Abstract Background: Driver mutations are the genetic components responsible for tumor initiation and progression. These variants, which may be inherited, influence cancer risk and therefore underlie many familial cancers. The present study examines the potential association between SNPs in driver genes SF3B1 (rs4685), TBX3 (rs12366395, rs8853, and rs1061651) and MAP3K1 (rs72758040) and BC in BRCA1/2-negative Chilean families. Methods: The SNPs were genotyped in 486 BC cases and 1258 controls by TaqMan Assay. Results: Our data do not support an association between rs4685:C > T, rs8853:T > C, or rs1061651:T > C and BC risk. However, the rs12366395-G allele (A/G + G/G) was associated with risk in families with a strong history of BC (OR = 1.2 [95% CI 1.0–1.6] p = 0.02 and OR = 1.5 [95% CI 1.0–2.2] p = 0.02, respectively). Moreover, rs72758040-C was associated with increased risk in cases with a moderate-to-strong family history of BC (OR = 1.3 [95% CI 1.0–1.7] p = 0.02 and OR = 1.3 [95% CI 1.0–1.8] p = 0.03 respectively). Finally, risk was significantly higher in homozygous C/C cases from families with a moderate-to-strong BC history (OR = 1.8 [95% CI 1.0–3.1] p = 0.03 and OR = 1.9 [95% CI 1.1–3.4] p = 0.01, respectively). We also evaluated the combined impact of rs12366395-G and rs72758040-C. Familial BC risk increased in a dose-dependent manner with risk allele count, reflecting an additive effect (p-trend = 0.0002). Conclusions: Our study suggests that germline variants in driver genes TBX3 (rs12366395) and MAP3K1 (rs72758040) may influence BC risk in BRCA1/2-negative Chilean families. Moreover, the presence of rs12366395-G and rs72758040-C could increase BC risk in a Chilean population.

Abstract Breast cancer (BC), a heterogeneous, aggressive illness with high mortality, is essentially a genomic disease. While the high-penetrance genes BRCA1 and BRCA2 play important roles in tumorigenesis, moderate- and low-penetrance genes are also involved. Single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes have recently been identified as BC risk factors. miRNA genes are currently classified as low-penetrance. SNPs are the most common variations in the human genome. While the role of miRNA SNPs in BC susceptibility has been studied extensively, results have been inconsistent. This review analyzes the results of association studies between miRNA SNPs and BC risk from countries around the world. We conclude that: (a) By continent, the largest proportion of studies to date were conducted in Asia (65.0 %) and the smallest proportion in Africa (1.8 %); (b) Association studies have been completed for 67 different SNPs; (c) 146a, 196a2, 499, 27a, and 423 are the most-studied miRNAs; (d) The SNPs rs2910164 (miRNA-146a), rs11614913 (miRNA-196a2), rs3746444 (miRNA-499) and rs6505162 (miRNA-423) were the most widely associated with increased BC risk; (e) The majority of studies had small samples, which may affect the precision and power of the results; and (f) The effect of an SNP on BC risk depends on the ethnicity of the population. This review also discusses potential explanations for controversial findings.

Abstract Background: Helicobacter pylori is detected by pathogen recognition receptors including toll–like receptors (TLR) and nucleotide–binding oligomerization domain (NOD)–like receptors, eliciting an innate immune response against this bacteria. The aim of this study was to assess if polymorphisms of TLR2, TLR4, TLR5, NOD1 and NOD2 genes are associated with gastric cancer, in particular in individuals infected with H. pylori. Results: A case–control study of 297 gastric cancer patients and 300 controls was performed to assess the association of 17 polymorphisms. Analyses performed under the allele model did not find association with gastric cancer. However, NOD1 rs2075820 (p.E266K) showed association with intestinal–type gastric cancer among H. pylori infected subjects (OR = 2.69, 95% CI 1.41–5.13, p = 0.0026). The association was not statistically significant in diffuse–type gastric cancer cases (OR = 1.26, 95% CI 0.63–2.52, p = 0.51). When the analyses were performed in patients carrying H. pylori strains harboring the cag pathogenicity island (cagPAI), we noticed significant association with NOD1 rs2075820 (OR = 4.90, 95% CI 1.80–3.36, p = 0.0019), in particular for intestinal–type gastric cancer cases (OR = 7.16, 95% CI 2.40–21.33, p = 4.1 × 10−4) but not among diffuse–type gastric cancer cases (OR = 3.39, 95% CI 1.13–0.10, p = 0.03). Conclusions: NOD1 rs2075820 increases the risk of intestinal–type gastric cancer among individuals infected with H. pylori, particularly in those harboring the cagPAI.

Abstract Amelogenesis imperfecta (AI) is a group of enamel development disorders that alter the structure and chemical composition of the tissue. There is great variability in the clinical presentation; according to Witkop, AI can be categorized into 14 subtypes, which makes its diagnosis extremely complex. Objective: This study aimed to describe and determine the frequency of clinical and radiographic features and inheritance patterns found in 41 Chilean families diagnosed with diverse types of AI. Material and Methods: We analyzed the clinical records, photographs, pedigrees and radiographs of 121 individuals recruited between 2003 and 2016. All of the information was included in a database that was analyzed using the application Stata 14. Results: The 72 affected individuals had average age of 16 years, and no sex association with the presence of AI was found. The most frequent clinical subtypes were as follows: 43% hypomature, 25% hypoplastic, 21% hypomature/hypoplastic, 7% hypocalcified and 4% hypocalcified/hypoplastic. The number of severely affected teeth was 22, which occurred in the patients with hypocalcified and hypocalcified/hypoplasic AI who presented the highest number of damaged teeth. Caries and periodontal disease were found in 47 and 32% of the patients, respectively. Malocclusions were observed in 43% of the individuals with AI, with open bite being the most frequent. Radiographically, the thickness of the enamel decreased in 51% of the patients, and 80% showed decreased radiopacity of the enamel compared to that of dentin. Autosomal dominant inheritance pattern was found in 37% of the families with hypoplastic AI, and autosomal recessive pattern was present in 56% of the other clinical subtypes, but more frequently in those affected with hypomature and hypocalcified AI. Conclusion: Of the five clinical subtypes, autosomal recessive hypomature, autosomal dominant hypoplastic and autosomal recessive hypomature/hypoplastic AI were the most prevalent subtypes in this group.

Abstract Breast cancer (BC) is the most common malignancy among women worldwide. A major advance in the understanding of the genetic etiology of BC was the discovery of BRCA1 and BRCA2 (BRCA1/2) genes, which are considered high-penetrance BC genes. In non-carriers of BRCA1/2 mutations, disease susceptibility may be explained of a small number of mutations in BRCA1/2 and a much higher proportion of mutations in ethnicity-specific moderate- and/or low-penetrance genes. In Central and South American populations, studied have focused on analyzing the distribution and prevalence of BRCA1/2 mutations and other susceptibility genes that are scarce in Latin America as compared to North America, Europe, Australia, and Israel. Thus, the aim of this review is to present the current state of knowledge regarding pathogenic BRCA variants and other BC susceptibility genes. We conducted a comprehensive review of 47 studies from 12 countries in Central and South America published between 2002 and 2017 reporting the prevalence and/or spectrum of mutations and pathogenic variants in BRCA1/2 and other BC susceptibility genes. The studies on BRCA1/2 mutations screened a total of 5956 individuals, and studies on susceptibility genes analyzed a combined sample size of 11,578 individuals. To date, a total of 190 different BRCA1/2 pathogenic mutations in Central and South American populations have been reported in the literature. Pathogenic mutations or variants that increase BC risk have been reported in the following genes or genomic regions: ATM, BARD1, CHECK2, FGFR2, GSTM1, MAP3K1, MTHFR, PALB2, RAD51, TOX3, TP53, XRCC1, and 2q35.

With the aim of contributing information to help clarify the association between oral health, periodontal disease and ischemic cardiomyopathy, a comparative study was performed on hospitalized patients with and without acute coronary syndrome (ACS), evaluating atherogenic risk factors (ARF), level of oral hygiene and dental and periodontal health status. The study included patients in the coronary unit with ACS and patients in regular floor bed without evidence of cardiovascular pathology at Hospital Español, Buenos Aires , Argentina. The following ARFs were analyzed for all patients: hypertension, cholesterol, diabetes, obesity and smoking. The clinical dental examination included recording dental charts and variables related to oral hygiene, epidemiological indices and diagnosis of periodontal disease. The data collected were used to compare the ACS Group to the Control Group regarding prevalence of the ARFs and clinical dental variables studied. A total of 146 patients were studied: 81 male and 65 female, with average age 69.8±10.14 years. Prevalence of hypercholesterolemia was found to be significantly higher in patients in the ACS group than in the control group (p=0.043). The other ARFs considered did not differ. The levels of oral hygiene were similar in both study groups. The prevalence of decayed and filled teeth was similar in both groups, although there was a significantly higher number of missing teeth in the ACS group (p< 0.001). Patients with ACS had more severe periodontal disease and higher levels of gingival inflammation than the control group (p<0.001). Conclusion: Oral health of patients with ACS was worse than oral health of patients without cardiovascular disease. The difference was shown by greater severity of periodontal disease in patients with ACS even though the level of oral hygiene was similar in both groups.

Con el objetivo de aportar información que permita esclarecer la relación entre la salud bucal, la enfermedad periodontal y la cardiopatía isquémica, se efectuó un estudio comparativo en pacientes internados con y sin síndrome coronario agudo (SCA) evaluando factores de riesgo aterogénicos (FRA), nivel de higiene bucal, estado de salud dental y periodontal. Se incorporaron al estudio pacientes internados en unidad coronaria con SCA y pacientes internados en sala general sin evidencia de patología cardiovascular del Hospital Español, Buenos Aires, Argentina. En todos los pacientes se consignaron los FRA: hipertensión arterial, colesterol, diabetes, obesidad y tabaquismo. En el examen clínico odontológico se registró: odontograma, variables relacionadas con la higiene bucal, se confeccionaron índices epidemiológicos y se realizó el diagnóstico del cuadro periodontal. Con los datos recolectados, se realizó un examen comparativo entre los dos grupos de estudio (Grupo con SCA vs Grupo Control) respecto a la prevalencia de los FRA y las variables clínicas odontológicas estudiadas. Se estudiaron 146 pacientes, 81 hombres - 65 mujeres, con promedio de edad de 69.8±10.14 años. Se observó que la prevalencia de hipercolesterolemia fue significativamente mayor en los pacientes del grupo SCA respecto a los controles (p=0.043). Los restantes FRA considerados no mostraron diferencias. Los niveles de higiene bucal fueron semejantes entre ambos grupos de estudio. El grupo SCA tuvo similar prevalencia de caries y restauraciones respecto al grupo Control, sin embargo, perdieron significativamente más piezas dentarias (p<0.001). Los enfermos con SCA tuvieron cuadros periodontales más severos y niveles de inflamación gingival superiores en comparación con el grupo control (p<0.001). Conclusión: El estado de salud bucal de los pacientes con SCA fue peor respecto de aquellos pacientes que no presentaban enfermedad cardiovascular. La diferencia se objetivó en una mayor severidad de la enfermedad periodontal en pacientes con SCA a pesar de observarse niveles de higiene similares entre ambos grupos.

Background- Studies investigating effects of periodontal treatment (PT) on markers of inflammation in healthy subjects show conflicting results. Few studies have investigated the effects ofPT among subjects with coronary heart disease (CHD) risk factors. Aim: To report the results of a pilot prospective study on the effects of periodontal treatment on markers of inflammation among subjects with CHD risk factors. Material and methods: Seventy three patients aged 53±6 years (25% males) with chronic periodontitis, dyslipidemia and other CHD risk factors were subjected to PT consisting on root planning and oral metronidazol and amoxicillin for 7 days. Periodontal clinical parameters, serum C-reactive protein (CRP), fibrinogen levels and erythrocyte sedimentation rate (ESR) were assessed before and at 6 weeks añerPT. Polymorphisms at the ILlA-889 andIL1B+3954genes were also genotyped. Results: After the treatment period, CRP levels significantly increased from 3.6±3.7 mg/ L to 5.4±5.7 mg/L (p =0.001). No significant changes were observed in fibrinogen levels and ESR. Higher post-treatment CRP levels were significantly associated with the composite polymorphic genotype at the ILlA-889 and IL1B+3954 genes (p =0.0001), and extensive periodontitis (p =0.005). Moderate alcohol consumption appeared as a protective factor for CRP elevation (p =0.029). Conclusions: The increase of the CRP levels after PT in patients with CVD risk factors appeared associated with IL-1 gene polymorphisms and extensive periodontitis.

Nonsyndromic cleft lip/palate (NSCLP) is a congenital malformation with features of a complex genetic trait. Several studies have reported positive association and linkage between NSCLP and microsatellite markers in the 4q28-4q33 region particularly with the D4S192 (4q31) marker. We hypothesized that the candidate genes SMAD1 and HHIP (4q31) could be involved in the etiology of NSCLP based on previous positive linkage results and their important role in maxillofacial development. We evaluated the possible association between microsatellite markers located at less than 1 cM from these genes and NSCLP using a sample of 58 Chilean case-parent trios. Microsatellite markers were analyzed using the polymerase chain reaction (PCR) with fluorescent labeled primers. Electrophoresis of the PCR products was performed on a laser-fluorescent automatic DNA sequencer. The extended transmission disequilibrium test (ETDT) was used to analyze allelic transmissions from the parents to their affected progeny. No significant association due to linkage disequilibrium was detected between both markers and NSCLP.

BRCA1 gene mutations account for nearly all families with multiple cases of both early onset breast and/or ovarian cancer and about 30% of hereditary breast cancer. Although to date more than 1,237 distinct mutations, polymorphisms, and variants have been described, several mutations have been found to be recurrent in this gene. We have analyzed 63 Chilean breast/ovarian cancer families for eighteen frequent BRCA1 mutations. The analysis of the five exons and two introns in which these mutations are located was made using mismatch PCR assay, ASO hybridization assay, restriction fragment analysis, allele specific PCR assay and direct sequentiation techniques. Two BRCA1 mutations (185delAG and C61G) and one variant of unknown significance (E1250K) were found in four of these families. Also, a new mutation (4185delCAAG) and one previously described polymorphism (E1038G) were found in two other families. The 185delAG was found in a 3.17 % of the families and the others were present only in one of the families of this cohort. Therefore these mutations are not prominent in the Chilean population. The variant of unknown significance and the polymorphism detected could represent a founder effect of Spanish origin

Breast cancer is the most common malignancy among women. Chilean studies reveal that this cancer presents the third highest mortality rate. A family history of breast cancer is one of the major risk factors for the development of this disease. BRCA1 and BRCA2 are the two main hereditary breast cancer susceptibility genes, and mutations in these genes are related to inherited breast cancer. In specific populations only some mutations have been found to be associated with susceptibility. The purpose of this study was to establish the frequency of 5382insC (BRCA1) and 6174delT (BRCA2) germline mutations in 382 healthy Chilean women with at least two relatives affected with breast cancer and in probands and their relatives from 8 high risk families for breast cancer, using mismatch PCR assay. The results obtained showed that 5382insC and 6174delT mutations were not found in either of the groups studied. The ethnic origin of the contemporary Chilean population and the data reported in the literature suggest that these mutations may be absent or have a very low frequency in this population.. This genetic study is part of a breast cancer screening program that also includes annual mammography and clinical breast examination over a five-year period. Strategies to reduce morbidity and mortality associated with breast cancer lie in early detection in women with genetic risk.

A população urbana Chilena contemporânea deriva da mistura de ameríndios nativos com espanhóis, apresentando uma incidência média de fissura labial não sindrômica associada ou não a fissura palatina (NSCLP) de 1,8 por 1000 nascimentos vivos. A análise de segregação complexa usando o programa de computador POINTER foi feita em 249 pedigrees estendidos, distribuídos em 202 famílias simplex e 47 famílias multiplex obtidas de probands de NSCLP afetados (157 homens e 92 mulheres). Esses pedigrees deram origem a 326 indivíduos afetados e mais de 1454 parentes. Oito modelos hipotéticos foram examinados e comparados pelo teste <FONT FACE="Symbol">c</font> 2 log2 razão de máxima verossimilhança. Os modelos que postulam que NSCLP não era transmitida nestas famílias foram rejeitados, assim como os modelos que postulam apenas um componente multifatorial (P < 0,0001). O modelo que postula não haver componente poligênico para a transmissão não pôde ser rejeitado mas o modelo de não transmissão do efeito mais importante foi rejeitado (P < 0,0001). Entre os modelos do locus mais importante apenas o modelo recessivo de transmissão foi rejeitado, enquanto que as heranças codominante e dominante sem um componente multifatorial não puderam ser excluídas. O modelo não restrito sugere que a freqüência do alelo de suscetibilidade a NSCLP no locus mais importante é 0,0037 e sua penetrância é de 92%.