Implementing Standard Diagnosis and Treatment for Locally Advanced Breast Cancer Through Global Research in Latin America: Results From a Multicountry Pragmatic Trial.

PURPOSE: Breast cancer mortality rates in Latin America (LA) are higher than those in the United States, possibly because of advanced disease presentation, health care disparities, or unfavorable molecular subtypes. The Latin American Cancer Research Network was established to address these challenges and to promote collaborative clinical research. The Molecular Profiling of Breast Cancer Study (MPBCS) aimed to evaluate the clinical characteristics and treatment outcomes of LA participants with locally advanced breast cancer (LABC). PATIENTS AND METHODS: The MPBCS enrolled 1,449 participants from Argentina, Brazil, Chile, Mexico, and Uruguay. Through harmonized procedures and quality assurance measures, this study evaluated clinicopathologic characteristics, neoadjuvant chemotherapy response, and survival outcomes according to residual cancer burden (RCB) and the type of surgery. RESULTS: Overall, 711 and 480 participants in the primary surgery and neoadjuvant arms, respectively, completed the 5-year follow-up period. Overall survival was independently associated with RCB (worse survival for RCBIII-adjusted hazard ratio, 8.19, P < .001, and RCBII [adjusted hazard ratio, 3.69, P < .008] compared with RCB0 [pathologic complete response or pCR]) and type of surgery (worse survival in mastectomy than in breast-conserving surgery [BCS], adjusted hazard ratio, 2.97, P = .001). The hormone receptor-negative-human epidermal growth factor receptor 2-positive group had the highest proportion of pCR (48.9%). The analysis of the ASCO Quality Oncology Practice Initiative breast module revealed high compliance with pathologic standards but lower adherence to treatment administration standards. Notably, compliance with trastuzumab administration varied widely among countries (33.3%-88.7%). CONCLUSION: In LABC, we demonstrated the survival benefit of BCS and the prognostic effect of the response to available neoadjuvant treatments despite an important variability in access to key treatments. The MPBCS represents a significant step forward in understanding the real-world implementation of oncologic procedures in LA.

Trastuzumab-induced cardiotoxicity in early breast cancer over a 10-year period in Uruguay.

This srudy aimed to estimate the prevalence of trastuzumab-induced cardiotoxicity in Uruguayan women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive breast cancer over a 10-year period, who were treated under the financial coverage of the National Resources Fund (Fondo Nacional de Recursos). This was an observational, descriptive study based on the analysis of an anonymized database of Uruguayan women diagnosed with HER2-positive breast cancer who received adjuvant trastuzumab treatment from to 2006 to 2016, provided by the Fondo Nacional de Recursos. Statistical analysis was performed using SPSS Statistics version 25, and variables were assessed using measures of central tendency, dispersion, contingency tables, and proportions. The chi-square test was used to analyze the association between the different variables. The study included 1401 patients diagnosed with stage I to III HER2-positive breast cancer. The mean age at diagnosis was 52 years. The prevalence of cardiotoxicity was 20.3%. Most patients who discontinued treatment owing to cardiotoxicity eventually resumed treatment (92.6%). Moreover, the prevalence of cardiotoxicity was similar among patients who received regimens with and without anthracyclines. No association was observed between prior cardiovascular events or trastuzumab administration (concurrent vs sequential) and the development of cardiotoxicity. In the present study, the prevalence of cardiotoxicity was similar to that reported nationally and internationally. Most patients did not develop cardiotoxicity, while the ones who developed it remained asymptomatic and cardiotoxicity was reversible.

Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women.

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients.

Purposes: Most molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and Methods: We collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. Results: PAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. Conclusions: This is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT02326857).

Population-based screening of Uruguayan Ashkenazi Jews for recurrent BRCA1 and BRCA2 pathogenic sequence variants.

In Ashkenazi Jews (AJ) three recurring pathogenic sequence variants (PSVs) are detected in ~2.5% of the general population in the BRCA1 (c.68_69del = 185delAG, c.5266dup = 5382insC), and BRCA2 (c.5946del = 6174delT). Population-based screening for these PSVs in AJ women is part of the health basket in Israel. To assess the feasibility and outcome of BRCA genotyping in the Jewish population of Uruguay, AJ in the greater Montevideo area were recruited using ethically approved protocol and without pretest counseling were genotyped for the three predominant AJ PSVs in the BRCA genes. Independently confirmed PSV carriers were counseled, and genetic testing was offered to additional family members. Overall, 327 participants were enrolled: 312 (95%) female, 261 (80%) had all four grandparents AJ, and 14 (4%) women were breast cancer survivors with a mean age ± standard deviation (SD) 50 ± 11.5 years. The BRCA1 c.68_69del PSV was detected in three cancer free participants (0.92%, CI 95% 0.31-2.6), all with a suggestive family history. No carriers of the other two recurrent PSVs were detected. Online oncogenetic counseling was provided for all carriers. In conclusion, the rate of the BRCA1 c.68_69del PSV was similar with the rate in other AJ communities. AJ population BRCA genotyping screens in Uruguay seem feasible and should be promoted.

Prevalence of Known Risk Factors in Uruguayan Women Treated for Breast Cancer at a University Hospital.

INTRODUCTION: In Uruguay, breast cancer has the highest incidence and mortality of all cancer in women. Knowledge of the distribution of risk factors related to disease development supports the implementation of prevention strategies in routine clinical practice. This study aimed to determine the epidemiological profile for breast cancer and the frequency of mammographic surveillance in the surveyed population. MATERIALS AND METHODS: A survey was conducted among Uruguayan women diagnosed with breast cancer who were assisted in the mastology unit of the oncology service of the Hospital de Clínicas in Montevideo, Uruguay, from September 1, 2018, to March 1, 2020. RESULTS: This study included 398 respondents, with a median (SD) age at diagnosis of 61 (34-86) years. A total of 310 respondents (78.0%) had 1 or more risk factors. Most women aged over 50 years (264 out of a total of 338 [78.1%]) underwent mammographic surveillance at least biennially. CONCLUSIONS: Consistent with international reports, most respondents had a risk factor. Among the group of respondents aged over 50 years, most underwent mammographic and clinical surveillance at least biennially. Although it is only possible to formulate conclusions about the surveyed women because of the study design, the obtained data further our understanding of the epidemiological profile of the Uruguayan population, which can contribute to prevention practices.

Discovery of novel DNA methylation biomarkers for non-invasive sporadic breast cancer detection in the Latino population.

Human diversity is one of the main pitfalls in the development of robust worldwide biomarkers in oncology. Epigenetic variability across human populations is associated with different genetic backgrounds, as well as variable lifestyles and environmental exposures, each of which should be investigated. To identify potential non-invasive biomarkers of sporadic breast cancer in the Uruguayan population, we studied genome-wide DNA methylation using Illumina methylation arrays in leukocytes of 22 women with sporadic breast cancer and 10 healthy women in a case-control study. We described a panel of 38 differentially methylated CpG positions that was able to cluster breast cancer patients (BCP) and controls, and that also recapitulated methylation differences in 12 primary breast tumors and their matched normal breast tissue. Moving forward, we simplified the detection method to improve its applicability in a clinical setting and used an independent well-characterized cohort of 80 leukocyte DNA samples from BCP and 80 healthy controls to validate methylation results at specific cancer-related genes. Our investigations identified methylation at CYFIP1 as a novel epigenetic biomarker candidate for sporadic breast cancer in the Uruguayan population. These results provide a proof-of-concept for the design of larger studies aimed at validating biomarker panels for the Latin American population.

Evaluación de la eficacia de la consulta telefónica y el nivel de satisfacción de las pacientes asistidas en la Unidad Docente Asistencial de Mastología durante la alerta sanitaria por COVID 19 / Evaluation of the effectiveness of telephone consultations and the level of satisfaction of patients assisted at the Mastology Teacher Assistance Department with this modality during the COVID health emergency / Avaliação da eficácia da consulta telefônica e do nível de satisfação das pacientes atendidas na Unidade de Docência Assistencial de Mastologia durante o alerta de saúde para o COVID 19

Resumen: Introducción: en marzo de 2020 se decretó la emergencia sanitaria por COVID-19, lo que produjo cambios en la organización de los servicios de la salud. Uno de los objetivos de la reorganización fue minimizar las consultas presenciales (CP) y promocionar las telefónicas (CT). Objetivo: evaluar la eficacia de la CT y el nivel de satisfacción de las pacientes asistidas en la Unidad de Mastología con la misma durante la alerta sanitaria por COVID. Material y métodos: se aplicó una encuesta para valorar la eficacia de la CT y el nivel de satisfacción con la misma. Resultados: se encuestaron 42 pacientes, 69% se encontraba recibiendo tratamiento adyuvante y 14,2% paliativo. En cuanto a la eficacia de la CT, 76,1% fueron resueltas en forma telefónica; 78,6% de las pacientes prefirió realizar la consulta en forma telefónica; 97,6% creyó que el tiempo empleado fue suficiente y que el horario en que se la contactó fue adecuado. Las respuestas mostraron un alto grado de satisfacción con la asistencia. La atención médica cumplió con las expectativas de todas las pacientes, 83,3% creyó que una vez recuperada la normalidad, la CT es una opción para su situación. Conclusión: la CT fue valorada con un alto grado de satisfacción y permitió mantener la asistencia durante la emergencia. Si bien es pronto para evaluar el impacto asistencial de la CT y su capacidad resolutiva, resultados preliminares muestran que es una herramienta útil y valiosa en la práctica clínica durante periodos de emergencia sanitaria.

Summary: Introduction: in March 2020, a national health emergency was declared due to the COVID-19, what resulted in changes in the organization of health services. One of the objectives of this restructure was to minimize in person consultations and to promote telephone consultations. that took place was a reduction in face-to-face consultations (FTFC), and the promotion of telephone consultations (TC). Objective: to evaluate the effectiveness of telephone consultations and the level of satisfaction of patients assisted at Mastology Department with this modality during the COVID 19 health emergency. Materials and methods: a survey was used to assess the effectiveness of telephone consultations and the level of satisfaction with this modality. Results: forty-two patients were surveyed, 69% of which were receiving adjuvant treatment and 14.2% of which were receiving palliative treatment. With regard to the effectiveness of telephone consultations, 76.1% of those surveyed had their need solved by telephone; 78.6% of patients preferred to do the consultation by telephone; 97.6% believed that sufficient time was spent and that the timing of the appointment was appropriate. The responses showed a high level of satisfaction with the care received. The medical care met the expectations of all patients, and 83.3% believed that once the situation went back to normal, telephone consultations would be an option for their requirements. Conclusion: the telephone consultation method was evaluated with a high level of satisfaction and it allowed health care services to be maintained during the emergency. Although it is early to assess the healthcare impact of telephone consultations and the modality's capacity to resolve issues, preliminary results show that it is a useful and valuable tool in clinical practice during periods of healthcare emergency.

Resumo: Introdução: em março de 2020, foi decretada a emergência sanitária decorrente do COVID-19, o que produziu mudanças na organização dos serviços de saúde. Um dos objetivos da reorganização era minimizar as consultas presenciais (CP) e promover as consultas telefônicas (CT). Objetivo: avaliar a eficácia da CT e o nível de satisfação das pacientes atendidas na Unidade de Docência Assistencial de Mastologia com a prestada previamente durante o alerta de saúde para o COVID. Material e métodos: foi realizada uma pesquisa telefônica para avaliar a eficácia da TC e o nível de satisfação com a mesma. Resultados: foram entrevistadas 42 pacientes, 69% estavam recebendo tratamento adjuvante e 14,2% paliativo. Em relação à eficácia da CT, 76,1% foram resolvidas por telefone; 78,6% das pacientes preferiram fazer a consulta por telefone; 97,6% consideraram que o tempo despendido foi suficiente e que o momento em que foram contatados foi adequado. As respostas mostraram alto grau de satisfação com o atendimento. O atendimento médico atendeu às expectativas de todos os pacientes, 83,3% acreditam que, uma vez restaurada a normalidade, a CT é uma opção para sua situação. Conclusão: a CT foi avaliada com alto grau de satisfação e permitiu manter o atendimento durante a emergência. Embora seja muito cedo para avaliar o impacto da CT na saúde e sua capacidade de resolução, resultados preliminares mostram que é uma ferramenta útil e valiosa na prática clínica durante períodos de emergência de saúde.

Genomic Diversity in Sporadic Breast Cancer in a Latin American Population.

Among Latin American women, breast cancer incidences vary across populations. Uruguay and Argentina have the highest rates in South America, which are mainly attributed to strong, genetic European contributions. Most genetic variants associated with breast cancer were described in European populations. However, the vast majority of genetic contributors to breast cancer risk remain unknown. Here, we report the results of a candidate gene association study of sporadic breast cancer in 176 cases and 183 controls in the Uruguayan population. We analyzed 141 variants from 98 loci that have been associated with overall breast cancer risk in European populations. We found weak evidence for the association of risk variants rs294174 (ESR1), rs16886165 (MAP3K1), rs2214681 (CNTNAP2), rs4237855 (VDR), rs9594579 (RANKL), rs8183919 (PTGIS), rs2981582 (FGFR2), and rs1799950 (BRCA1) with sporadic breast cancer. These results provide useful insight into the genetic susceptibility to sporadic breast cancer in the Uruguayan population and support the use of genetic risk scores for individualized screening and prevention.

Expresión tumoral de BRCA1 y resultados clínicos en pacientes uruguayas diagnosticadas de cáncer de mama antes de los 40 años / BRCA1 tumor expression and clinical results in uruguayan patients diagnosed with breast cancer before the age of 40 years old / Expressão tumoral de BRCA1 e resultados clínicos em pacientes uruguaias com diagnóstico de câncer de mama antes dos 40 anos

Resumen: Las mutaciones de BRCA1 son raras en el cáncer de mama (CM) esporádico; sin embargo, su expresión a nivel tumoral se encuentra disminuida o ausente en 30%-50% de los casos. Objetivo: valorar la expresión tumoral de BRCA1 por inmunohistoquímica (IHQ) en mujeres uruguayas diagnosticadas de CM antes de los 40 años. Material y método: se incluyeron pacientes diagnosticadas de CM antes de los 40 años. Se utilizaron los anticuerpos monoclonales anti-BRCA1 MS110 contra el extremo N-terminal y GLK-2 contra el extremo C-terminal. Se calculó la sobrevida global (SVG) y la sobrevida libre de enfermedad (SVLE), para la construcción de las curvas se utilizó el método de Kaplan-Meier y la diferencia de sobrevida se evaluó mediante el test de log rank. Resultados: se incluyeron 40 pacientes, la SVG y la SVLE a cinco años fueron de 73% y 60% respectivamente. La expresión de BRCA1 mediante GLK-2 fue <10% en 16 de las 40 pacientes (40%). La SVG y la SVLE a cinco años para las pacientes con expresión <10% fue de 56% vs 85% para las pacientes con expresión >10% (p=0,015) y de 40% vs 72% (p=0,034) respectivamente. La expresión de BRCA1 mediante MS110 fue <10% en 11 de las 40 pacientes (27,5%). No se encontraron diferencias en la SVG ni en la SVLE a cinco años con este marcador. Conclusión: la pérdida de la expresión tumoral de BRCA1 determinada mediante GLK-2 se encontró en el 40% de las pacientes incluidas y se asoció a una menor SVG y SVLE, por lo que podría tener un valor pronóstico desfavorable en estas pacientes.

Summary: BRCA1 mutations are rare in sporadic breast cancer (CM), however their expression at the tumor level is diminished or absent in 30-50% of cases. Objective: to assess the tumor expression of BRCA1 using immunohistochemistry (IHC) in Uruguayan women diagnosed with BC before the age of 40 years. Material and methods: patients diagnosed with BC before the age of 40 between. The antibodies used were anti BRCA1 MS110 monoclonal antibodies against the N-terminal end and GLK-2 against the C-terminal. Overall survival (OS) and disease free survival (DFS) were calculated; the curves were developed using the Kaplan-Meier method and the difference in survival was evaluated through the log rank test. Results: the average age of the 40 patients included was 36 years. The 5-year OS and DFS were 73% and 60% respectively. The expression of BRCA1 with GLK-2 was <10% in 16 of the 40 patients included (40%). The 5-year OS and DFS for patients with <10% expression was 56% vs. 85% for patients with >10% (p=0.015) and 40% vs. 72% (p = 0.034) respectively. The expression of BRCA1 by MS110 was <10% in 11 of the 40 patients included (27.5%). No differences were found in the 5-year OS or DFS based on the expression of this marker. Conclusion: The loss of BRCA1 expression using GLK-2, which suggests the presence of a truncated protein, was associated with a statistically significantly lower OS and DFS, that the decrease in the BRCA1 protein as determined by GLK2 has an unfavorable prognostic value for young patients with BC.

Resumo: As mutações de BRCA1 são raras no câncer de mama (CM) esporádico; no entanto sua expressão no nível tumoral está diminuída ou ausente em 30-50% dos casos. Objetivo: avaliar a expressão tumoral de BRCA1 por imuno-histoquímica (IHQ) em mulheres uruguaias com diagnóstico de CM antes dos 40 anos. Material e métodos: foram incluídas pacientes com diagnóstico de CM antes dos 40 anos. Foram utilizados anticorpos monoclonais anti BRCA1 MS110 contra o extremo N-terminal e GLK-2 contra o extremo C-terminal. A sobrevida global (SVG) e a sobrevida livre de enfermidade (SVLE) foram calculadas; o método de Kaplan-Meier foi utilizado para a construção das curvas e a diferença de sobrevida foi avaliada usando o teste de log-rank. Resultados: foram incluídas 40 pacientes; a SVG e a SVLE aos 5 anos foram 73% e 60% respectivamente. A expressão de BRCA1 mediante GLK-2 foi <10% em 16 das 40 pacientes (40 %). A SVG e a SVLE aos 5 anos para as pacientes com expressão £10% foi 56% vs. 85% para as pacientes com expressão >10% (p=0,015) e 40% vs. 72% (p=0,034) respectivamente. A expressão de BRCA1 mediante MS110 foi =10% em 11 das 40 pacientes (27,5%). Não foram encontradas diferenças na SVG nem na SVLE aos 5 anos com este marcador. Conclusão: foi encontrada perda da expressão tumoral de BRCA1 determinada por GLK-2 em 40% das pacientes incluídas e foi associada a uma menor SVG e SVLE, o que poderia ter um valor prognóstico desfavorável nestas pacientes.

Síndrome de Li Fraumeni: análisis clínico de un caso y revisión de la literatura / Li-Fraumeni syndrome: clinical case study and literature survey / Síndrome de Li Fraumeni: análise clínica de um caso e uma revisão da literatura

Resumen: El síndrome de Li-Fraumeni (SLF) es una enfermedad hereditaria autosómica dominante con elevada penetrancia, que se caracteriza por la aparición precoz de múltiples tumores en un individuo y una marcada agregación familiar. Aproximadamente el 70% de los pacientes que cumplen criterios clínicos para su diagnóstico son portadores de la mutación germinal del gen TP53 localizado en el cromosoma 17p13. El gen TP53 es un supresor tumoral que cumple una importante función en el control de la estabilidad genómica. Se estima que el riesgo de desarrollar cáncer es del 50 % para las mujeres a los 31 años de edad y para los hombres a los 46 años y cerca del 100 % para ambos sexos a los 70 años. El curso clínico de la enfermedad es similar que en pacientes sin SLF a excepción de la edad más temprana al diagnóstico. Presentamos el caso de una paciente de 31 años a la que se diagnostica un condrosarcoma pelviano tratado con cirugía y al momento de la recidiva, aproximadamente 8 meses después, un cáncer de mama localizado. En otro miembro de su familia se había identificado la mutación 375G>C en el gen TP53 mediante secuenciación Sanger, la cual fue detectada posteriormente en nuestra paciente. Se discuten aspectos particulares del manejo como la minimización de la exposición a la radioterapia (por reportes de tumores malignos en zonas irradiadas) y el especial manejo de la repercusión del diagnóstico a nivel de los otros integrantes de la familia.

Abstract: The Li-Fraumeni syndrome (SLF) is a highly penetrant condition with an autosomal dominant inheritance pattern, characterized by an early onset of multiple tumors in a subject and a marked familial occurrence. About 70 % of patients meeting clinical criteria for diagnosis of the disease carry the germline mutation of TP53 gene located in chromosome 17p13. TP53 is a tumor suppressor gene known for its major role in genome stability control. It has been estimated that risk of cancer development is 50 % for women at the age of 31 and for men at the age of 46 and nearly 100 % for both men and women at 70 years of age. Except at earlier ages of diagnosis, the clinical course of the disease for healthy patients and for patients suffering SLF shows similarities. We present the case of a 31-year-old patient diagnosed both with pelvic chondrosarcoma treated surgically and localized breast cancer during relapse, about 8 months later. By Sanger sequencing, mutation 375G>C had been identified in TP53 gene in another family member, and said mutation was later detected in our patient. We discuss particular aspects of treatment procedures, such as minimizing radiotherapy exposure (due to reports of malignancies in radiated areas) and the special management of diagnosis implications for other family members.

Resumo: A síndrome de Li-Fraumeni (SLF) é uma doença hereditária autorexistente dominante com pena de penetração, que caracteriza a aparição precoz de múltiplos tumores em um indivíduo e uma coletânea familiar. Aproximadamente o 70% dos pacientes com critérios clínicos para o diagnóstico em crianças portadores da mutação germinal do gen TP53 localizado no cromosoma 17p13. El gen TP53 é um tumor tumoral que cumple uma função importante no controle da estabilização genómica. Se estima que o riesgo do desengate faz dos 50% para as mulheres aos 31 anos de idade e para os 40 anos e cerca de 100% para ambos os sexos aos 70 anos. O curso clínico da doença é semelhante ao que ocorre com a SLF a exceção da doença mais tem sido diagnosticada. Presentamos o caso de um paciente de 31 años que diagnostica um paciente de pélvico com relato ao momento da recidiva, aproximadamente 8 meses depois, em um lugar de mama próximo. En otio miembro de la familia se habiocuident to the mutación 375G> C en el gen TP53 por secuenciación Sanger, a cual fue detectada em recente paciente. A discussão foi feita sobre os aspectos do tratamento com a minimização da exposição à radioterapia (por tumores malignos em zonas irradiadas) e o especial manejo da repercussão do diagnóstico a nível dos otros integrantes da familia

Evaluación de la calidad de la asistencia y el nivel de satisfacción de las pacientes asistidas en una Unidad Docente Asistencial de Mastología del Hospital de Clínicas "Dr. Manuel Quintela" / Assessing assistance quality and degree of patient satisfaction at a Breast Teaching and Care Unit at Hospital de Clinicas"Dr. Manuel Quintela" / Avaliação da qualidade dos cuidados e do nível de satisfação dos pacientes atendidos em uma Unidade de Ensino Assistido de Mastologia do Hospital de Clínicas "Dr. Manuel Quintela"

RESUMEN: Introducción: En los últimos años ha adquirido gran relevancia evaluar la satisfacción de los usuarios con los servicios sanitarios, lo que se asocia en forma significativa con los resultados obtenidos en salud. La satisfacción de los pacientes juega un importante papel en el mantenimiento de la utilización de los servicios de salud, en la continuidad de la relación médico-paciente y en la adherencia a los tratamientos indicados. Objetivos: Conocer el grado de satisfacción manifestado por las pacientes asistidas en la Unidad Docente Asistencial de Mastología del Hospital de Clínicas e identificar los aspectos a mejorar. Material y métodos: Estudio prospectivo, aprobado por el comité de ética del Hospital de Clínicas, en el que se aplicó una encuesta anónima de satisfacción con 13 preguntas cerradas y una abierta y se recogieron datos sobre la edad y tipo de tratamiento oncológico recibido. Resultados: Se encuestaron 91 pacientes que concurrieron a la consulta en un período de dos meses. Las respuestas muestran un alto grado de satisfacción de las pacientes con la asistencia global recibida, con una puntuación media de 3,26 (IC 95% 3.18-3.34) (rango: 1: pobre; 5: excelente), siendo este resultado independiente del grupo etario y del tipo de tratamiento oncológico recibido. Sin embargo el 38,5 % de las pacientes que trabaja piensa que no pudo discutir el impacto de la enfermedad en su trabajo (media 1,82; IC 95% 1,66-1,97) (rango 0: nada; 3: tanto como quise) y un 27 % del total de las encuestadas piensa que no pudo discutir el impacto que su enfermedad tuvo en sus actividades diarias (media 2,13 IC 95% 2,12 - 2,14) (rango: 0 : nada ; 3: si tanto como quise) ni en sus relaciones personales (27; 30 %, media 2,0 IC 95% 1,93-2,2) (rango: 0: nada ; 3: si tanto como quise). Conclusiones: La puntuación global es muy satisfactoria, con dimensiones que deben mejorarse con un mayor énfasis en la comunicación sobre el impacto de la enfermedad en las actividades diarias, las relaciones personales y el trabajo. Consideramos importante implementar evaluaciones periódicas de la calidad de atención que permitan comparar los resultados y desarrollar un proceso de mejora continua.

ABSTRACT: Introduction: During the last years, assessing the degree of patient satisfaction of health services has become extremely important; and it is more often associated to the results obtained in terms of health. The degree of patient satisfaction plays a significant role in fostering the use of health care services, in developing the physician-patient relationship and in adhering to indicated treatments. Objective: To find out the degree of patient satisfaction at the Breast Teaching and Care Unit at Hospital de Clinicas and identify aspects that need improving. Materials and methods: prospective study, approved by the ethics committee of Hospital de Clinicas, where an anonymous satisfaction survey, with 1 open and 13 closed questions, was conducted. The survey also included data related to the age and oncological treatment received. Results: Over two months, 91 assisting patients were interviewed. Responses show a high degree of satisfaction of patients with the global care received, with a mean score of 3.26 (CI 95 % 3.18-3.34) (range: 1: poor; 5: excellent), regardless of age group and the type of oncological treatment received. However, 38.5 % of working patients believe that they were not able to discuss the impact of their disease at their jobs (mean 1.82; CC 95% 1.66-1.97) (range: 0: not at all; 3: as much as I wanted) and 27 % of patients consider that they were not able to discuss the impact of their disease on their daily activities (mean 2.13; CI 95 % 2.12 - 2.14) (range: 0: not at all; 3: as much as I wanted) or their personal relations (27; 30 %, mean 2.0 CI 95 % 1.93-2.2) (range: 0: not at all; 3: as much as I wanted). Conclusions: The global score is very satisfactory, and there are aspects to be improved, such as a better communication on the impact of the disease on daily activities, personal relations and work. We believe it is important to implement regular assessments of assistance quality that may enable to compare results and develop a continuous improvement process.

RESUMO: Introdução: Nos últimos anos, tornou-se muito importante avaliar a satisfação dos usuários com serviços de saúde, o que está significativamente associado aos resultados obtidos em saúde. A satisfação do paciente desempenha um papel importante na manutenção do uso dos serviços de saúde, na continuidade da relação médico-paciente e na adesão aos tratamentos indicados. Objetivos: Conhecer o grau de satisfação expressado pelos pacientes atendidos na Unidade de Assistência de Ensino de Mastologia do Hospital de Clínicas e identificar os aspectos a serem melhorados. Material e métodos Estudo prospectivo, aprovado pelo comitê de ética do Hospital de Clínicas, no qual foi aplicada uma pesquisa de satisfação anônima com 13 perguntas fechadas e uma aberta e dados coletados sobre a idade eo tipo de tratamento oncológico recebido. Resultados: Foram entrevistados 91 pacientes que participaram da consulta em um período de dois meses. As respostas mostram um alto grau de satisfação do paciente com a assistência geral recebida, com uma pontuação média de 3,26 (IC 95% 3,18-3,34) (intervalo: 1: pobre; 5: excelente), sendo este resultado independente da faixa etária e o tipo de tratamento contra o câncer recebido. No entanto, 38,5% dos pacientes que trabalham pensam que não poderiam discutir o impacto da doença em seus trabalhos (média 1,82, IC 95%: 1,66-1,97) (intervalo 0: nenhum; tanto quanto eu queria) e 27% do total de entrevistados pensam que não poderiam discutir o impacto que sua doença teve em suas atividades diárias (média 2.13 IC 95% 2.12 - 2.14) (intervalo: 0: nada ; 3: sim, tanto quanto eu queria) ou em seus relacionamentos pessoais (27; 30%, média 2,0 IC 95% 1,93-2,2) (classificação: 0: nada; 3: sim, tanto quanto eu queria). Conclusões: A pontuação geral é muito satisfatória, com dimensões que devem ser melhoradas com maior ênfase na comunicação sobre o impacto da doença nas atividades diárias, nas relações pessoais e no trabalho. Consideramos importante implementar avaliações periódicas da qualidade dos cuidados que nos permitem comparar os resultados e desenvolver um processo de melhoria contínua.

Características clínico-patológicas y evolución del cáncer de mama en mujeres uruguayas jóvenes / Clinical and pathological characteristics of breast cancer in young uruguayan women

Introducción: en Uruguay el cáncer de mama (CM) es la principal causa de muerte por esta afección en la mujer. Aproximadamente 5,4% de los casos se diagnostican en menores de 40 años, es decir, en mujeres en edad reproductiva y laboralmente activas. Objetivo: investigar la frecuencia, características clínico-patológicas y evolución de pacientes uruguayas diagnosticadas con CM antes de los 40 años y su sobrevida de acuerdo al subtipo biológico. Material y método: se recolectaron datos relacionados con las características clínico-patológicas y la evolución de pacientes menores de 40 años tratadas por CM en el período comprendido entre el 1º de enero de 2006 y 31 de diciembre de 2012 asistidas en las instituciones participantes. Se calculó la sobrevida global (SVG) y la sobrevida libre de enfermedad (SVLE) para todas las pacientes, globalmente, y según el subtipo biológico. Resultados: se incluyeron 107 pacientes; edad mediana: 35 años (rango 24 a 39 años); las características clínico-patológicas fueron: carcinoma ductal: 89,7%; GH 2-3: 93,5%; estadio: II-III: 75%; metástasis axilares: 57%; HER2- RE/RP+ 53%; HER2+ 24,5%, y triple negativas (TN) 22,5%. El 17% de las pacientes presentaron antecedentes familiares (AF) significativos y la totalidad realizaron los tratamientos según pautas vigentes. La SVG y la SVLE a cinco años para la totalidad de las pacientes fueron 79% y 72%, respectivamente. La SVG y la SVLE fueron 97% y 90%, respectivamente, para las pacientes ER/PR+/HER2-; de 54% y 49% para las HER2+, y de 60% y 20% para las TN. Las curvas de SVLE fueron similares para las pacientes TN y HER2+, mientras que las pacientes ER/PR+/HER2- tuvieron una mayor SVG y SVLE (Log Rank, p < 0,0001). Conclusiones: las pacientes uruguayas diagnosticadas de CM antes de los 40 años incluidas tuvieron una SVG y una SVLE menor a la reportada en pacientes de la población general y de mayor rango etario. Si bien la peor evolución se ha vinculado al retraso en el diagnóstico, la mayoría de nuestras pacientes fueron diagnosticadas en estadios localizados y la totalidad realizó los tratamientos según las pautas vigentes. Por otra parte, la proporción de subtipos desfavorables (TN y HER2+) fue mayor a lo reportado para mujeres de todas las edades con CM, por lo que su peor evolución podría estar relacionada con el perfil biológico.

Introduction: In Uruguay, breast cancer is the main cause of death for this condition. Approximately 5.4% of cases are diagnosed in women younger than 40 years old, in other words, in women in their reproductive age, when they may be part of the labor force. Objective: To investigate the frequency, clinical and pathological characteristics and evolution of Uruguayan patients who are diagnosed with breast cancer before they are 40 years old, and their survival according to the biological sub-type. Method: the data in connection with the clinical and pathological characteristics and the evolution of patients was collected for women younger than 40 years old who had been treated for breast cancer at the participating institutions between January 1, 20016 and December 31, 2012. Global survival and disease-free survival was calculated for all patients, globally and according to the biological sub-type. Results: 107 students were included in the study; median age: 35 years old, range (24 to 39 years old); clinical and pathological characteristics: ductal carcinoma: 89.7%; Grade 2-3: 93.5%; stage II-III: 75% axillary metastasis: 57%; HER2- ER/PR 53%; HER"+ 24.5% and triple negative 22.5%. 17% of patients evidenced significant family history, and all of them were treated according to protocols in force. Global survival and disease free-survival after five years was 79% and 72% respectively. Global survival and disease free-survival was 97% and 90% respectively for patients RE/RP+/HER2-; of 54% and 49% for HER2+, and of 60% and 20% for triple negative. Disease-free survival curves were similar for patients triple negative and HER2+, whereas patients RE/RP+/HER2-evidenced a greater global survival and disease-free survival (Log Rank, p ? 0,0001). Conclusions: Uruguayan patients diagnosed with breast cancer before the age of 40 years old included in the study evidenced a lower global survival and disease free-survival rate than that reported for patients of the general population and older than 40 years old. In spite of the fact that the worse evolution has been associated to delays in diagnostic, most patients were diagnosed in the localized stage and all of them were treated according to protocols in force. Likewise, the proportion of the unfavorable sub-types (triple negative and HER2+) was greater than that reported for women of all ages with breast cancer. Thus, the worse evolution could be associated with the biological profile.

Introdução: no Uruguai o câncer de mama (CM) é a principal causa de morte das mulheres por este tipo de patologia. Aproximadamente 5,4% dos casos são diagnosticados em mulheres com menos de 40 anos, ou seja, mulheres em idade reprodutiva e economicamente ativas. Objetivo: pesquisar a frequência, características clínico-patológicas e evolução de pacientes uruguaias diagnosticadas com CM antes dos 40 anos e sua sobrevida de acordo com o subtipo biológico. Material e método: foram coletados dados relacionados com as características clínico-patológicas e a evolução de pacientes com menos de 40 anos tratadas por CM no período 1º de janeiro de 2006 - 31 de dezembro de 2012 atendidas nas instituições participantes. A sobrevida global (SVG) e a sobrevida livre de doença (SVLE) foi calculada para todas as pacientes, e segundo o subtipo biológico. Resultados: 107 pacientes foram incluídas com idade mediana 35 anos (intervalo 24 a 39 anos); as características clínico-patológicas foram: carcinoma ductal: 89,7%; GH 2-3: 93,5%; estadio: II-III: 75%; comprometimento axilar: 57%; HER2- RE/RP+ 53%; HER2+ 24,5%, e triplo negativo (TN) 22,5%. 17% das pacientes apresentavam antecedentes familiares (AF) significativos e todas foram tratadas observando-se as pautas vigentes. A SVG e a SVLE aos cinco anos para o total de pacientes foram 79% e 72%, respectivamente. A SVG e a SVLE foram 97% e 90%, respectivamente, para as pacientes ER/PR+/HER2-; 54% e 49% para as HER2+, e 60% e 20% para as TN. As curvas de SVLE foram similares para as pacientes TN e HER2+, porém as pacientes ER/PR+/HER2- apresentaram SVG e SVLE maiores (Log Rank, p ? 0,0001). Conclusões: as pacientes uruguaias diagnosticadas com CM antes dos 40 anos incluídas neste estudo apresentaram SVG e SVLE menores às registradas para pacientes da população em geral e com idades superiores. Embora a pior evolução esteja vinculada ao diagnóstico tardio, a maioria das pacientes estudadas foi diagnosticada em estádios localizados e todas receberam tratamento de acordo com as pautas vigentes. Por outra lado, a proporção de subtipos desfavoráveis (TN y HER2+) foi maior ao informado para mulheres de todas as idades com CM, por isso uma pior evolução poderia estar relacionada com o perfil biológico.

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.

Evaluación de la calidad de la asistencia en la unidad docente asistencial de mastología del hospital de clínicas / Evaluation of the quality of assistance at the mastology teaching unit of the university hospital

Introducción: el cáncer de mama (CM) es el cáncer más frecuente en la mujer uruguaya, cada año se registran unos 1.840 casos nuevos y unas 660 mujeres mueren como consecuencia de esta enfermedad. Con el fin de mejorar la calidad de la asistencia de las pacientes portadoras de patología mamaria se creó la Unidad Docente Asistencial de Mastología (UDAM) en el año 2009. Objetivo: valorar la calidad de la asistencia en la UDAM del Hospital de Clínicas. Material y método: estudio observacional, retrospectivo, que incluyó a las pacientes diagnosticadas y tratadas por CM en una UDAM desde junio de 2009 hasta junio de 2014. Para valorar la calidad de la asistencia se utilizaron los indicadores propuestos por la Sociedad Europea de Mastología (EUSOMA) en 2010. Resultados: se incluyeron 115 pacientes tratadas por CM; la mediana de edad fue de 63 años, la mayoría de las pacientes tuvieron CM limitados a la mama o axila, receptores hormonales (RRHH) positivos / HER2 negativos. Se cumplieron los criterios de calidad relacionados con el diagnóstico preoperatorio, informe anatomopatológico, tratamiento quirúrgico, radiante y oncológico. Sin embargo, en el 40% de los casos el intervalo de tiempo entre el diagnóstico y el primer tratamiento oncológico fue superior a seis semanas. Conclusiones: la atención recibida por las pacientes asistidas en nuestra UDAM en el período de referencia cumplió con la mayoría de los indicadores propuestos por EUSOMA. Se destaca la necesidad de mejorar el tiempo de espera entre el diagnóstico y el primer tratamiento oncológico.

Introduction: breast cancer is the most frequent types of cancer in Uruguayan women. Every year there are 1,840 new cases and around 660 women die from this disease. The Mastology Teaching Unit was created in 2009 to improve the quality of assistance in patients with breast cancer. Objective: to evaluate the quality of assistance at the Mastology Teaching Unit of the University Hospital. Method: observational, retrospective study that included women diagnosed and treated for breast cancer in a Mastology Teaching Unit from June 2009 through June, 2014. In order to evaluate the quality of assistance the indicators suggested by the European Society of Mastology in 2010 were used. Results: 115 patients treated for breast cancer were included in the study. Average age was 63 years old, most patients had breast cancer limited in the breast or armpit, (RRHH) positive hormonal receptors, HER2 negative. The quality criteria associated to preoperative diagnosis, pathology analysis, surgical treatment, radiotherapy and oncologic treatment were met. However, in 40% of cases the time interval between diagnosis and the first oncologic treatment was over six weeks. Conclusions: care received by patients seen at the Mastology Unit during the referred period met most indicators suggested by the European Society of Mastology. The need to improve the waiting time between diagnosis and the first oncologic treatment is emphasized.

Introdução: no Uruguai o câncer de mama (CM) é o tipo mais frequente na mulher; a cada ano aproximadamente 1.840 casos novos são registrados e 660 mulheres morrem como consequência desta patologia. Buscando melhorar a qualidade da assistência prestada às pacientes portadoras desta patologia mamaria, em 2009, foi criada a Unidade Docente Assistencial de Mastologia (UDAM). Objetivo: avaliar a qualidade da assistência na UDAM do Hospital de Clínicas. Material e método: estudo observacional, retrospectivo, incluindo as pacientes diagnosticadas e tratadas por CM na UDAM no período junho de 2009 - junho de 2014. Para avaliar a qualidade da assistência foram utilizados os indicadores propostos em 2010 pela Sociedade Europeia de Mastologia (EUSOMA). Resultados: foram incluídas 115 pacientes tratadas por CM; a mediana de idade foi 63 anos; a maioria das pacientes apresentaram CM limitados a mama ou axila, receptores hormonais (RRHH) positivos / HER2 negativos. Os critérios de qualidade relacionados com diagnóstico pré-operatório, laudo anatomopatológico, tratamento cirúrgico, radiante e oncológico foram observados. No entanto, em 40% dos casos o intervalo de tempo entre o diagnóstico e o primeiro tratamento oncológico foi superior a seis semanas. Conclusões: a atenção recebida pelas pacientes assistidas na UDAM no período de estudo cumpriu com a maioria dos indicadores propostos pela EUSOMA. Destaca-se a necessidade de melhorar o tempo de espera entre o diagnóstico e o primeiro tratamento oncológico.

Effect of genetic ancestry on leukocyte global DNA methylation in cancer patients.

BACKGROUND: The study of genetic variants alone is not enough to explain a complex disease like cancer. Alterations in DNA methylation patterns have been associated with different types of tumor. In order to detect markers of susceptibility for the development of cutaneous melanoma and breast cancer in the Uruguayan population, we integrated genetic and epigenetic information of patients and controls. METHODS: We performed two case-control studies that included 49 individuals with sporadic cutaneous melanoma and 73 unaffected controls, and 179 women with sporadic breast cancer and 209 women controls. We determined the level of global leukocyte DNA methylation using relative quantification of 5mdC by HPLC, and we compared methylation levels between cases and controls with nonparametric statistical tests. Since the Uruguayan population is admixed and both melanoma and breast cancer have very high incidences in Uruguay compared to other populations, we examined whether individual ancestry influences global leucocyte DNA methylation status. We carried out a correlation analysis between the percentage of African, European and Native American individual ancestries, determined using 59 ancestry informative markers, and global DNA methylation in all participants. RESULTS: We detected global DNA hypomethylation in leukocytes of melanoma and breast cancer patients compared with healthy controls (p < 0.001). Additionally, we found a negative correlation between African ancestry and global DNA methylation in cancer patients (p <0.005). CONCLUSIONS: These results support the potential use of global DNA methylation as a biomarker for cancer risk. In addition, our findings suggest that the ancestral genome structure generated by the admixture process influences DNA methylation patterns, and underscore the importance of considering genetic ancestry as a modifying factor in epigenetic association studies in admixed populations such as Latino ones.

Breast cancer risk and genetic ancestry: a case-control study in Uruguay.

BACKGROUND: Uruguay exhibits one of the highest rates of breast cancer in Latin America, similar to those of developed nations, the reasons for which are not completely understood. In this study we investigated the effect that ancestral background has on breast cancer susceptibility among Uruguayan women. METHODS: We carried out a case-control study of 328 (164 cases, 164 controls) women enrolled in public hospitals and private clinics across the country. We estimated ancestral proportions using a panel of nuclear and mitochondrial ancestry informative markers (AIMs) and tested their association with breast cancer risk. RESULTS: Nuclear individual ancestry in cases was (mean ± SD) 9.8 ± 7.6% African, 13.2 ± 10.2% Native American and 77.1 ± 13.1% European, and in controls 9.1 ± 7.5% African, 14.7 ± 11.2% Native American and 76.2 ± 14.2% European. There was no evidence of a difference in nuclear or mitochondrial ancestry between cases and controls. However, European mitochondrial haplogroup H was associated with breast cancer (OR = 2.0; 95% CI 1.1, 3.5). CONCLUSIONS: We have not found evidence that overall genetic ancestry differs between breast cancer patients and controls in Uruguay but we detected an association of the disease with a European mitochondrial lineage, which warrants further investigation.

Translational machinery and protein folding: evidence of conformational variants of the estrogen receptor alpha.

As an approach to understand how translation may affect protein folding, we analyzed structural and functional properties of the human estrogen receptor alpha synthesized by different eukaryotic translation systems. A minimum of three conformations of the receptor were detected using limited proteolysis and a sterol ligand-binding assay. The receptor in vitro translated in rabbit reticulocyte lysate was rapidly degraded by protease, produced major bands of about 34kDa and showed a high affinity for estradiol. In a wheat germ translation system, the receptor was more slowly digested. Two soluble co-existing conformations were evident by different degradation patterns and estradiol binding. Our data show that differences in the translation machinery may result in alternative conformations of the receptor with distinct sterol binding properties. These studies suggest that components of the cellular translation machinery itself might influence the protein folding pathways and the relative abundance of different receptor conformers.

Expression of urea transporter (UT-A) mRNA in papilla and pelvic epithelium of kidney in normal and low protein fed sheep.

The identification and cloning of the urea transporter (UT) in papilla and upper pelvic epithelium of sheep kidney and the effect of a 5-week-lasting low protein diet on UT mRNAs expression in these structures are reported. Using degenerate primers we cloned by RT-PCR a 770-base pairs UT-A cDNA fragment. The deduced amino acid sequence shared 92% and 93% identity with UT-A2 protein from rabbit and rat, and from human, respectively. Quantification of UT-A mRNAs expression after LP diet was performed by quantitative RT-PCR using UT-A mutant cRNA. Compared to normal protein fed sheep, low protein diet was associated with a significant reduction of UT-A mRNA levels in pelvic epithelium (852+/-172 vs. 2024+/-260 molecules, P<0.01) and a tendency to its increase in papilla (7959+/-1741 vs. 5447+/-1040 molecules, NS). Functional studies confirmed that kidneys of low protein fed sheep increased their ability to reduce urea losses. The reduction of UT-A expression in the pelvic epithelium lining the outer medulla could be relevant for the renal conservation of urea in protein restricted sheep.