Diagnosis of patients with Lynch syndrome lacking the Amsterdam II or Bethesda criteria.

BACKGROUND: Lynch Syndrome (LS) is an autosomal dominant inheritance disorder characterized by genetic predisposition to develop cancer, caused by pathogenic variants in the genes of the mismatch repair system. Cases are detected by implementing the Amsterdam II and the revised Bethesda criteria, which are based on family history. MAIN BODY: Patients who meet the criteria undergo posterior tests, such as germline DNA sequencing, to confirm the diagnosis. However, these criteria have poor sensitivity, as more than one-quarter of patients with LS do not meet the criteria. It is very likely that the lack of sensitivity of the criteria is due to the incomplete penetrance of this syndrome. The penetrance and risk of developing a particular type of cancer are highly dependent on the affected gene and probably of the variant. Patients with variants in low-penetrance genes have a lower risk of developing a cancer associated with LS, leading to families with unaffected generations and showing fewer clear patterns. This study focuses on describing genetic aspects of LS cases that underlie the lack of sensitivity of the clinical criteria used for its diagnosis. CONCLUSION: Universal screening could be an option to address the problem of underdiagnosis.

Microbiota composition and its impact on DNA methylation in colorectal cancer.

Colorectal cancer is a complex disease resulting from the interaction of genetics, epigenetics, and environmental factors. DNA methylation is frequently found in tumor suppressor genes to promote cancer development. Several factors are associated with changes in the DNA methylation pattern, and recently, the gastrointestinal microbiota could be associated with this epigenetic change. The predominant phyla in gut microbiota are Firmicutes and Bacteroidetes; however, an enrichment of Bacteroides fragilis, Fusobacterium nucleatum, and Streptococcus bovis, among others, has been reported in colorectal cancer, although the composition could be influenced by several factors, including diet, age, sex, and cancer stage. Fusobacterium nucleatum, a gram-negative anaerobic bacillus, is mainly associated with colorectal cancer patients positive for the CpG island methylator phenotype, although hypermethylation in genes such as MLH1, CDKN2A, MTSS1, RBM38, PKD1, PTPRT, and EYA4 has also been described. Moreover, Hungatella hathewayi, a gram-positive, rod-shaped bacterium, is related to hypermethylation in SOX11, THBD, SFRP2, GATA5, ESR1, EYA4, CDX2, and APC genes. The underlying epigenetic mechanism is unclear, although it could be implicated in the regulation of DNA methyltransferases, enzymes that catalyze the transfer of a methyl group on cytosine of CpG sites. Since DNA methylation is a reversible event, changes in gut microbiota could modulate the gene expression through DNA methylation and improve the colorectal cancer prognosis.

Epidemiology of environmental factors related to beta-catenin pathway and its impact on the development and progression of colorectal cancer.

Colorectal cancer (CRC) is a complex disease, determined by genetic, environmental and lifestyle-associated risk factors. Genetic (inherited) factors have great influence on its development; however, most cases of CRC are sporadic and gradually develop over several years. The main environmental risk factors are associated with b-catenin signaling pathway, including obesity, lack of physical activity, consumption of red and processed meats, alcoholism, and smoking. The pathway is related to cell homeostasis regulation and cell self-renewal during embryogenesis and adulthood. The main recommendation for preventing the development of CRC is to reduce the risk factors, increase the consumption of fruits, vegetables and grains, exercise regularly and limit the consumption of both alcohol and tobacco. However, family history and the presence of a hereditary syndrome increase the risk, which is why carrying out periodic examinations to detect CRC is suggested, using development predictors such as biochemical and molecular markers, which are discussed in this work.

El cáncer colorrectal (CCR) es una enfermedad compleja determinada por factores de riesgo genéticos, ambientales y de estilo de vida. Los factores genéticos (hereditarios) tienen gran influencia en su desarrollo, sin embargo, la mayoría de los casos de CCR son esporádicos y se desarrollan gradualmente a lo largo de varios años. Los principales factores ambientales de riesgo están asociados a la vía de señalización de ß-catenina, entre ellos obesidad, falta de actividad física, consumo de carnes rojas y procesadas, alcoholismo y tabaquismo. La vía está relacionada con la regulación de la homeostasis celular, autorrenovación celular durante la embriogénesis y edad adulta. La principal recomendación para evitar el desarrollo del CCR es reducir los factores de riesgo, aumentar el consumo de frutas, verduras y granos, hacer ejercicio de manera rutinaria y limitar el consumo tanto de alcohol como de tabaco. Dado que los antecedentes familiares y la presencia de un síndrome hereditario aumentan el riesgo, se sugiere hacer exámenes periódicos para detectar CCR y emplear predictores del desarrollo como los marcadores bioquímicos y moleculares, los cuales se presentan en este trabajo.

Epidemiología de los factores ambientales relacionados con la vía β-catenina y su impacto en el desarrollo y progresión del cáncer colorrectal / Epidemiology of environmental factors related to beta-catenin pathway and its impact on the development and progression of colorectal cancer

Resumen El cáncer colorrectal (CCR) es una enfermedad compleja determinada por factores de riesgo genéticos, ambientales y de estilo de vida. Los factores genéticos (hereditarios) tienen gran influencia en su desarrollo, sin embargo, la mayoría de los casos de CCR son esporádicos y se desarrollan gradualmente a lo largo de varios años. Los principales factores ambientales de riesgo están asociados a la vía de señalización de β-catenina, entre ellos obesidad, falta de actividad física, consumo de carnes rojas y procesadas, alcoholismo y tabaquismo. La vía está relacionada con la regulación de la homeostasis celular, autorrenovación celular durante la embriogénesis y edad adulta. La principal recomendación para evitar el desarrollo del CCR es reducir los factores de riesgo, aumentar el consumo de frutas, verduras y granos, hacer ejercicio de manera rutinaria y limitar el consumo tanto de alcohol como de tabaco. Dado que los antecedentes familiares y la presencia de un síndrome hereditario aumentan el riesgo, se sugiere hacer exámenes periódicos para detectar CCR y emplear predictores del desarrollo como los marcadores bioquímicos y moleculares, los cuales se presentan en este trabajo.

Abstract Colorectal cancer (CRC) is a complex disease, determined by genetic, environmental and lifestyle-associated risk factors. Genetic (inherited) factors have great influence on its development; however, most cases of CRC are sporadic and gradually develop over several years. The main environmental risk factors are associated with β-catenin signaling pathway, including obesity, lack of physical activity, consumption of red and processed meats, alcoholism, and smoking. The pathway is related to cell homeostasis regulation and cell self-renewal during embryogenesis and adulthood. The main recommendation for preventing the development of CRC is to reduce the risk factors, increase the consumption of fruits, vegetables and grains, exercise regularly and limit the consumption of both alcohol and tobacco. However, family history and the presence of a hereditary syndrome increase the risk, which is why carrying out periodic examinations to detect CRC is suggested, using development predictors such as biochemical and molecular markers, which are discussed in this work.

Serum nitric oxide concentration in generalized chronic and aggressive periodontitis in the Mexican population is not related to the severity of the disease / La concentración de óxido nítrico en suero de pacientes con periodontitis agresiva y crónica generalizada no está relacionada con la gravedad de la enfermedad

Introduction: Periodontitis is an inflammatory disease that affects the supporting tissues of teeth, the effects of excess of nitric oxide, may contribute to the symptoms of periodontitis. Objective: To determine the serum nitric oxide concentration in generalized chronic and aggressive periodontitis patients and to compare it with a healthy subject group from the Mexican population. Materials and methods: A case and control study was performed. Sixty-nine individuals were recruited from the Clínica de Posgrado de Periodoncia of the Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, México. Patients with clinical features of generalized chronic periodontitis (GCP group, n=19), generalized aggressive periodontitis (GAP group, n=11), and a group of healthy subjects (HS group, n=39) were included in the study. Informed consent was obtained from each subject, and serum nitric oxide concentration was measured by an enzyme-linked immunosorbent assay. Results: Nitric oxide concentration in the study groups was greater in the GCP group (462.57 ± 16.57 µmol/L) than in the GAP group (433.84 ± 18.61 µmol/L) and the HS group (422.46 ± 12.07 µmol/L). A comparison using Student's t-test (one-tailed) between healthy subjects and generalized chronic periodontitis showed borderline significance (p<0.04), whereas no significant differences were observed in HS and GAP groups, with a p-value of 0.64, and the GAP vs. GCP p-value was 0.33. Conclusion: The serum nitric oxide concentration observed in the present study suggests that nitric oxide plays a major role in the inflammatory process, which cannot necessarily be linked to the severity of the disease and periodontal tissue destruction.

Introducción. La periodontitis es una enfermedad inflamatoria que afecta los tejidos de soporte dental; los efectos del exceso de óxido nítrico pueden contribuir a los síntomas de la periodontitis. Objetivo. Determinar la concentración de óxido nítrico en el suero de los pacientes con periodontitis agresiva y crónica generalizada, y compararla con la de individuos sanos de población mexicana. Materiales y métodos. Se trata de un estudio de casos y controles. Se incluyeron 69 individuos de la Clínica de Posgrado de Periodoncia del Centro Universitario de Ciencias de la Salud de la Universidad de Guadalajara. Se dividieron en tres grupos: pacientes con periodontitis crónica generalizada (GCP, n=19), pacientes con periodontitis agresiva generalizada (GAP, n=11) e individuos sanos periodontalmente (HS, n=39). Se obtuvo el consentimiento informado de todos los participantes. Se utililizó la prueba ELISA para medir la concentración de óxido nítrico en suero. Resultados. Las concentraciones de óxido nítrico observadas fueron mayores en el grupo GCP (462,57 ± 16,57 µmol/L) que en los grupos GAP (433,84 ± 18,61 µmol/L) y HS (422,46 ± 12,07 µmol/L). La comparación entre HS y GCP mediante la prueba estadística t de Student (una cola), mostró diferencias significativas (p<0,04), y no se observaron diferencias entre los grupos HS y GAP (p=0,64), ni entre GAP y GCP (p=0,33). Conclusiones. La concentración de óxido nítrico en suero, observada en el presente estudio, sugiere que el óxido nítrico desempeña un importante papel en el proceso inflamatorio, lo que no necesariamente está ligado a la gravedad de la enfermedad ni a la destrucción del tejido periodontal.

Serum nitric oxide concentration in generalized chronic and aggressive periodontitis in the Mexican population is not related to the severity of the disease / La concentración de óxido nítrico en suero de pacientes con periodontitis agresiva y crónica generalizada no está relacionada con la gravedad de la enfermedad

Introduction: Periodontitis is an inflammatory disease that affects the supporting tissues of teeth, the effects of excess of nitric oxide, may contribute to the symptoms of periodontitis. Objective: To determine the serum nitric oxide concentration in generalized chronic and aggressive periodontitis patients and to compare it with a healthy subject group from the Mexican population. Materials and methods: A case and control study was performed. Sixty-nine individuals were recruited from the Clínica de Posgrado de Periodoncia of the Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, México. Patients with clinical features of generalized chronic periodontitis (GCP group, n=19), generalized aggressive periodontitis (GAP group, n=11), and a group of healthy subjects (HS group, n=39) were included in the study. Informed consent was obtained from each subject, and serum nitric oxide concentration was measured by an enzyme-linked immunosorbent assay. Results: Nitric oxide concentration in the study groups was greater in the GCP group (462.57 ± 16.57 µmol/L) than in the GAP group (433.84 ± 18.61 µmol/L) and the HS group (422.46 ± 12.07 µmol/L). A comparison using Student's t-test (one-tailed) between healthy subjects and generalized chronic periodontitis showed borderline significance (p<0.04), whereas no significant differences were observed in HS and GAP groups, with a p-value of 0.64, and the GAP vs. GCP p-value was 0.33. Conclusion: The serum nitric oxide concentration observed in the present study suggests that nitric oxide plays a major role in the inflammatory process, which cannot necessarily be linked to the severity of the disease and periodontal tissue destruction.

Introducción. La periodontitis es una enfermedad inflamatoria que afecta los tejidos de soporte dental; los efectos del exceso de óxido nítrico pueden contribuir a los síntomas de la periodontitis. Objetivo. Determinar la concentración de óxido nítrico en el suero de los pacientes con periodontitis agresiva y crónica generalizada, y compararla con la de individuos sanos de población mexicana. Materiales y métodos. Se trata de un estudio de casos y controles. Se incluyeron 69 individuos de la Clínica de Posgrado de Periodoncia del Centro Universitario de Ciencias de la Salud de la Universidad de Guadalajara. Se dividieron en tres grupos: pacientes con periodontitis crónica generalizada (GCP, n=19), pacientes con periodontitis agresiva generalizada (GAP, n=11) e individuos sanos periodontalmente (HS, n=39). Se obtuvo el consentimiento informado de todos los participantes. Se utililizó la prueba ELISA para medir la concentración de óxido nítrico en suero. Resultados. Las concentraciones de óxido nítrico observadas fueron mayores en el grupo GCP (462,57 ± 16,57 µmol/L) que en los grupos GAP (433,84 ± 18,61 µmol/L) y HS (422,46 ± 12,07 µmol/L). La comparación entre HS y GCP mediante la prueba estadística t de Student (una cola), mostró diferencias significativas (p<0,04), y no se observaron diferencias entre los grupos HS y GAP (p=0,64), ni entre GAP y GCP (p=0,33). Conclusiones. La concentración de óxido nítrico en suero, observada en el presente estudio, sugiere que el óxido nítrico desempeña un importante papel en el proceso inflamatorio, lo que no necesariamente está ligado a la gravedad de la enfermedad ni a la destrucción del tejido periodontal.

Molecular Profiling of Tumor Tissue in Mexican Patients with Colorectal Cancer.

Colorectal cancer is a heterogeneous disease with multiple genomic changes that influence the clinical management of patients; thus, the search for new molecular targets remains necessary. The aim of this study was to identify genetic variants in tumor tissues from Mexican patients with colorectal cancer, using massive parallel sequencing. A total of 4813 genes were analyzed in tumoral DNA from colorectal cancer patients, using the TruSight One Sequencing panel. From these, 192 variants with clinical associations were found distributed in 168 different genes, of which 46 variants had not been previous reported in the literature or databases, although genes harboring those variants had already been described in colorectal cancer. Enrichment analysis of the affected genes was performed using Reactome software; pathway over-representation showed significance for disease, signal transduction, and immune system subsets in all patients, while exclusive subsets such as DNA repair, autophagy, and RNA metabolism were also found. Those characteristics, whether individual or shared, could give tumors specific capabilities for survival, aggressiveness, or response to treatment. Our results can be useful for future investigations targeting specific characteristics of tumors in colorectal cancer patients. The identification of exclusive or common pathways in colorectal cancer patients could be important for better diagnosis and personalized cancer treatment.

Interaction of CCND2, CDKN1A, and POLD3 Variants in Mexican Patients with Colorectal Cancer.

BACKGROUND: Colorectal cancer is the second cause of death by cancer around the world. Sporadic colorectal cancer is the most frequent (75%), and it is produced by the interaction of environmental, epigenetic, and genetic factors. The accumulation of single-nucleotide variants in genes associated with cell proliferation, DNA repair, and/or apoptosis could confer a risk to cancer. The aim of this study was to analyze the gene-gene interactions among CCND2 (rs3217901), CDKN1A (rs1059234 and rs1801270), and POLD3 (rs3824999) variants in Mexican patients with colorectal cancer. METHODS: We collected peripheral blood samples from 185 patients with sporadic colorectal cancer before treatment and from 185 unrelated blood donors as the reference group; all participants signed an informed consent form. DNA extraction was performed by Miller and Cetyltrimethylammonium bromide (CTAB)/ Dodecyltrimethylammonium bromide (DTAB) methods. Polymerase chain reaction- restriction fragment length polymorphism followed by polyacrylamide gel electrophoresis stained with AgNO3 methods were used to identify the variants rs3217901, rs1059234, rs1801270, and rs3824999. Odds ratio and single-nucleotide variant interaction were determined by single-locus analysis and Multifactorial Dimensionality Reduction software, respectively. RESULTS: No association was found for CCND2 and CDKN1A variants; yet, a significant association for the GG genotype, G allele, and recessive and additive models for the POLD3 variant was observed (P < .05). The single-nucleotide variant-single-nucleotide variant interaction revealed the combination rs1059234, rs3217901, and rs3824999 as the best model and the comparison showed an increased risk (P < .05). CONCLUSION: Single-locus and gene-gene interaction analyses disclosed that both the rs3824999 (POLD3) variant and the combination of rs3217901 (CCND2), rs1059234 (CDKN1A), and rs3824999 (POLD3) genotypes increase the risk for colorectal cancer in Mexican population.

Bioinformatic Analysis of the Effect of Silver Nanoparticles on Colorectal Cancer Cell Line.

Colorectal cancer (CRC) is the most diagnosed cancer with the highest mortality rate each year globally. Although there are treatments for CRC, the development of resistance to therapies decreases the success of treatments. In vitro studies using the Caco-2 cell line have revealed the anticancer properties of silver nanoparticles (AgNPs) as a possible treatment for this disease. This study considered four researches that evaluated the proteomic profiles of cells of the Caco-2 line exposed to AgNPs. We performed a bioinformatics analysis to predict protein-protein interaction, hub genes, Gene Ontology (molecular function, biological process, and cellular components), KEGG pathways, analysis of expression, and immune cell infiltration. For these analyses, the STRING, DAVID, UALCAN, GEPIA2, and TISIDB databases were used. The results in Gene Ontology show that AgNPs cause a deregulation of genes related to cell-cell adhesion, the cytoplasm, the centriole, and carbon metabolism. Hub genes were identified, including GADPH, ENO1, EEF2, and ATP5A1, which showed differential expression in patients with adenocarcinoma of the colon and rectum. Additionally, the expression of the hub genes and immune cells was correlated. It was found that ATP5A1 and ENO1 were positively correlated with the infiltration of CD4+ T lymphocytes in colon adenocarcinoma and a negative correlation between GADPH and PDIA3 with the infiltration of NK cells and CD4+ T lymphocytes in rectal adenocarcinoma, respectively. In conclusion, the administration of AgNPs causes an alteration of biological processes, cellular components, metabolic pathways, deregulation of hub genes, and the activity of immune cells leading to a potential anticancer effect.

Anticancer Activity of Selenium Nanoparticles In Vitro Studies.

Health systems worldwide consider cancer a disease that causes the highest number of deaths per year. The low efficacy of current cancer therapies has led other areas of science to search for new alternatives, including nanomaterial sciences. Selenium nanoparticles have anticancer activity, as revealed by in vitro tests performed on prostate, breast, cervical, lung, colorectal, and liver cancer cell lines. Studies attribute anticancer activity to the anti-metastatic effect due to the inhibition of migration and invasion processes. The antiproliferative effect is the low expression of molecules such as cyclin D1, cyclin E, and CDK2. In addition to the activation of cell apoptosis by caspase-dependent mechanisms, there is a low expression of anti-apoptotic proteins such as Bcl-2 and a high expression of the apoptotic proteins like Bax and Bad. Other studies attribute anticancer activity to the activation of cell necroptosis, where molecules such as TNF and IRF1 participate. The pharmacological potential of selenium nanoparticles depends primarily on the administered dose, particle size, and chemical composition. Furthermore, several studies have shown that the administration of these nanoparticles is safe due to their low toxicity in non-cancerous cells. In this review, the most relevant antecedents on the anticancer potential of selenium nanoparticles in prostate, breast, cervical, lung, liver, and colorectal cancer cell lines are discussed.

Association between genetic variant rs2267716 of CRHR2 gene with colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and one of the main causes of death around the world. Multiple lines of evidence have suggested the role of the corticotropin-releasing hormone (CRH) family in CRC induction, including the low expression of corticotropin-releasing hormone receptor 2 (CRHR2), which is an angiogenesis inhibitor and inflammatory modulator. Previous research suggests that CRHR2 expression in colonic intestinal cells can regulate migration, proliferation and apoptosis through the modulation of several pathways. The aim of this study was to analyze the association of the rs10250835, rs2267716 and rs2267717 variants of CRHR2 gene with CRC in the Mexican population in order to consider its predictive value in CRC. This cross-sectional study included a group of 187 unrelated patients with sporadic CRC and a control group of 191 healthy blood donors. DNA extraction from peripheral blood was carried out using the Miller method. Identification of the rs10250835 variant was performed using PCR-restriction fragment length polymorphism (RFLP) and the rs2267716 and rs2267717 variants using TaqMan allelic discrimination assay. The minor allele homozygous CC of the rs2267716 variant of CRHR2 showed significant difference between CRC and control group (p=0.025), as well as the GCA haplotype (p=0.007), corresponding to the rs10250835, rs2267716 and rs2267717 variants, respectively. Our results suggest that the rs2267716 variant and GCA haplotype of CRHR2 represent a risk factor for CRC development in Mexican patients.

Matrix metalloproteinases 7, 8, 12, 13 gene haplotypes associated with colorectal cancer in a Mexican population.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in tumor invasion and progression in colorectal cancer (CRC). Variants rs11568818, rs11225395, rs2276109 and rs2252070 have been associated with this neoplasm. OBJECTIVE: To evaluate MMPs 7, 8, 12, and 13 haplotypes and their association with CRC. MATERIAL AND METHODS: One-hundred and four patients and 112 healthy individuals were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). For the association analysis, odds ratio and confidence interval values were calculated. Haplotype and linkage disequilibrium (LD) analysis was performed with Arlequin software, v3.5. RESULTS: LD was present between rs2276109 and rs2252070. Haplotypes rs11568818(A)-rs11225395(T)-rs2276109(A)-rs2252070(A) and rs11568818(A)-rs11225395(C)-rs2276109(A)-rs2252070(G) were associated with CRC risk, and haplotypes rs11568818(G)-rs11225395(C)-rs2276109(A)-rs2252070(A) and rs11568818(A)-rs11225395(T)-rs2276109(A)-rs2252070(G), with protection. CONCLUSION: Variants rs2276109 and rs2252070 showed genetic linkage. Two haplotypes were associated with the development of CRC (ATAA and ACAG) and two were associated with protection (GCAA and ATAG). This study represents the first report on variants rs11225395 and rs2276109 frequency in a Mexican population.

ANTECEDENTES: Las metaloproteinasas (MMP) se involucran en invasión y progresión tumoral en cáncer colorrectal (CCR). Las variantes rs11568818, rs11225395, rs2276109 y rs2252070 se han asociado con esta neoplasia. OBJETIVO: Evaluar haplotipos de las MMP 7, 8, 12, y 13 y su asociación con CCR. MATERIAL Y MÉTODOS: Se genotipificaron 104 pacientes y 112 individuos sanos mediante reacción en cadena de la polimerasa con análisis del polimorfismo de los fragmentos de restricción (PCR-RFLP). Para el análisis de asociación fueron calculados valores de odds ratio e intervalo de confianza. El análisis de haplotipos y desequilibrio de ligamiento (LD) se realizó con el software Arlequin v3.5. RESULTADOS: Se presentó LD entre rs2276109 y rs2252070. Los haplotipos rs11568818(A)-rs11225395(T)-rs2276109(A)-rs2252070(A) y rs11568818(A)-rs11225395(C)-rs2276109(A)-rs2252070(G) se asociaron con riesgo de CCR y los haplotipos rs11568818(G)-rs11225395(C)-rs2276109(A)-rs2252070(A) y rs11568818(A)-rs11225395(T)-rs2276109(A)-rs2252070(G) con protección. CONCLUSIÓN: Las variantes rs2276109 y rs2252070 mostraron ligamiento génico. Dos haplotipos fueron asociados con el desarrollo de CCR (ATAA y ACAG) y dos fueron asociados con protección (GCAA y ATAG). Este estudio representa el primer reporte de frecuencias de las variantes rs11225395 y rs2276109 en población mexicana.

High frequency of MLH1 promoter methylation mediated by gender and age in colorectal tumors from Mexican patients.

INTRODUCTION: Several genes determine the development of colorectal cancer (CRC), such as MLH1, which encodes a protein that participates in DNA repair. MLH1 hypermethylation has been associated with gene silencing. OBJECTIVE: To analyze the methylation of five regions of MLH1 CpG island in colorectal tumors from Mexican patients. MATERIALS AND METHODS: One hundred and one tumor tissue samples were obtained from Mexican patients with CRC who provided informed consent. DNA was subjected to bisulfite conversion. Methylation of all five regions of the CpG island was evaluated using methylation-specific PCR. RESULTS: The frequency of methylation in Mexican patients with CRC was 25%. Regions A and B methylation was the main observed pattern (60%). Female patients showed a higher frequency of methylation (71%; OR 3.085; CI: 1.85-8.03; p = 0.02), and out of total methylated samples, 80% corresponded to individuals older than 45 years (p < 0.05). CONCLUSION: We calculated a methylation frequency for the MLH1 gene of 25% in Mexican patients with CRC, with this being the first report for this population. Female patients and patients older than 45 years showed a higher frequency of methylation.

INTRODUCCIÓN: Varios genes determinan el desarrollo de cáncer colorrectal (CCR), como MLH1, el cual codifica una proteína que participa en la reparación del ADN. La hipermetilación de MLH1 ha sido asociado con silenciamiento génico. OBJETIVO: Analizar la metilación de cinco regiones de la isla CpG de MLH1 en tumores colorrectales de pacientes mexicanos. MATERIALES Y MÉTODOS: Se obtuvieron 101 muestras de tejido tumoral de pacientes mexicanos con CCR, quienes proporcionaron su consentimiento informado. El ADN fue sometido a conversión por bisulfito. La metilación de las cinco regiones de la isla CpG fue evaluada utilizando PCR específica para metilación. RESULTADOS: La frecuencia de metilación en pacientes mexicanos con CCR fue del 25%. La metilación de las regiones A y B fue el principal patrón observado (60%). Las pacientes de sexo femenino mostraron una mayor frecuencia de metilación (71%) (odds ratio: 3.085; intervalo de confianza; 1.85-8.03; p = 0.02); y del total de muestras metiladas, el 80% fueron individuos mayores de 45 años (p < 0.05). CONCLUSIÓN: Calculamos una frecuencia de metilación para el gen MLH1 del 25% en pacientes mexicanos con CCR, siendo el primer reporte para esta población. Pacientes de sexo femenino y pacientes mayores de 45 años mostraron una mayor frecuencia de metilación.

Prevalence of the BRAF p.v600e variant in patients with colorectal cancer from Mexico and its estimated frequency in Latin American and Caribbean populations.

This study aimed to investigate the frequency of the somatic BRAF p.V600E in patients with colorectal cancer (CRC) in Mexico and compare it with those estimated for Latin American and Caribbean populations. One hundred and one patients with CRC with AJCC stages ranging I-IV from Western Mexico were included, out of which 55% were male and 61% had AJCC stage III-IV, with a mean age of 60 years. PCR-Sanger sequencing was used to identify the BRAF p.V600E variant. In addition, a systematic literature search in PubMed/Medline database and Google of the 42 countries in Latin America and the Caribbean led to the collection of information on the BRAF p.V600E variant frequency of 17 population reports. To compare the BRAF variant prevalence among populations, a statistical analysis was performed using GraphPad Prism V.6.0. We found that 4% of patients with CRC were heterozygous for the p.V600E variant. The χ2 test showed no significant difference (p>0.05) in p.V600E detection when comparing with other Latin American and Caribbean CRC populations, except for Chilean patients (p=0.02). Our observational study provides the first evidence on the frequency of BRAF p.V600E in patients with CRC from Western Mexico, which is 4%, but increases to 7.8% for all of Latin America and the Caribbean. The patient mean age and genetic descent on the observed frequencies of the variant in populations could influence the frequency differences.

Somatic deletion of KDM1A/LSD1 gene is associated to advanced colorectal cancer stages.

AIMS: KDM1A/LSD1 and ZNF217 are involved in a protein complex that participates in transcriptional regulation. ZNF217 has been analysed in numerous cancers and its amplification has been associated with advanced stages of disease; however, a similar role for KDM1A/LSD1 has not been uncovered. In this study, we estimated the number of KDM1A/LSD1 and ZNF217 gene copies in tissue samples from patients diagnosed with colorectal cancer (CRC), as well as its association with clinicopathological features in patients with CRC. METHODS: Paraffin-embedded tumour samples from 50 patients with CRC with a histopathological diagnosis of CRC were included. The number of copies of KDM1A/LSD1 and ZNF217 genes was determined by fluorescence in situ hybridisation (FISH). We also analysed the association between copy numbers of selected genes and clinicopathological data based on multivariate analysis. RESULTS: Deletion of the KDM1A/LSD1 gene occurred in 19 samples (38%), whereas ZNF217 gene amplification was identified in 11 samples (22%). We found a significant association between lymph node metastasis or advanced tumour stage and KDM1A/LSD1 gene deletion (p value=0.0003 and p value=0.011, respectively). CONCLUSIONS: KDM1A/LSD1 gene deletion could be considered a novel prognostic biomarker of late-stage CRC.

Methylation analysis of MIR200 family in Mexican patients with colorectal cancer.

The present study aimed to analyze the methylation pattern of the MIR200 family in the colorectal tissues and peripheral blood of colorectal cancer (CRC) patients. Previous informed consent, 102 samples of colorectal tissues (tumor and adjacent normal tissues) and 40 peripheral blood samples were collected from CRC patients. Additionally, we included a reference group of 40 blood samples. DNA extraction was done for colorectal tissues and peripheral blood. For methylation-specific PCR, we used bisulfite-treated DNA and controls for methylated and unmethylated DNA were included to each assay. PCR fragments were separated by 6% polyacrylamide gel electrophoresis. Methylation-positive and methylation-negative results were confirmed by bisulfite genomic sequencing technique. We analyzed 102 colorectal tissues and 40 blood samples from 51 CRC patients. MIR200B/MIR200A/MIR429 methylation analysis discloses no differences among tissues (p>0.05). However, MIR200C/MIR141 methylation showed differences between colorectal tissues and peripheral blood of CRC patients (p<0.0001) and mainly methylated alleles were observed in peripheral blood. These findings suggest a tissue-specific methylation pattern for the MIR200C/MIR141 promoter.

ADIPOQ rs2241766 SNP as protective marker against DIBC development in Mexican population.

BACKGROUND: Adiponectin protein and some variations in its gene, ADIPOQ have recently been associated with cancer because they regulate glucose and lipid metabolism as well as anti-apoptotic and anti-inflammatory proteins. AIM: The aim of this study was to analyse the relationship between selected biochemical markers, anthropometric indices and ADIPOQ rs2241766 and rs1501299 SNPs in ductal infiltrating breast cancer (DIBC) in a Mexican population. METHODS: This cross-sectional study included 64 DIBC patients and 167 healthy women. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed to identify the genotypes of the rs2241766 (exon 2) and rs1501299 (intron 2) ADIPOQ polymorphisms. Corporal composition and biochemical markers included body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-hip ratio (WHR), glucose, cholesterol, triglycerides and high- and low-density lipoprotein cholesterol. RESULTS: Patients with DIBC had higher serum glucose, WC and WHR than controls. Intergroup differences in allele and genotype frequencies were found for both polymorphisms (P < 0.05). Patients carrying the rs2241766 TT and TG genotypes had higher values of WC, HC and WHR, but only TG carriers had higher levels of glucose. For the SNP rs1501299, carriers of the GG genotype in the DIBC group had higher values of glucose, WC, HC and WHR than the respective control group. CONCLUSIONS: These results suggest that WC, HC and WHR are better predictors of DIBC than BMI. The ADIPOQ SNP rs2241766 emerges as a protective factor, whereas rs1501299 is a risk factor for DIBC development in a Mexican population.

Association of the SLC6A4 gene 5HTTLPR polymorphism and ADHD with epilepsy, gestational diabetes, and parental substance abuse in Mexican mestizo children / Asociación del polimorfismo 5HTTLPR del gen SLC6A4 y TDAH con epilepsia, diabetes gestacional y adicción de los padres en niños mestizos mexicanos

Abstract Introduction Attention deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric conditions in childhood and a multifactorial condition attributable to genetic and/or environmental influence. Allelic variants in the serotonin transporter gene (SLC6A4) have been associated to lower transcriptional efficiency, changes in serotonin concentration in several brain regions, and ADHD development. Objective To identify the association between the SLC6A4 alleles and ADHD diagnosis and risk factor phenotypes in children from a Mexican mestizo population. Method In this study, 134 unrelated children were included and evaluated for ADHD, genotypification for the 5HTTLPR polymorphism, and identification of multiple phenotypes from their clinical records and family background for association analysis. Results The following distribution of genotypes was observed: 23% SS, 49% SL, and 28% LL. From the phenotypes evaluated in the present study, gestational diabetes mellitus (p = .045), history of epilepsy (p = .047), and parental substance abuse (p = .033) showed an association with ADHD development in regression analysis along with the S variant. Discussion and conclusion Results suggest that interaction of the S allele and some of the phenotypes analyzed may play a relevant role in the development of ADHD in the studied population.

Resumen Introducción El trastorno por déficit de atención e hiperactividad (TDAH) es uno de los padecimientos neuropsiquiátricos más comunes en la infancia. Como su naturaleza es multifactorial, es atribuible a influencias genéticas y/o ambientales. Las variantes alélicas del gen transportador de serotonina (SLC6A4) se han asociado previamente con cambios en los niveles de serotonina en algunas regiones cerebrales, así como con el desarrollo de TDAH. Objetivo Identificar la posible asociación entre los alelos del gen SLC6A4 y el diagnóstico de TDAH, así como factores de riesgo en niños mestizos mexicanos. Método En el presente estudio se incluyeron 134 niños, los cuales fueron evaluados para TDAH, genotipificación del polimorfismo 5HTTLPR e identificación de múltiples fenotipos en su historia clínica y antecedentes familiares para su análisis de asociación estadística. Resultados Se mostró la siguiente distribución de genotipos: 23% SS, 49% SL y 28% LL. En un modelo de regresión, los fenotipos de diabetes mellitus gestacional (p = .045), historia de epilepsia (p = .047) y el abuso de sustancias de los padres (p = .033) mostraron asociación con la variante S y el desarrollo de TDAH. Discusión y conclusión El presente estudio sugiere que el alelo S en conjunto con algunos fenotipos puede cumplir un papel importante en el desarrollo de TDAH en nuestra población.

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.

BACKGROUND: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. METHODS: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. RESULTS: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. CONCLUSION: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.