our RMI follow-up program for women who are carriers of mutations managed to attract a high percentage of candidates. A significant amount of women failed to join the program because of their treating physician's or their own disapproval. Evidence obtained reveals the dramatic need to reinforce educational programs that emphasize on the importance of RMI follow-up of high risk patients in our country.

Introdução: a predisposição hereditária causada por mutações germinativas patogênicas (GMP) explica até 10% dos cânceres de mama. Para reduzir seu impacto em mulheres com mutações, diferentes estratégias têm sido propostas, como cirurgias de redução de risco ou ressonância magnética (RM) das mamas. Métodos: neste estudo observacional retrospectivo, os registros de mulheres portadoras de MPG foram analisados para avaliar as diferentes ações tomadas após o teste genético. Pacientes não mastectomizadas foram recomendadas a entrar em um programa anual de triagem por ressonância magnética e foram avaliados o percentual de adesão ao plano, o número de biópsias realizadas e o número de cânceres de mama detectados. Resultados: foram incluídas 134 mulheres com MPG, com uma distribuição de terços iguais dos genes BRCA1, BRCA2 e não-BRCA. Entre as mulheres com mutações com indicação de acompanhamento, 64% entraram no programa de triagem por ressonância magnética. Os motivos que levaram as mulheres a não ingressarem ao programa de acompanhamento foram: oposição do médico assistente (53%), oposição da paciente (38%) e falta de recursos (9%). Seis biópsias foram realizadas devido a achados de ressonância magnética, entre os quais foi detectado um câncer de mama. A incidência de câncer foi de 11 por 1.000 mulheres-ano de risco. Conclusões: nosso programa de acompanhamento de ressonância magnética para pacientes com mutação conseguiu capturar uma alta porcentagem de candidatas. Uma proporção significativa de mulheres não entrou devido à falta de aprovação do médico assistente ou da própria paciente. As evidências obtidas revelam a necessidade urgente de reforçar programas educacionais que destaquem a importância do acompanhamento por RM de pacientes de alto risco no Uruguai.

Genetic variants associated with methotrexate-induced mucositis in cancer treatment: A systematic review and meta-analysis.

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in at least one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0-2, OR 2.53, 95 %CI [1.48-4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95 %CI [1.16-3.73], FDR-corrected p-value 0.042).

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America.

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%-80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.

Genetic markers in methotrexate treatments.

Methotrexate (MTX), a structural analog of folic acid, is widely employed in the treatment of different cancers and autoimmune diseases. Despite the successful results observed, the main disadvantage lies in interpatient variability in the pharmacokinetic and pharmacodynamic parameters. In particular, adverse events and toxicities induced by MTX are a matter of concern and can be the cause of dose reduction or treatment discontinuation. Among the different approaches to reduce MTX therapeutic limitations, pharmacogenomics contributes by considering the effect of inherited genetic differences on those parameters. This review provides an update on MTX pharmacogenomics. It reports the contribution of main gene polymorphisms involved in the influx, efflux, cellular effect, and elimination on MTX toxicity and efficacy, on all the diseases treated with this drug. From the analysis of the data presented in this review, we concluded that only gene polymorphisms MTHFR rs1801133, SLC19A1 rs1051266, and TYMS rs34743033 could influence clinical decision-making.

Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance.

Familial adenomatous polyposis (FAP) is an autosomal dominant genetic condition, caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Desmoid tumors (DTs) are seen in 15% to 20% of FAP patients. Specific location of mutation serves as a guide to predict colonic and extra colonic manifestations and their aggressiveness. A severe FAP-phenotypic family was registered in a genetic counselling high-risk Uruguayan hereditary cancer clinic. Proband's DNA was analysed by NGS, detecting a pathogenic mutation in APC gene. All willing family members were counselled and encouraged to be tested. Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two-base deletion mutation: c.4393_4394delAG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3' end of APC gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients' quality of life.

Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases.

BACKGROUND: Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. METHODS: 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. RESULTS: Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28bp copy number variation, SLCO1B1 T521C, DHFR C-1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19bp indel. Multivariate analysis showed that DHFR-1610G/T (OR=0.107, p=0.018) and MTHFR677T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. CONCLUSIONS: The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.

Cáncer de mama y ovario hereditario en Uruguay: resultados del screening para mutaciones en genes de susceptibilidad por secuenciación de nueva generación / Hereditary breast and ovary cancer in Uruguay: screening results for mutations in susceptibility genes by new generation sequencing

Introducción: el cáncer de mama representa la primera causa de muerte por cáncer en mujeres de Uruguay. Se estima que cerca de 7% son causados por mutaciones en el ácido desoxirribonucleico germinal. Los costos de la secuenciación genética han descendido dramáticamente gracias a la aparición de la secuenciación de nueva generación (NGS). El cambio tecnológico abrió una nueva etapa en el estudio del cáncer hereditario en nuestro país. Objetivo: comunicar los resultados de la utilización de tecnología NGS y paneles multigénicos en familias uruguayas con alto riesgo de cáncer de mama hereditario. Pacientes y método: se secuenciaron 135 familias de alto riesgo que provenían de la consulta de consejería genética que funciona en el Grupo Colaborativo Uruguayo: Investigación de afecciones oncológicas hereditarias. Cuando la historia familiar sugería claramente un síndrome de cáncer de mama y ovario hereditario se efectuó secuenciación NGS exclusiva de los genes BRCA1 y 2; cuando el patrón familiar no configuraba claramente se utilizó un panel multigénico. Resultados: se efectuó NGS exclusiva de genes BRCA1 y 2 en 62 familias y un panel multigénico en 73 familias. Se identificaron en total 29 mutaciones patógenas (21 en genes BRCA y 8 en otros genes). Dos de ellas fueron noveles y tres pueden considerarse recurrentes en la población uruguaya. Conclusiones: este trabajo es el primero en Uruguay en reportar el resultado de esta nueva tecnología en el cáncer de mama hereditario. El hallazgo de 29 mutaciones patógenas nos ayuda a delinear el perfil mutacional de nuestro país.

Introduction: breast cancer is women's first cause of death in Uruguay. According to estimations, around 7% of cases result from germinal mutations by deoxyribonucleic acid. The cost of genetic sequencing has dramatically dropped thanks to the arrival of next-generation sequencing (NGS). This technological change opened a new era in the study of hereditary cancer in our country. Objective:to communicate the results of using NGS technology and multigenic panels in Uruguayan families with high risk of hereditary breast cancer. Method: 135 high risk families referred by the genetic counselling consultation that is provided at the Uruguayan Collaborative Group (Hereditary Oncological Conditions Research) were sequenced. When the family history clearly suggested hereditary breast and ovary cancer was a possibility, exclusive NGS sequencing was done for BRCA1 and BRCA2 genes; when the family pattern was not clear to this respect, multigenic panels were used. Results: exclusive NGS sequencing for BRCA1 and BRCA2 genes was done in 62 families, and multigenic panels were used in 73 families. 29 pathogenic mutations were identified (21 in BRCA genes and 8 in other genes). Two of them were new to the disease and three could be considered recurrent in the Uruguayan population. Conclusions:this study is the first one in Uruguay to report the results of this new technology in hereditary breast cancer. The finding of 29 pathogenic mutations contributes to outlining the mutational profile of our country.

Introdução: o câncer de mama é a primeira causa de morte por câncer em mulheres no Uruguai. Estima-se que aproximadamente 7% sejam causados por mutações no ácido desoxirribonucleico germinal. Os custos da sequenciação genética diminuíram dramaticamente graças ao aparecimento da sequenciação de nova geração (NGS). Esta nova tecnologia deu inicio a uma nueva etapa no estudo do câncer hereditário no nosso país. Objetivo: comunicar os resultados da utilização de tecnologia NGS e painéis mutagênicos em famílias uruguaias com alto risco de câncer de mama hereditário. Pacientes e método: 135 famílias de alto risco originárias do aconselhamento genético que funciona no Grupo Colaborativo Uruguaio: Pesquisa de afecções oncológicas hereditárias foram sequenciadas. Quando a história familiar sugeria uma síndrome de câncer de mama e ovário hereditários fez-se a secuenciacao NGS exclusivamente dos genes BRCA1 e 2; quando o padrão familiar não era claro foi utilizado um painel multigênico. Resultados: realizou-se NGS exclusivamente de genes BRCA1 e 2 em 62 famílias e um painel multigênico em 73 famílias. Foram identificadas 29 mutações patogênicas (21 em genes BRCA e 8 em outros genes). Duas eram novas e três podem ser consideradas como recorrentes na população uruguaia. Conclusões: este trabalho é o primeiro que apresenta os resultados desta nova tecnologia aplicada ao câncer de mama hereditário no Uruguai. O achado de 29 mutações patogênicas ajuda a definir o perfil mutacional do nosso país.

Análisis molecular de familias uruguayas con Enfermedad de Huntington / Molecular analysis of the Uruguayan families with Huntington’s Disease

Introducción: La Enfermedad de Huntington (EH) es un trastorno neurodegenerativo; autosómico dominante, con expresividad variable y penetrancia completa. La prevalencia estimada es entre 1-4 cada 100.000 habitantes. Es causada por expansión de tripletes CAG en el exón 1 del gen IT-15 que conduce a la síntesis de una proteína con una región de poliglutaminas expandidas que forman agregados en el núcleo celular induciendo a la apoptosis. Los alelos normales presentan un número menor a 26 tripletes CAG, y aquellos con más de 40 conducirán siempre a la enfermedad. Alelos de entre 26 a 36 repetidos se consideran normales “mutables” y de 36 a 39 repetidos generan un riesgo aumentado de desarrollar la enfermedad. Objetivo: Poner a punto el diagnóstico molecular en una población uruguaya, mediante la determinación del tamaño exacto de la mutación en personas afectadas o con sospecha clínica de EH, mediante el uso de técnicas de biología molecular. Métodos: Pacientes de la Policlínica de Enfermedad de Parkinson y Movimientos Anormales del Hospital de Clínicas. La determinación del número de repetidos se realizó mediante técnicas de amplificación del ADN por PCR y posterior análisis en geles de poliacrilamida y secuenciación. Resultados: Realizamos el diagnóstico molecular de 16 pacientes, 15 con un diagnóstico clínico previo, y uno asintomático. Se descartó el diagnóstico de EH en otros dos individuos analizados. Conclusiones: Hemos logrado la puesta a punto del estudio molecular para la enfermedad de EH por primera vez en nuestro país. Esta prueba es de gran utilidad como diagnóstico confirmatorio, etiológico o diferencial de EH.

Introduction: Huntington disease (HD) is a neurodegenerative disorder with an autosomal dominant inheritance mode, complete penetrance and variable clinical expressivity. The estimated prevalence is 1 to 4 per 100.000 individuals. It is caused by a CAG triplet expansion in exon 1 of the IT-15 gene which codes for a protein with an enlarged polyglutamine region. This leads to the formation of protein aggregates in the cell nucleus and induces apoptosis. Normal alleles show less than 26 CAG repeats, and those over 40 always lead to the disease. Alleles with 26 to 36 repeats are considered normal “mutable” alleles and those between 36 to 39, are considered in a gray zone with increased risk of developing the disease. Aims: To develop a diagnosis of HD in a uruguayan population and determine the exact size of the mutation in clinically affected subjects using molecular biology techniques. Methods: Patients were derived from Neurology Clinic of the “Hospital de Clínicas”. The determination of the CAG repeat number was done using polymerase chain reaction (PCR) technique, subsequent analysis on polyacrilamide gels and sequencing. Results: We performed the molecular diagnosis in 18 patients with clinical suspicion of HD. Fifteen of them had a previous clinical diagnosis and one had no symptoms. Besides, in two additional individuals this test allowed us to discard HD. Conclusions: A molecular diagnostic for HD disease was developed for the first time in our country. This test is of great clinical utility as a confirmatory, etiological, or differential diagnosis.

Polimorfismos de ApoE y daño vascular en diabéticos tipo 2 / ApoE polymorphisms and vascular damage in type 2 diabetics

La apolipoproteína E (ApoE) es un constituyente de las lipoproteínas plasmáticas con un importante rol en el metabolismo como ligando de receptores de lipoproteínas.Las variaciones en el locus de ApoE se vinculan a variaciones en las concentraciones de lipoproteínas de baja densidad (LDL) plasmáticas. El alelo E4 se ha vinculado a aumento delriesgo cardiovascular, a progresión de la nefropatía diabética así como a severidad y progresión de neuropatía y retinopatía diabéticas. El alelo E2 se asocia a un efecto final protector para el desarrollo de enfermedad cardiovascular. Objetivos: estudiar la asociación entre este polimorfismoy las repercusiones macroangiopáticas, en especial cardiopatía isquémica, y el lipidograma en los pacientes diabéticos.Material y método: se estudiaron 78 pacientes diabéticos tipo 2, menores de 85 años de edad, valorando la asociaciónentre el polimorfismo de ApoE y las repercusiones macroangiopáticas y microangiopáticas de la diabetes, el lipidograma y la edad al diagnóstico de la diabetes. La determinación genotípica se realizó por métodos estándar de amplificación-restricción previo consentimiento informado. Las variables se analizaron utilizando chi cuadrado y prueba de Fisher. Error alfa menor a 0,05. Resultados: la frecuencia de portadores del alelo E4 de la Apo E entre los individuos con complicaciones macroangiopáticas (43,5%) fue mayor que entre los que estaban libres deestas complicaciones (26,2%), si bien las diferencias no fueron estadísticamente significativas. La presencia de cardiopatía isquémica se asoció en forma significativa con el alelo E4, 56% versus 25%. La presencia del alelo E4 se asoció significativamente con un diagnóstico de diabetes antes de los 40 años. Los pacientes con alelos de riesgo presentaron valores de LDL y triglicéridos (TG) aumentados. Conclusiones: el alelo E4 se asoció a un mayor riesgo de cardiopatía isquémica y una edad al diagnóstico de DM2 menor a 40 años...

Apolipoproiten E (ApoE) is a constituentof plasma lipoproteins that plays an important role in metabolism acting as lipoprotein receptor ligand. Variations in the ApoE locus are associated to variations in concentration of low plasma density lipoproteins. Allele E4 has been associated to an increase of risk for cardiovascular disease, progress in diabetic nephropathies and severity and progression of diabetic neuropathiesand retinopathies. Allele E2 is associated to conferring protection from coronary heart disease (CHD). Objectives: to study the association between this polymorphism and the macroangiopathic effects, especially in terms of ischemic cardiopathy, and lipidogram in diabetic patients. Method:78 patients less than 85 years old with type 2 diabetes mellitus were studied, being the association between the ApoE polymorphism and the macroangiopathic and microangiopathic effects of diabetes assessed, as well as the lipidogram and age of patients at time of diagnosis. Genotype determination was done withstandard extending-restricting methods following informed consent. Variables were analysed using Chi-scuared and the Fisher exact test. Alpha error rate was lower than 0.05. Results:frequency of carriers of ApoE allele E4among individuals with acroangiopathic complications was larger than among those who were free of these complications (26.2%), although differences were not statistically significant. The presence of ischemic heart disease was significantly associated with E4 allele, that is 56% versus 25%. The presence of the E4 allele was significantly associated to thediagnosis of diabetes earlier than 40 years old. Patients with risk alleles evidenced increased values of LDL and triglycerides. Conclusions: allele E4 was associated with a larger risk for ischemic cardiopathy and age of diagnosing type 2 diabetes mellitus lower than 40 years old. The strongeffect of genotype ApoE was evidence on the lipid profile of patients with T2DM.

A apolipoproteína E (ApoE) é um dos elementos das lipoproteínas plasmáticas e tem um papel importante no metabolismo como ligando dos receptores de lipoproteínas. As variações no lócus de ApoE estão vinculadas a variações nas concentrações de lipoproteínas plasmáticas de baixa densidade (LDL). O alelo E4 está vinculado a um aumento do risco cardiovascular, à progressão da nefropatia diabética como tambémà gravidade e a progressão de neuropatia e retinopatia diabéticas. O alelo E2 está associado a um efeito finalprotetor para o desenvolvimento de doença cardiovascular. Objetivos:estudar a associação entre este polimorfismo e as repercussões macroangiopáticas, especialmente cardiopatia isquêmica, e o lipidograma em pacientes diabéticos. Material e método: foram estudados 78 pacientesdiabéticos tipo 2, com menos de 85 anos de idade, para avaliar a associação entre o polimorfismo de ApoE e asrepercussões macroangiopáticas e microangiopáticas da diabetes, o lipidograma e a idade no momento do diagnóstico da diabetes. A determinação genotípica foi realizada por métodos padrões de amplificação-restrição, com consentimento informado dos pacientes. As variáveis foram analisadas utilizando chi quadrado e prova de Fisher. Erro alfa menor a 0,05. Resultados: a frequência de portadores do alelo E4 de la Apo E entre os indivíduos com complicações macroangiopáticas (43,5%) foi maior que entre aqueles que não apresentavam essas complicações (26,2%), emboraas diferenças não tenham sido estatisticamente significativas. A presença de cardiopatia isquêmica foi associada significativamente com o alelo E4, 56% versus 25%. A presença do alelo E4 foi associado significativamente com diagnóstico de diabetes antes dos 40 anos. Os pacientes com alelos de risco apresentaram valores de LDL e triglicérides (TG) aumentados.Conclusões: o alelo E4 foi associado a um maior risco de cardiopatia isquêmica e idade no momento do diagnóstico de DM2 menor a 40 anos...

Mutación en el gen de apolipoproteína B responsable de hipercolesterolemia familiar: primeros dos casos clínicos reportados en Uruguay / Mutation in apolipoprotein B gene responsible for familial hypercholesterolemia: first two cases reported in Uruguay

Introducción: la apolipoproteína B 100 defectuosa familiar, debida a la mutación R3500Q en el gen de la apolipoproteína B es una causa conocida de hipercolesterolemia familiar heterocigota. Su frecuencia varía entre 1:500 y 1:700 en distintas poblaciones europeas. Se dispone de escasa información referente a su frecuencia en Uruguay y América Latina. Casos clínicos: en este trabajo se describe el hallazgo, realizado por vez primera en Uruguay, de dos pacientes con hipercolesterolemia familiar dominante con la presencia de la mutación R3500Q de la proteína ApoB. Para su hallazgo, se analizó un grupo de pacientes (n=96) de la Comisión Honoraria para la Salud Cardiovascular (CHSCV), con criterios clínicosy bioquímicos de hipercolesterolemia familiar heterocigota. Se realizó estudio molecular para la mutación R3500Q mediante la reacción en cadena de la polimerasa y posterior digestión con enzimas de restricción. Conclusiones: hemos encontrado dos primeros casos de HFh con una genética que explica su fenotipo debido a la mutación R3500Q en el gen ApoB. Por medio de esta estrategia, mostramos que el análisis genético ayuda a la estratificación de pacientes en riesgo, permite el diagnóstico familiar y constituiría el primer paso en el algoritmo diagnóstico etiológico de las hipercolesterolemias dominantes.

Farmacogenética y reacción adversa a medicamentos: valor predictivo delpolimorfismo en el gen de la uridindifosfato glucuronosil transferasa 1A1 / Farmacogenetics and adverse reaction to drugs: predictive value of polymorphism in the uridine diphosphate glucoronosyltransferase 1A1 gene

Introducción: las reacciones adversas a medicamentos constituyen un problema fundamental para los servicios de salud, la industria farmacéutica y los organismos reguladores. Gran parte de estas reacciones son relativamente leves y desaparecen al modificar la dosis, pero otras son más graves, pudiendo llegar a la muerte del individuo. El irinotecán es un agentecitotóxico activo en cáncer colorrectal y pulmonar. Está asociado a una severa toxicidad hematológica y gastrointestinal, impredecibles en la práctica. Su metabolito activo (SN-38)es detoxificado mediante la enzima UDP-glucuronosiltransferasa-1A1 (UGT1A1). La variación en la actividad de esta enzima ha sido relacionada con polimorfismos en el gen UGT1A1, produciendo los efectos adversos observados. El polimorfismo más importante se presenta en la región promotora y consiste en un número variable de repeticiones timinaadenina.El alelo mayoritario tiene seis repeticiones (TA)6, siendo el polimorfismo de siete repeticiones la variante alélica más frecuente.Objetivo: diseño de un ensayo molecular para el estudio de las variantes alélicas de la región promotora del gen UGT1A1.Material y método: se seleccionó un grupo de 50 voluntarios sin vínculo familiar. Las determinaciones moleculares se realizaron mediante amplificación y posterior secuenciaciónde la región promotora. Resultados y conclusiones: se logró la puesta a punto del diagnóstico molecular propuesto yse determinó que 8% de esa población es homocigoto (TA)7. Planteamos la ventaja de incorporar los resultados de este ensayo molecular en la toma de decisiones terapéuticas y así tender a una farmacoterapia personalizada en medicina oncológica.

Introduction: adverse reactions to drugs constitute an essential problem for health services, the pharmaceuticalindustry and the regulatory bodies. Most of these reactions are relatively mild and they disappear when dosageis modified, although others are more serious and they may result in death. Irinotecan is an active cytotoxic agentin colorectal and lung cancer. It is associated to severe hematological and gastrointestinal toxicity, unpredictablein practice. Its active metabolite (SN-38) is detoxified by the uridine diphosphate glucoronosyltransferase1A1enzyme (UGT1A1). (UGT1A1). Variation in the activity of this enzyme has been associated to polymorphismsin the UGT1A1 gene, what results in the adverse reactions observed. The most important polymorphisms appearin the polymorphism of the promoting region, which consists in a variable repetition of thymine-adenine repetitions. The main allele has six repetitions (TA)6, being the seven repetition polymorphism the most frequent allelic variant. Objetive: to design a molecular test to study allelicvariants of the promoting region in the UGT1A1 gene. Method: We selected a group of 50 volunteers with no family bonds. Amplification and subsequent sequencing of the promoting region were used to determine molecules.Results: we managed to update the suggested molecular diagnosis and determined that 8% of this populationis a homozygote (TA)7. We propose the advantage of incorporating the results of this molecular test for the making of therapeutic decisions and thus make progress toward a more personalized oncologic medicine.

Introdução: as reações adversas a medicamentos são um problema importante para os serviços de saúde, a indústria farmacêutica e os organismos reguladores. Muitas destas reações são relativamente leves e desaparecem com a modificação da dose, porém outras são mais graves podendo levar à morte do paciente. O irinotecan é um agentecitotóxico ativo em câncer colorretal e pulmonar. Está associado à toxicidade hematológica e gastrointestinal grave, imprevisível na prática. Seu metabólito ativo (SN-38) é detoxificado pela enzima UDP-glucuronosiltransferase-1A1 (UGT1A1). A variação da atividade desta enzima foi relacionada com polimorfismos no gene UGT1A1,produzindo os efeitos adversos observados. O polimorfismo mais importante se apresenta na região promotora e consiste num número variável de repetições timinaadenina.O alelo mais numeroso tem seis repetições (TA)6, sendo que o polimorfismo de sete repetições é a variante alélica mais frequente.Objetivo: projeto de um ensaio molecular para estudar as variantes dos alelos da região promotora do geneUGT1A1. Material e método: um grupo de 50 voluntários sem vínculo familiar foi selecionado. As determinações moleculares foram realizadas por amplificação e posterior seqüenciação da região promotora. Resultados e conclusões: foi possível realizar o diagnóstico molecular proposto e determinar que 8% da população estudada era homozigota. (TA)7. Discutimos a vantagem de incorporar os resultados deste ensaio molecularna tomada de decisões terapêuticas e dessa forma estabelecer uma tendência à farmacoterapia personalizadaem oncologia.

Genotipo de los genes VKORC1 y CYP2C9 en la respuesta individual a la warfarina / Genotype of the VKORC1 and CYP2C9 genes in individual response to warfarin

Introducción: la warfarina es un fármaco ampliamente utilizado como anticoagulante oral. Su estrecho rango terapéutico y marcada variabilidad interindividual en la respuesta requieren un control riguroso en su administración para evitar accidentes hemorrágicos. Objetivos: correlacionar las variantes genéticas de CYP2C9*2 y *3 y VKORC1 (C1173T) con la respuesta y los efectos adversos. Material y método: los genotipos CYP2C9*1, *2, *3, y VKORC1 fueron obtenidos por PCR-RFLP y los resultados analizados usando el paquete estadístico SPSS 12.0. Resultados: hay una tendencia a la reducción de dosis en relación con la presencia de alelos polimórficos. Los portadores de CYP2C9*3 requirieron la menor dosis de mantenimiento, seguidos por los portadores de CYP2C9*2 y homocigotos CYP2C9 *1, en ese orden, (4,4±1,0 vesus 5,4±2,3 versus 7,0±3,6 mg/d, p=0,03). Los portadores CYP2C9*3 tuvieron, además, un aumento del riesgo de sobreanticoagulación y requirieron casi el doble de ajustes de dosis para lograr una adecuada anticoagulación. Para VKORC1, los homocigotas T/T necesitaron la dosis más baja, seguidos por los heterocigotas C/T y homocigotas C/C, en ese orden (3,6±0,6 versus 5,5±0,5 y 7,9±0,7 mg/d, p <0,001). Los pacientes T/T tuvieron un mayor riesgo de sobreanticoagulación que los C/T y C/C. El genotipo T/T de VKORC1 produce en todas las combinaciones con CYP2C9 una disminución cercana a 50% de la dosis diaria de warfarina. Conclusiones: se confirma una sensibilidad aumentada a la warfarina en pacientes portadores de alelos *2 y *3 de CYP2C9, y T de VKORC1. Se demuestra un efecto combinado (aproximadamente aditivo) de los alelos variantes de ambos genes.

Summary Introduction: warfarin is a widely used oral anticoagulant. Its narrow therapeutic range (NTR) and its large interindividual variability requires strict control when administered to avoid hemorrhagic accidents. Objectives: to correlate CYP2C9*2 and *3 and VKORC1 (C1173T) genetic variants with response and adverse side effects. Method: CYP2C9*1, *2, *3, and VKORC1 genotypes were obtained by a commonly used PCR-RFLP procedure. The results were analyzed using SPSS 12.0. statistical package. Results: there is a tendency to reduce the dosage in connection with the presence of polymorphic alleles. CYP2C9*3 carriers require the lower maintenance dosage, followed by CYP2C9*2 carriers and then by CYP2C9 *1 homozygotes (4.4±1.0 versus 5.4±2.3 versus 7.0±3.6 mg/d, p=0.03). CYP2C9*3 carriers also showed an increase in the anticoagulation risk, which required almost twice the number of dose adjustments to achieve appropriate anticoagulation. As to VKORC1, T/T homozygotes needed the lowest dose, followed by the C/T heterozygotes, and then by the C/C homozygotes (3.6±0.6 versus 5.5±0.5 and 7.9±0.7 mg/d, p <0,001). Risk of overcoagulation was higher in T/T patients than in C/T or C/C patients. T/T genotype of VKORC1 causes a decrease of nearly 50% in the warfarine daily dosage for all combinations with CYP2C9. Conclusions: we confirmed an increased sensitivity to warfarine in patient carriers of *2 and *3 CYP2C9 alleles and T VKORC1 alleles. We showed a combined effect (approximately accumulative) of variant alleles in both genes.

Résumé Introduction: la warfarine est une drogue très utilisée comme anticoagulant oral. Étant donné son restreint rang thérapeutique et sa remarquable variabilité interindividuelle, un contrôle rigoureux du dosage s’avère indispensable afin d’éviter des accidents hémorragiques. Objectifs: mettre en rapport les variantes génétiques de CYP2C9*2 et *3 et VKORC1 (C1173T) avec la réponse et les effets adverses. Matériel et méthode: les génotypes CYP2C9*1,*2,*3, et VKORC1 résultent par PCR-RFLP et les résultats analysés au moyen du paquet statistique SPSS 12.0. Résultats: il existe une tendance à réduire la dose par la présence d’allèles polymorphiques. Les porteurs de CYP2C9*3 ont requis une dose plus basse de maintien, puis les porteurs de CYP2C9*2 et homozygotes CYP2C9*1, dans cet ordre, (4,4±1,0 versus 7,0±3,6 mg/d, p=0,03). Les porteurs CYP2C9*3 ont aussi subi une augmentation du risque de suranticoagulation et ont requis presque le double d’ajustement de la dose pour atteindre une anticoagulation adéquate. Pour VKORC1, les homozygotes T/T ont requis une dose plus basse, suivis des hétérozygotes C/T et des homozygotes C/C, dans cet ordre (3,6±0,6 versus 5,5±0,5 et 7,9±0,7 mg/d, p <0,001). Les patients T/T ont subi un plus grand risque de suranticoagulation que les C/T et C/C. Le génotype T/T de VKORC1 provoque dans toutes les combinaisons avec CYP2C9 une diminution de 50% environ de la dose par jour de warfarine. Conclusions: on confirme une sensibilité augmentée à la warfarine chez les patients porteurs d’allèles *2 et *3 de CYP2C9, et T de VKORC1. Un effet combiné (à peu près aditif) des allèles variantes des deux gènes reste évident.

Resumo Introdução: a warfarina é uma droga muito usada como anticoagulante oral. Sua administração deve ser controlada rigorosamente para evitar acidentes hemorrágicos devido a uma aplicação terapêutica restrita e a variação da resposta individual. Objetivos: correlacionar as variantes genéticas de CYP2C9*2 e *3 y VKORC1 (C1173T) com a resposta e os efeitos adversos. Material e método: os genótipos CYP2C9*1, *2, *3, e VKORC1 foram obtidos por PCR-RFLP e os resultados foram analisados usando o programa SPSS 12.0. Resultados: observa-se uma tendência à redução da dose na presença de alelos polimórficos. Os portadores de CYP2C9*3 necessitam doses de manutenção mais baixas, seguidos pelos portadores de CYP2C9*2 e homozigotos CYP2C9 *1 (4,4±1,0 versus 5,4±2,3 versus 7,0±3,6 mg/d, p=0,03). Os portadores de CYP2C9*3 apresentaram também um aumento do risco de sobreanticoagulaçao e necessitam o dobro do número de ajustes de dose para obter uma anticoagulaçao adequada. Para VKORC1, os homozigotos T/T necessitaram a dose mais baixa, seguidos pelos heterozigotos C/T e homozigotos C/C (3,6±0,6 versus 5,5±0,5 y 7,9±0,7 mg/d, p <0,001). Os pacientes T/T apresentaram um risco maior de sobreanticoagulação que os C/T e C/C. O genótipo T/T de VKORC1 produz uma redução de aproximadamente 50% da dose diária de warfarina em todas as combinações com CYP2C9. Conclusões: confirma-se a sensibilidade aumentada à warfarina de pacientes portadores de alelos *2 y *3 de CYP2C9, e T de VKORC1. Demonstram-se um efeito combinado (aproximadamente aditivo) dos alelos variantes de ambos os genes.

Curso on-line: Introducción a la medicina genómica. Primera experiencia / On-line Course: Introduction to genomic medicine. First experience

Las nuevas modalidades académicas de educación continua flexible o a distancia, o ambas, que fortalecen la capacidad de autoaprendizaje y el uso de las nuevas tecnologías de la información y comunicación, compensan en parte las condiciones adversas impuestas por la actividad laboral de nuestro medio, que dificulta la asistencia a cursos presenciales de larga duración. La complejidad y vertiginosa generación del conocimiento biomédico actual y las transformaciones de la medicina genómica encuentran dificultad en su integración a la clínica por la escasa preparación de los médicos uruguayos en esta disciplina. Se describe la primera experiencia en nuestro medio de realización de un curso on-line de Introducción a la medicina genómica, destinado a médicos de diversas especialidades. Se comentan los resultados del mismo y se extraen algunas conclusiones que creemos de importancia para la discusión de las alternativas de educación médica continua en los albores del siglo XXI. Se discute especialmente la necesidad de desarrollar estrategias que permitan la formación en el uso de herramientas informáticas y comunicacionales para aprender, investigar e interaccionar en grupos y con las fuentes de información. Se plantea que estas estrategias serán de creciente importancia para la investigación clínica y las prácticas biomédicas en la era de la nueva genética.