Medium and large alleles of the PGC gene are risk factors for gastric cancer.

BACKGROUND: A 100-bp insertion/deletion polymorphism in the pepsinogen C gene has been associated with the risk of gastric cancer (GC). OBJECTIVE: We analyzed the relationships of the 100-bp insertion/deletion polymorphism with GC, atrophic gastritis (AG), and intestinal metaplasia (IM) in the Mexican general population (MGP). METHODS: We studied the genomic DNA of subjects with GC n = 80, AG and IM n = 60, controls n = 110, and the MGP n = 97. PGC gene insertion/deletion polymorphism was identified by means of PCR, capillary electrophoresis and GeneScan software. RESULTS: Different allele sizes of PGC polymorphism were observed in the studied groups, from 266 bp to 499 bp, which were grouped for the analysis as short alleles of 266-399 bp, medium alleles of 400-433 bp and large alleles of 434-499 bp. Carriers of one or two medium alleles, had an increased risk of GC, with OR of 1.99 (CI95% 1.08-3.67 p = 0.026) compared to homozygotes (no medium/no medium). CONCLUSIONS: Previous studies have related PGC short alleles to risk for or protection against GC depending on the ethnic origin of the population. In our study, medium alleles were related to risk for GC. Further studies are required to establish the importance of this polymorphism in the origin of gastric neoplasia.

Role of the BMP6 protein in breast cancer and other types of cancer.

The BMP6 protein (Bone Morphogenetic Protein 6) is part of the superfamily of transforming growth factor-beta (TGF-ß) ligands, participates in iron homeostasis, inhibits invasion by increasing adhesions and cell-cell type interactions and induces angiogenesis directly on vascular endothelial cells. BMP6 is coded by a tumor suppressor gene whose subexpression is related to the development and cancer progression; during neoplastic processes, methylation is the main mechanism by which gene silencing occurs. This work presents a review on the role of BMP6 protein in breast cancer (BC) and other types of cancer. The studies carried out to date suggest the participation of the BMP6 protein in the epithelial-mesenchymal transition (EMT) phenotype, cell growth and proliferation; however, these processes are affected in a variable way in the different types of cancer, the methylated CpG sites in BMP6 gene promoter, as well as the interaction with other proteins could be the cause of such variation.

Molecular and Hematological Analysis of Alpha- and Beta-Thalassemia in a Cohort of Mexican Patients.

Introduction: Alpha- and beta-thalassemia are caused by reduced or absent synthesis of hemoglobin (Hb) subunits α and/or ß. HBA2, HBA1, and HBB mutations are the main cause of thalassemias. The aim of this article is to analyze molecular and hematological features of α- and ß-thal in a cohort of Mexican patients. Methods: One hundred forty-one thalassemia patients were studied. Peripheral blood was collected for blood cell count, electrophoresis, Hb quantification, and molecular testing. Molecular screening was performed by Gap-PCR, ARMS-PCR, Sanger sequencing, and MLPA. Results: Fifty-four patients had α-thal, 75 ß-thal, and 12 patients were complex cases, we observed 13 α- and 18 ß-thal alleles in 43 genotypes, -α3.7/αα and ßCd39C>T/ß were the most frequent. Four α-thal deletions (-Mex4 included HBA2 and HBA1, whereas (αα)Mex5, Mex6 and Mex7 involved MCS-R), a hereditary persistence of fetal hemoglobin-2 like (HPFH-2 like) deletion and six alleles not previously reported in Mexicans (α-59C>Tα, -α4.2, αPlasenciaα, ß-32C>T, ßInitCdA>C and ßFSCd71/72+A) were identified. Conclusion: The observed alleles denote the high heterogeneity and multiple origin admixture of Mexican population. Hematological data are consistent with genotypes, variability in simple carriers, from asymptomatic forms to mild or moderate anemia, was ascertained. We emphasize the importance to consider hematological parameters to establish adequate molecular screening strategies.

The Relationship of Single Nucleotide Polymorphisms in the TRPV1 Gene with Lipid Profile, Glucose, and Blood Pressure in Mexican Population.

Aim: We analyzed the frequencies of the rs222749 G>A, rs222747 G>C, rs224534 G>A, and rs8065080 C > T polymorphisms in the TRPV1 gene and their relationships with biomarkers in a Mexican population. Materials and Methods: We included 195 students from two Mexican universities (72.3% female and 27.7% male, mean age, 20.8 ± 3.3 years). The biomarkers analyzed were lipid profile, glucose levels, blood pressure (BP), and body mass index. DNA was obtained from leukocytes by the dodecyltrimethylammonium bromide and cetyltrimethylammonium bromide method and polymorphisms were determined with TaqMan single nucleotide polymorphism (SNP) genotyping assays. Results: Alterations in lipid profile were total cholesterol ≥200 mg/dL in 9.7% of participants, triglycerides (TG) ≥150 mg/dL in 9.2%, high-density lipoprotein (HDL) <35 mg/dL in 6.7%, and low-density lipoprotein (LDL) ≥130 mg/dL in 6.2% of participants. Moreover, 8.2% of the subjects had BP values consistent with hypertension. The most frequent alleles were rs222749G (89.2%), rs222747G (69.2%), rs224534G (59.7%), and rs8065080T (62.3%). An analysis of the associations between the genotypic data and the biomarkers showed that the rs222749GA and rs224534GA genotypes were associated with higher diastolic and systolic BP values, respectively; the rs222747CC genotype was associated with lower LDL levels; the rs224534AA genotype was associated with higher HDL levels and lower triglycerides and LDL. The GGGC/GCAT and GGGT/GCAT haplotypes were associated with higher systolic BP. Conclusions: This study suggests a possible association between TRPV1 gene polymorphisms and BP and lipid profiles in a Mexican population.

CDH1 somatic alterations in Mexican patients with diffuse and mixed sporadic gastric cancer.

BACKGROUND: Diffuse gastric cancer (DGC) is associated with the reduction or absence of the expression of the cell adhesion protein E-cadherin (encoded by the CDH1 gene). Molecular characteristics are less well described for mixed gastric cancer (MGC). The main somatic alterations that have been described in the CDH1 gene are mutations, loss of heterozygosity (LOH) and promoter methylation. The aim was to analyze CDH1 somatic alterations in Mexican patients with diffuse and mixed gastric cancer. METHODS: We searched for mutations in the CDH1 gene in tumor DNA from DGC (n = 13) and MGC (n = 7) patients by next generation sequencing (NGS). Validation of findings was performed using Sanger sequencing. LOH was analyzed using dinucleotide repeat markers surrounding the CDH1 gene, and methylation was investigated by DNA bisulfite conversion and sequencing. E-cadherin protein deficiency was analyzed by immunohistochemistry. RESULTS: Seventeen point variants were identified by NGS, 13 of them were validated by Sanger sequencing. Only 1/13 had not been previously reported (c.-137C > A), and 12/13 were already reported as polymorphisms. Two DGC cases presented LOH at the locus 16q22.1 (13.3%). CDH1 promoter methylation was positive in (7/11) 63.6% and (4/6) 66.6% of the cases with DGC and MGC, respectively. E-cadherin protein deficiency was observed in 58.3% of DGC cases while 100% in MGC cases. CONCLUSIONS: While no pathogenic somatic mutations were found that could explain the diffuse histology of gastric cancer in DGC and MGC, methylation was the most common somatic inactivation event of the CDH1 gene, and LOH was rare. The previously unreported c.-137C > A variant modify the CDH1 gene expression since it alters the binding sites for transcription factors.

TYMS 2R3R polymorphism and DPYD [IVS]14+1G>A gene mutation in Mexican colorectal cancer patients.

OBJECTIVE: To examine the association between TYMS 2R3R polymorphism and DPYD [IVS]14+1G>A mutation by comparing healthy subjects with colorectal cancer (CRC) patients in the Mexican population. METHOD: Genotyping of the 2R/3R was performed by polymerase chain reaction (PCR) and [IVS]14+1G>A mutation by real-time PCR analysis. RESULTS: The observed frequencies of the TYMS 2R3R polymorphism and the -[IVS]14+1G>A mutation in DPYD did not indicate an increased risk for CRC (p>0.05). However we observed an association of the 2R/2R (OR 3.08, 95% CI 1.66-6.08, p=0.0017) and heterozygous (OR 1.98, 95% CI 1.32-2.97, p=0.0012) genotypes as risk factors when comparing controls and CRC patients that were also tobacco consumers. An association between the genotype and the disease was evident. The distribution of the 2R/2R genotype and hematological toxicity (adjusted OR 2.26, 95% CI 1.54-4.45, p=0.0259), heterozygous (2R/3R) with tumor stage III-IV (OR 1.81, 95% CI 1.11-2.94, p=0.020) and 2R/2R-2R/3R in non-chemotherapy response CRC patients with hematological (OR 2.3, 95% CI 1.21-4.4, p=0.014) and gastric toxicities (OR 3.11, 95% CI 1.18-8.2, p=0.035) confirmed that this factor may significantly contribute to the CRC susceptibility. CONCLUSION: TYMS 2R3R polymorphism and the -[IVS]14+1G>A mutation in DPYD was not associated with susceptibility to CRC. However, the 2R/2R and 2R/3R genotypes of TYMS polymorphism could significantly contribute to hematological and gastric toxicity in CRC patients in this sample population.

[Risk factors associated to diffuse gastric cancer and intestinal histological patterns in an adult population from Western Mexico]. / Factores de riesgo asociados a adenocarcinoma gástrico de patrones histológicos de tipo intestinal y difuso en población adulta del occidente de México.

INTRODUCTION: Gastric cancer (GC) is the third leading cause of cancer death worldwide, and is divided histologically in diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC). Multiple risk factors have been associated with GC in different populations. The objective was to analyze the risk factors associated to DGC and IGC in a population from the western region of Mexico. MATERIAL AND METHODS: The DGC (n = 27) and IGC (n = 26) cases, each matched by age and sex with a control group, were analyzed. Diet and lifestyle data were obtained by a questionnaire. Statistical analysis was performed with the software SPSSv18. The association of risk was calculated in odds ratio (OR); a value of p < 0.05 was considered significant. RESULTS: In the DGC group, the factors with significant OR values were: consumption of pork OR: 3.4 (1.11-10.4; p =0.032), smoking OR: 4.7 (1.5-15.0; p =0.007), green vegetables OR: 0.16 (0.03-0.83; p =0.029) and fruit OR: 0.28 (0.08-0.88; p =0.029). In the IGC group, the consumption of canned sardines was a significant risk factor OR: 4.07 (1.25-13.24; p =0.019). CONCLUSIONS: This work is the first to analyze the risk factors associated with GC in a population from western Mexico.

Los receptores epidérmicos humanos en el cáncer gástrico: alteraciones moleculares y su papel como diana terapéutica.

Gastric cancer (GC) is the third leading cause of cancer death worldwide; both environmental and genetic factors are involved in the etiology of this neoplasia. The human epidermal receptor (HER) pathway is essential for proliferation and differentiation of normal cells; but it is also implicated in the growth of cancer cells. In this work we investigate the molecular alterations in genes that encodes for HER receptors reported in GC, as well the role as therapeutic targets. We reviewed the literature reported to date regarding overexpression of HER-receptors, amplification and somatic mutations in ERBB genes occurred in gastric tumors, as well as the anti-HER therapies tested for treatment of GC. In GC, the overexpression of HER family is reported in a range of 12-87% of cases; up to 67% of cases with amplification, and 90 somatic mutations in ERBB genes. The only drug anti-HER approved for using combined with chemotherapy, in treatment of patients with advanced GC is trastuzumab; however, other targeted therapies are being investigated. The role of the HER family as a therapeutic target has not shown significant improvements in recent years; hence, further studies are required to find better options for treatment of GC.

Analysis of the polymorphisms EGFR-r521K and ERBB2-I655V in Mexican patients with gastric cancer and premalignant gastric lesions.

The proto-oncogenes epidermal growth factor receptor (EGFR) and erythroblastic leukemia viral oncogene homolog 2 (ERBB2), are involved in the development of diverse malignant tumors, including gastric cancer. We analyzed the association of SNPs EGFR-R521K and ERBB2-I655V with gastric cancer and premalignant gastric lesions in Mexican patients. Through restriction fragment length polymorphisms, we analyze both SNPs in the DNA from 155 patients with gastric cancer and premalignant gastric lesions, 121 controls, and 103 people from the Mexican general population. The frequencies of both SNPs did not differ significantly between any of the groups (chi2 p = NS); Odds ratio analysis showed that the alleles EGFR-521K and ERBB2-655V were not related to gastric cancer or premalignant gastric lesions in the Mexican population. Our data suggest that the EGFR-R521K and ERBB2-I655V polymorphisms are not suitable as markers for identifying individuals with a higher risk for developing gastric cancer in our population.

Types and frequencies of hemoglobin disorders in the pacific coast of four states of Mexico.

INTRODUCTION: Hemoglobin disorders are classified into three main groups: structural variants, thalassemias (thal) and hereditary persistence of fetal hemoglobin (HPFH). OBJECTIVE. This study describes the types and frequencies of hemoglobinopathies from four states of the Pacific coast of Mexico (Jalisco, Colima, Nayarit and Michoacan). MATERIAL AND METHODS. We studied 1513 Mexican individuals by hematological and biochemical analysis following the conventional methods, DNA analysis was carried out in abnormal samples. RESULTS. The frequency of hemoglobinopathies was 1.258%. Structural variants were the most common type (0.726%), with seven carriers (0.462%) and one homozygote (0.066%) for Hb S, and three heterozygotes of the following hemoglobins: C (beta6 Glu-->Lys), Fannin-Lubbock I (beta119 Gly-->Asp) and Colima (beta49 Ser-->Cys), with a frequency of 0.066% each. We observed a frequency of 0.466% for the thalassemia group, with one homozygote for the alpha3.7 (-thal) allele (0.066%), and 6 heterozygotes for beta-thal (0.40%), with the allele IVS1:110 G-->A in three subjects, and the alleles Cd 39, IVS1:5 G-->A and -28 A-->C in the three other. HPFH was detected in one subject (0.066%). Jalisco and Colima had the highest frequencies of hemoglobinopathies, 3.015% and 1.331% respectively, and the latter showed the most diversity of hemoglobin disorders. CONCLUSIONS: The observed heterogeneity of types and frequencies of hemoglobinopathies in the regions studied illustrate the importance of further investigation of these abnormalities in Mexico.

[Polymorphism analysis of G199A, Ncol in ANK1 and Memphis I in SLC4A1 genes in Mexican healthy individuals and subjects affected with hereditary spherocytosis]. / Andálisis de los polimorfismos G199A, NcoI del gen ANK1 y Memphis I del gen SLC4A1 en individuos sanos y pacientes mexicanos con esferocitosis hereditaria.

BACKGROUND: In Mexico, Hereditary Spherocytosis (HS) is the main cause of hereditary hemolytic anemia, due to mutations of one or more genes involved in the erythrocyte membrane, making it difficult to identify the primary gene. OBJECTIVE: With the purpose of estimating the use of the polymorphisms G199A and NcoI of ANK1 gene, and Memphis I of SLC4A1 gene, as genetic markers to screen this disease, we searched the allelic and genotypic frequencies in 45 DNA samples of HS patients and 28 from healthy individuals. RESULTS: Allelic and genotypic frequencies were similar in both studied groups for the G199A and Memphis I polymorphisms, with low frequency of heterozygosis showing its limited use as a genetic marker. The allelic and genotypic frequencies of the NcoI polymorphism were also similar in both groups, however a higher heterozygote frequency was observed (0.49 and 0.43 in patients and healthy individuals), a feature that may turn it into a useful genetic marker. CONCLUSIONS: Since there are other genes implicated in the molecular pathology of the HS, we consider it necessary to continue analyzing other polymorphisms of the genes involved in Hereditary Spherocytosis among the Mexican population.

Andálisis de los polimorfismos G199A, NcoI del gen ANK1 y Memphis I del gen SLC4A1 en individuos sanos y pacientes mexicanos con esferocitosis hereditaria / Polymorphism analysis of G199A, Ncol in ANK1 and Memphis I in SLC4A1 genes in Mexican healthy individuals and subjects affected with hereditary spherocytosis

Antecedentes. En México la esferocitosis hereditaria (EH) es la causa principal de anemia hemolítica hereditaria y se debe a mutaciones en uno o más genes implicados en la membrana eritrocitaria, lo que dificulta la identificación del gen primario. Objetivo. Con el fin de valorar la utilización de los polimorfismos G199A y NcoI del gen ANK1, y Memphis I del gen SLC4A1 como marcadores genéticos para identificar esta enfermedad, estimamos sus frecuencias alélicas y genotípicas en 45 muestras de ADN de pacientes con EH y 28 de individuos sanos, las cuales fueron similares en uno y otro grupos para los polimorfismos G199A y Memphis I, con baja frecuencia de heterocigotos, lo que limita su utilidad como marcador genético. Resultados. El polimorfismo NcoI no mostró diferencias alélicas y genotípicas en los grupos de estudio, pero sí mayor frecuencia de heterocigotos (0.49 y 0.43 en enfermos y sanos respectivamente), característica que le confiere ventajas para ser utilizado como marcador genético en familias con EH. Conclusiones. Finalmente, debido a que existen otros genes implicados en la patología molecular de la EH, consideramos que es necesario analizar otros polimorfismos de genes que codifican para las proteínas involucradas en las deficiencias que conducen a esferocitosis hereditaria en la población mexicana.

BACKGROUND: In Mexico, Hereditary Spherocytosis (HS) is the main cause of hereditary hemolytic anemia, due to mutations of one or more genes involved in the erythrocyte membrane, making it difficult to identify the primary gene. OBJECTIVE: With the purpose of estimating the use of the polymorphisms G199A and NcoI of ANK1 gene, and Memphis I of SLC4A1 gene, as genetic markers to screen this disease, we searched the allelic and genotypic frequencies in 45 DNA samples of HS patients and 28 from healthy individuals. RESULTS: Allelic and genotypic frequencies were similar in both studied groups for the G199A and Memphis I polymorphisms, with low frequency of heterozygosis showing its limited use as a genetic marker. The allelic and genotypic frequencies of the NcoI polymorphism were also similar in both groups, however a higher heterozygote frequency was observed (0.49 and 0.43 in patients and healthy individuals), a feature that may turn it into a useful genetic marker. CONCLUSIONS: Since there are other genes implicated in the molecular pathology of the HS, we consider it necessary to continue analyzing other polymorphisms of the genes involved in Hereditary Spherocytosis among the Mexican population.