Portadoras de mutaciones en BRCA1 y 2 en familias de alto riesgo del área de Ciudad Real (España): prevalencia mutacional y características clínico-patológicas del cáncer de mama y ovario / Carriers of BRCA1 and 2 mutations in high-risk families from Ciudad Real (Spain): mutational prevalence and clinical-pathological characteristics of breast and ovarian cancer

Objetivo: Determinar la prevalencia mutacional en BRCA1 y 2 de mujeres afectas por cáncer de mama/ovario en el área de Ciudad Real y describir las características clinicopatológicas de dichas neoplasias. Pacientes y métodos: Estudio descriptivo. Se evaluaron 111 pacientes de familias de alto riesgo y se analizaron los antecedentes oncológicos, familiares y las mutaciones halladas en BRCA1 y 2. Resultados: La prevalencia de mutaciones patogénicas en BRCA fue del 21,6% (16 en BRCA2 y 8 en BRCA1). En las portadoras de mutaciones en BRCA1 predominó el cáncer de mama: 10 casos (90,9%), tipo ductal infiltrante: 8 (72,7%), estadioII: 6 (54,5%), luminalA: 4 (36,4%), triple negativo: 4 (36,4%) y grado histológico2: 3 (27,3%) y3: 3 (27,3%). Las portadoras de mutaciones en BRCA2 desarrollaron cáncer de mama en 16 casos (80%), tipo ductal infiltrante: 11 (55%), estadioII: 11 (55%), luminalA: 10 (50%) y grado histológico2: 5 (25%). Conclusiones: En nuestro análisis, la prevalencia de mutaciones en BRCA2 fue superior a la registrada en BRCA1, en correspondencia con algunos estudios previos nacionales. Las características clinicopatológicas de los cánceres de mama/ovario en las portadoras de estas mutaciones fueron similares al perfil descrito en la literatura

Objective: To determine the mutational prevalence in BRCA1 and 2 among women with breast/ovarian cancer in Ciudad Real and to describe the clinical-pathological characteristics of these neoplasms. Patients and methods: Descriptive study. A total of 111 patients from high-risk families were evaluated and the oncological history, family history, and BRCA1 and 2 mutations found were analysed. Results: The prevalence of pathogenic mutations in BRCA was 21.6% (16 in BRCA2 and 8 in BRCA1). In BRCA1 mutations, breast cancer was predominant: 10 cases (90.9%), infiltrating ductal type: 8 (72.7%), stageII: 6 (54.5%), luminalA: 4 (36.4%), triple negative: 4 (36.4%) and histological grade2: 3 (27.3%) and3: 3 (27.3%). Among BRCA2 mutation carriers, 16 (80%) developed breast cancer: infiltrating ductal type: 11 (55%), stageII: 11 (55%), luminalA: 50% (10) and histological grade2: 5 (25%). Conclusions: In our analysis, the prevalence of mutations was higher in BRCA2 than in BRCA1, in agreement with some previous national studies. The clinical-pathological characteristics of breast/ovarian cancer in the carriers of these mutations were similar to the profile described in the literature

[Methylenetetrahydrofolate reductase polymorphisms as risk factors for myelomeningocele]. / Estudio de asociación de base familiar entre polimorfismos de MTHFR y mielomeningocele en Chile.

BACKGROUND: Mandatory fortification with folic acid (FA) was implemented in Chile in 2000. Thereafter, the rate of spina bifida decreased by 52 to 55%. Genetic abnormalities in folate metabolism may be involved in the etiology of spina bifida. AIM: To evaluate the association between myelomeningocele (MM) and c.A1298C and c.C677T polymorphisms within the coding gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) in the Chilean population. MATERIAL AND METHODS: These polymorphisms were genotyped in 105 patients showing isolated MM, born after the onset of FA fortification, and in their parents. The transmission disequilibrium test (TDT) was performed to evaluate alterations in the transmission of both alleles and haplotypes MTHFR polymorphism. We also evaluated the presence of parent-origin-effect (POE) of alleles using the Clayton's extension of the TDT. RESULTS: TDT analysis showed no significant distortions in the transmission of alleles or haplotypes. Moreover, although the POE showed increased risk for maternally derived allele, this risk was not statistically significant. CONCLUSIONS: The studied variants in the MTHFR gene (c.C677T and c.A1298C) do not constitute risk factors for MM in this sample of Chilean patients and their parents.

Estudio de asociación de base familiar entre polimorfismos de MTHFR y mielomeningocele en Chile / Methylenetetrahydrofolate reductase polymorphisms as risk factors for myelomeningocele

Background: Mandatory fortification with folic acid (FA) was implemented in Chile in 2000. Thereafter, the rate of spina bifida decreased by 52 to 55%. Genetic abnormalities in folate metabolism may be involved in the etiology of spina bifida. Aim: To evaluate the association between myelomeningocele (MM) and c.A1298C and c.C677T polymorphisms within the coding gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) in the Chilean population. Material and Methods: These polymorphisms were genotyped in 105 patients showing isolated MM, born after the onset of FA fortification, and in their parents. The transmission disequilibrium test (TDT) was performed to evaluate alterations in the transmission of both alleles and haplotypes MTHFR polymorphism. We also evaluated the presence of parent-origin-effect (POE) of alleles using the Clayton’s extension of the TDT. Results: TDT analysis showed no significant distortions in the transmission of alleles or haplotypes. Moreover, although the POE showed increased risk for maternally derived allele, this risk was not statistically significant. Conclusions: The studied variants in the MTHFR gene (c.C677T and c.A1298C) do not constitute risk factors for MM in this sample of Chilean patients and their parents.

The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins.

BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germ line mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with 11 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 [west Castilla y León (WCL)], 20 [east Castilla y León (ECL)] and 6 (South of Spain) families. Mutation age was estimated with the Disequilibrium Mapping using Likelihood Estimation software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G > A, were located in a double-hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923 bp fragment of BRCA2, and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G > A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin loop of c.2808_2811del, and one affected the same position (c.2808A > G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG, BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin loops, suggesting that these structures may represent mutational hotspots.

Family-based association study between SLC2A1, HK1, and LEPR polymorphisms with myelomeningocele in Chile.

Obese/diabetic mothers present a higher risk to develop offspring with myelomeningocele (MM), evidence supporting the role of energy homeostasis-related genes in neural tube defects. Using polymerase chain reaction-restriction fragment length polymorphism, we have genotyped SLC2A1, HK1, and LEPR single-nucleotide polymorphisms in 105 Chilean patients with MM and their parents in order to evaluate allele-phenotype associations by means of allele/haplotype transmission test (TDT) and parent-of-origin effects. We detected an undertransmission for the SLC2A1 haplotype T-A (rs710218-rs2229682; P = .040), which was not significant when only lower MM (90% of the cases) was analyzed. In addition, the leptin receptor rs1137100 G allele showed a significant increase in the risk of MM for maternal-derived alleles in the whole sample (2.43-fold; P = .038) and in lower MM (3.20-fold; P = .014). Our results support the role of genes involved in energy homeostasis in the risk of developing MM, thus sustaining the hypothesis of diverse pathways and genetic mechanisms acting in the expression of such birth defect.

Pacientes con criterios clínicos de síndrome de Lynch con y sin mutación en genes reparadores del ADN ( MLH1 y MSH2). Un reto para el clínico / Patients with clinical criteria for Lynch syndrome with and without mutations in DNA repair genes ( MLH1 and MSH2). A challenge for the clinician

Fundamento y objetivo: El objetivo del estudio es conocer las características clínico-patológicas de los pacientes diagnosticados de cáncer colorrectal (CCR) con criterios clínicos de síndrome de Lynch, en nuestro medio, con el fin de valorar y mejorar la atención de los mismos y de sus familias, a través de la Unidad de Consejo Genético de nuestro centro.Pacientes y método: Se trata de un estudio con diseño observacional, transversal y con recogida de datos retrospectiva. La muestra objeto de estudio está constituida por todos los pacientes con criterios clínicos de síndrome de Lynch a los que se les realizó análisis molecular, a través de la Unidad de Consejo Genético de Salamanca, en el período 2004-2009. Se incluyeron variables relacionadas con el paciente, con el tumor, así como la presencia o ausencia de mutación en MLH1 y MSH2. Resultados: Se estudiaron un total de 76 pacientes, 15 de los cuales presentaban mutación, bien en MLH1 bien en MSH2. La edad media al diagnóstico del cáncer colorrectal fue de 51,2 y 54,3 años en el grupo sin y con mutación, respectivamente, con una distribución por sexos similar en ambos grupos. Se ha observado una amplia heterogeneidad fenotípica en la muestra analizada.Conclusiones: El síndrome de Lynch es una entidad difícil de categorizar desde un punto de vista clínico. Por lo tanto, es importante estar alerta para un mejor manejo de estos pacientes y de sus familias (AU)

Background and objectives: The objective was to study the clinicopathologic characteristics of patients diagnosed of colorectal cancer (CRC) with clinical criteria for Lynch syndrome, in our region, in order to assess and improve the care of them and their families in the Genetic Counseling Unit of our hospital. Patients and methods: This was an observational, transversal retrospective study. The studied sample was made up of all the patients with clinical criteria for Lynch syndrome, who underwent a molecular analysis test in the Genetic Counseling Unit of Salamanca, during the period 2004-2009. We included patient and tumor related variables and the presence or absence of mutations in MLH1 and MSH2. Results: A total of 76 patients were included in the analysis. Fifteen of them carried a mutation either in MLH1 or in MSH2. The mean age at diagnosis of colorectal cancer was 51.2 and 54.3 years in the group with and without mutation respectively, with a similar gender distribution in both groups. A wide phenotypic heterogeneity was found in the sample. Conclusions: Lynch syndrome is an entity difficult to categorize from a clinical point of view. Therefore, it is important to be alert for a better management of these patients and their families (AU)

[Patients with clinical criteria for Lynch syndrome with and without mutations in DNA repair genes (MLH1 and MSH2). A challenge for the clinician]. / Pacientes con criterios clínicos de síndrome de Lynch con y sin mutación en genes reparadores del ADN (MLH1 y MSH2). Un reto para el clínico.

BACKGROUND AND OBJECTIVES: The objective was to study the clinicopathologic characteristics of patients diagnosed of colorectal cancer (CRC) with clinical criteria for Lynch syndrome, in our region, in order to assess and improve the care of them and their families in the Genetic Counseling Unit of our hospital. PATIENTS AND METHODS: This was an observational, transversal retrospective study. The studied sample was made up of all the patients with clinical criteria for Lynch syndrome, who underwent a molecular analysis test in the Genetic Counseling Unit of Salamanca, during the period 2004-2009. We included patient and tumor related variables and the presence or absence of mutations in MLH1 and MSH2. RESULTS: A total of 76 patients were included in the analysis. Fifteen of them carried a mutation either in MLH1 or in MSH2. The mean age at diagnosis of colorectal cancer was 51.2 and 54.3 years in the group with and without mutation respectively, with a similar gender distribution in both groups. A wide phenotypic heterogeneity was found in the sample. CONCLUSIONS: Lynch syndrome is an entity difficult to categorize from a clinical point of view. Therefore, it is important to be alert for a better management of these patients and their families.

Combinatorial effects of splice variants modulate function of Aiolos.

The transcription factor Aiolos (also known as IKZF3), a member of the Ikaros family of zinc-finger proteins, plays an important role in the control of B lymphocyte differentiation and proliferation. Previously, multiple isoforms of Ikaros family members arising from differential splicing have been described and we now report a number of novel isoforms of Aiolos. It has been demonstrated that full-length Ikaros family isoforms localize to heterochromatin and that they can associate with complexes containing histone deacetylase (HDAC). In this study, for the first time we directly investigate the cellular localization of various Aiolos isoforms, their ability to heterodimerize with Ikaros and associate with HDAC-containing complexes, and the effects on histone modification and binding to putative targets. Our work demonstrates that the cellular activities of Aiolos isoforms are dependent on combinations of various functional domains arising from the differential splicing of mRNA transcripts. These data support the general principle that the function of an individual protein is modulated through alternative splicing, and highlight a number of potential implications for Aiolos in normal and aberrant lymphocyte function.