Evaluation of genetic alterations in hereditary cancer susceptibility genes in the Ashkenazi Jewish women community of Mexico.

Background: Individuals of Ashkenazi Jewish ancestry have been identified as having higher prevalence of specific pathogenic variants associated with susceptibility to specific rare and chronic diseases. In Mexico, the prevalence and composition of rare cancer predisposing germline variants in Ashkenazi Jewish individuals has not been evaluated. Aim and methods: We aimed to evaluate the prevalence of pathogenic variants by massive parallel sequencing in a panel of 143 cancer-predisposing genes in 341 women from the Ashkenazi Jewish community of Mexico, who were contacted and invited to participate in the study through the ALMA Foundation for Cancer Reconstruction. Pre- and posttest genetic counseling was given and a questionnaire on personal, gyneco-obstetric, demographic and lifestyle variables was conducted. From peripheral blood DNA, the complete coding region, and splicing sites of a panel of 143 cancer susceptibility genes, including 21 clinically relevant genes, were sequenced. The Mexican founder mutation BRCA1 ex9-12del [NC_000017.10(NM_007294):c. (825+1-826-1)_(4,589+1-4,590-1)del] was also evaluated. Results: Among study participants (mean age ±standard deviation: 47 ± 14) 15% reported a personal history of cancer (50/341). Fourteen percent of participants (48/341) were carriers of pathogenic and likely pathogenic variants distributed among seven high-risk genes (APC, CHEK2, MSH2, BMPR1A, MEN1, MLH1, and MSH6), whereas 18.2% (62/341) had variants of uncertain clinical significance in genes associated with breast and ovarian cancer susceptibility (list of genes with VUS). Pathogenic and likely pathogenic variants in 16 susceptibility genes with ambiguous or non-well-established risk association for cancer were detected in 17.6% (60/341) of participants. Sixty four percent of participants reported current alcohol consumption compared with the 39 percent prevalence of alcohol consumption in Mexican women. None of the participants carried the recurrent Ashkenazi and Mexican founder mutations in BRCA1 or BRCA2, but 2% (7/341) had pathogenic Ashkenazi Jewish founder variants in BLM. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of Ashkenazi Jewish ancestry in Mexico consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary breast cancer in this group and implement appropriate preventative programs.

Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach.

Purpose: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is responsible for ~5-10% of all diagnosed breast and ovarian cancers. Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women in Latin America (LA). The main objective of this study was to develop a comprehensive understanding of the genomic epidemiology of HBOC throughout the establishment of The Latin American consortium for HBOC-LACAM, consisting of specialists from 5 countries in LA and the description of the genomic results from the first phase of the study. Methods: We have recruited 403 individuals that fulfilled the criteria for HBOC from 11 health institutions of Argentina, Colombia, Guatemala, Mexico and Peru. A pilot cohort of 222 individuals was analyzed by NGS gene panels. One hundred forty-three genes were selected on the basis of their putative role in susceptibility to different hereditary cancers. Libraries were sequenced in MiSeq (Illumina, Inc.) and PGM (Ion Torrent-Thermo Fisher Scientific) platforms. Results: The overall prevalence of pathogenic variants was 17% (38/222); the distribution spanned 14 genes and varied by country. The highest relative prevalence of pathogenic variants was found in patients from Argentina (25%, 14/57), followed by Mexico (18%, 12/68), Guatemala (16%, 3/19), and Colombia (13%, 10/78). Pathogenic variants were found in BRCA1 (20%) and BRCA2 (29%) genes. Pathogenic variants were found in other 12 genes, including high and moderate risk genes such as MSH2, MSH6, MUTYH, and PALB2. Additional pathogenic variants were found in HBOC unrelated genes such as DCLRE1C, WRN, PDE11A, and PDGFB. Conclusion: In this first phase of the project, we recruited 403 individuals and evaluated the germline genetic alterations in an initial cohort of 222 patients among 4 countries. Our data show for the first time in LA the distribution of pathogenic variants in a broad set of cancer susceptibility genes in HBOC. Even though we used extended gene panels, there was still a high proportion of patients without any detectable pathogenic variant, which emphasizes the larger, unexplored genetic nature of the disease in these populations.

Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility.

Hereditary breast and ovarian cancer syndrome (HBOC) represents 5⁻10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.

El simulador ®Harvey¼ de paciente cardiológico: la utilización de simuladores, computadoras y equipo multimedia en el aprendizaje de la cardiología / Cardiologic Harvey simulator: utilizing simulators, computers and multimedia equipment in the learning of cardiology

A través de un maniquí y un programa multimedia es posible adquirir conocimientos y destrezas necesarios para la evaluación y tratamiento de múltiples situaciones clínicas en el área de cardiología. Desde 1968, en la Escuela de Medicina de la Universidad de Miami, se viene utilizando un simulador de paciente cardiológico conocido como Harvey con una gran aceptación por parte de paramédicos, estudiantes de medicina, residentes, adscritos y enfermeras. El maniquí está programado para simular 27 situaciones cardiológicas que representan el mínimo necesario que debe de conocer y manejar un estudiante de medicina en el cuarto año, durante su periodo de aprendizaje en la materia clínica de cardiología.

La prueba de aliento como método diagnóstico no invasico en la infección por Helicobacter pylori / Urea breath test as a non-invasive diagnostic method in Helicobacter pylori infection

Existen varios métodos para la detección de la infección por Helicobacter pylori, algunos de ellos (invasivos) requieren de un procedimiento endoscópico y biopsia como la prueba rápida de ureasa, el cultivo y la histología. Recientemente se han desarrollado y aprobado métodos no invasivos, sensibles, específicos, fáciles de realizar y bien aceptados por los pacientes como la prueba de aliento, basada en la hidrólisis de la urea marcada por la ureasa del Helicobacter pylori formando amonio y bicarbonato. El CO2 marcado pasa, a través de la circulación, a los pulmones y es espirado en el aliento de donde puede ser recolectado. La urea puede ser marcada en su átomo de carbono existiendo dos opciones: 13C estable, no radioactivo y 14 C inestable y radioactivo. La prueba de aliento con 13C se basa en la diferencia de masa atómica entre el 12C y 13C y requiere para su cuantificación de un espectómetro de masas y aproximadamente 40 minutos para su realización. La prueba de aliento con 14C contiene 1 uCi (un micro-curie) de radioactividad que corresponde a 1/300 de la radiación recibida en un año del medio ambiente; su realización toma 10 minutos y la lectura se realiza en un contador de centello. Ambas pruebas, no invasivas, han demostrado sensibilidad y especificidad comparables con los ®estándares de oro¼ establecido para el diagnóstico de infección por Helicobacter pylori