PTCH1 gene variants rs357564, rs2236405, rs2297086 and rs41313327, mRNA and tissue expression in basal cell carcinoma patients from Western Mexico.

BACKGROUND: Basal cell carcinoma (BCC) represents about 80% of all cases of skin cancer. The PTCH1 is a transmembrane protein of the Sonic Hedgehog signaling pathway that regulates cell proliferation. Genetic variants in PTCH1 gene have been previously described in association with BCC development. In addition, PTCH1 mRNA and protein expression analysis are also significant to understand its role in skin cancer physiopathology. METHODS: An analytical cross-sectional study was performed, and a total of 250 BCC patients and 290 subjects from the control group (CG) were included, all born in western Mexico. The genotypes and relative expression of the mRNA were determined by TaqMan® assay. The protein expression was investigated in 70 BCC paraffin-embedded samples with PTCH1 antibodies. Semi-quantitative analysis was performed to determine the expression level in the immunostained cells. RESULTS: We did not find evidence of an association between PTCH1 rs357564, rs2297086, rs2236405, and rs41313327 genetic variants and susceptibility to BCC. Likewise, no statistically significant differences were found in the comparison of the mRNA level expression between BCC and CG (p > 0.05). The PTCH1 protein showed a low expression in 6 of the analyzed samples and moderate expression in 1 sample. No association was found between genetic variants, protein expression, and demographic-clinical characteristics (p > 0.05). CONCLUSION: The studied PTCH1 variants may not be associated with BCC development in the Western Mexico population. The PTCH1 mRNA levels were lower in patients with BCC compared to the control group, but its protein was underexpressed in the tissue samples.

RAAS: A Convergent Player in Ischemic Heart Failure and Cancer.

The current global prevalence of heart failure is estimated at 64.34 million cases, and it is expected to increase in the coming years, especially in countries with a medium-low sociodemographic index where the prevalence of risk factors is increasing alarmingly. Heart failure is associated with many comorbidities and among them, cancer has stood out as a contributor of death in these patients. This connection points out new challenges both in the context of the pathophysiological mechanisms involved, as well as in the quality of life of affected individuals. A hallmark of heart failure is chronic activation of the renin-angiotensin-aldosterone system, especially marked by a systemic increase in levels of angiotensin-II, a peptide with pleiotropic activities. Drugs that target the renin-angiotensin-aldosterone system have shown promising results both in the prevention of secondary cardiovascular events in myocardial infarction and heart failure, including a lower risk of certain cancers in these patients, as well as in current cancer therapies; therefore, understanding the mechanisms involved in this complex relationship will provide tools for a better diagnosis and treatment and to improve the prognosis and quality of life of people suffering from these two deadly diseases.

PTCH1 Gene Variants, mRNA Expression, and Bioinformatics Insights in Mexican Cutaneous Squamous Cell Carcinoma Patients.

BACKGROUND: Skin cancer is one of the most frequent types of cancer, and cutaneous squamous cell carcinoma (cSCC) constitutes 20% of non-melanoma skin cancer (NMSC) cases. PTCH1, a tumor suppressor gene involved in the Sonic hedgehog signaling pathway, plays a crucial role in neoplastic processes. METHODS: An analytical cross-sectional study, encompassing 211 cSCC patients and 290 individuals in a control group (CG), was performed. A subgroup of samples was considered for the relative expression analysis, and the results were obtained using quantitative real-time PCR (qPCR) with TaqMan® probes. The functional, splicing, and disease-causing effects of the proposed variants were explored via bioinformatics. RESULTS: cSCC was predominant in men, especially in sun-exposed areas such as the head and neck. No statistically significant differences were found regarding the rs357564, rs2236405, rs2297086, and rs41313327 variants of PTCH1, or in the risk of cSCC, nor in the mRNA expression between the cSCC group and CG. A functional effect of rs357564 and a disease-causing relation to rs41313327 was identified. CONCLUSION: The proposed variants were not associated with cSCC risk in this Mexican population, but we recognize the need for analyzing larger population groups to elucidate the disease-causing role of rare variants.

Non-Melanoma Skin Cancer: A Genetic Update and Future Perspectives.

Skin cancer is one of the main types of cancer worldwide, and non-melanoma skin cancer (NMSC) is the most frequent within this group. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common types. Multifactorial features are well-known for cancer development, and new hallmarks are gaining relevance. Genetics and epigenetic regulation play an essential role in cancer susceptibility and progression, as well as the variety of cells and molecules that interact in the tumor microenvironment. In this review, we provide an update on the genetic features of NMSC, candidate genes, and new therapies, considering diverse perspectives of skin carcinogenesis. The global health situation and the pandemic have been challenging for health care systems, especially in the diagnosis and treatment of patients with cancer. We provide innovative approaches to overcome the difficulties in the current clinical dynamics.

[Population data of five STRs from the INTERPOL series in a mestizo population of western Mexico (State of Jalisco)]. / Datos poblacionales de cinco STRs de la serie INTERPOL en una población mestiza del Occidente de México.

INTRODUCTION: Short tandem repeats (STRs) are the DNA polymorphisms most widely used in forensic genetics and parentage testing. Most common series of STRs are those from FBI (CODIS) and from INTERPOL. While there are data related to the first group, no studies are still known in Mexican populations in regard of the INTERPOL set. OBJECTIVE: To describe the genetic characteristics of five INTERPOL STRs and to estimate their main forensic parameters in a population from western Mexico. MATERIAL AND METHODS: Samples from 100 random volunteers from the State of Jalisco were PCR typed for STRs F13B, D2S1338, FESFPS, Penta D and Penta E. RESULTS: Genotype proportions in all five STRs were in agreement with Hardy-Weinberg expectations (p > 0.05). Heterocygosity varied from 0.68 for FESFPS to 0.91 for Penta E markers. Power of discrimination (PD) and exclusion probability (EP) were in the 0.83-0.97 and 0.46-0.75 ranges, respectively. The five combined STRs give a PE > 0.99143 and PD > 0.99999. CONCLUSIONS: These results contribute to establish data bases representative of western Mexico and are useful in DNA forensic and parentage studies.

Decreased serum levels of sCD40L and IL-31 correlate in treated patients with Relapsing-Remitting Multiple Sclerosis.

The CD40/CD40L system is a binding key for co-stimulation of immune cells. Soluble form of CD40L has been widely studied as marker of inflammatory and autoimmune diseases. Here we analyze serum concentrations of sCD40L, as well as 14 cytokines, in patients with Multiple Sclerosis (MS) treated with Glatiramer acetate or Interferon beta. In the healthy control group, we found in serum a highly positive correlation between sCD40L and Interleukin (IL)-31, an anti-inflammatory Th2 cytokine. Additionally, an important reduction in IL-31 and sCD40L serum levels, as well as a significant reduction in CD40 mRNA expression and complete depletion of CD40L mRNA, detected from peripheral blood cells, was found in treated patients with MS. Therefore, sCD40L and IL-31 must be taken into account as possible prognostic markers when analyzing the disease progress of MS in order to provide more personalized treatment.

[Assessment of five thrombophilic genetic polymorphisms among couples with habitual abortion]. / Evaluación de cinco polimorfismos de genes trombofílicos en parejas con aborto habitual.

An association between thrombophilic genes and obstetric conditions with early pregnancy termination has been previously proposed. In the present study we attempted to evaluate the possible association between thrombophilic genetic polymorphisms and habitual abortion (HA). Samples from two groups of volunteers were analyzed. The experimental group (n>100) was conformed by women attending the Centro Medico de Occidente, IMSS and their male couples, with a reproductive history ofat least three miscarriages. The reference group (n > 200) was composed by male and female healthy adults living in the state of Jalisco, Mexico. DNA was extracted from peripheral blood, and polymorphisms FII G20210A , FVG1691A, MTHFR C677T, ECA IID y TNF G-308A were typed by PCR-RFLP or -SSP. Genotype proportions in the reference group were in agreement with the HardyWeinberg expectations. Allele, genotype, and phenotype proportion inter-group comparisons did not show statistically significant differences. The present results could not demonstrate that thrombophilic polymorphisms constitute risk factors for HA in Jalisco.

Ambiguous genitalia by 9p deletion inherent to a dic(Y;9)(q12;p24).

We describe here a 3-month-old male infant with brachy-plagyocephaly, short neck, widely spaced nipples, mild hypertonia, and ambiguous external genitalia but with both testes in the scrotum and no Müllerian derivates. His karyotype was 45,X,der(Y;9)(q12;p24).ish der(Y;9)(DYZ3+,SRY+,9ptel-) de novo. This patient's impaired sex differentiation is consistent with gonadal dysgenesis and compares with the male-to-female sex reversal secondary to a partial 9p deletion in spite of an intact Yp or SRY locus documented in 24 patients including a sex-reversed girl with a (Y;9) dicentric derivative. As for the cytogenetic findings, this case represents the second instance of a de novo pseudodicentric (Y;9) chromosome with loss of both distal 9p and Yq12 regions, apparent intactness of SRY, and consistent or preferential inactivation of the Y centromere. In addition, the possible 9p23p-p22 duplication observed in this case evokes the concomitant 9p22-p21 duplication documented in the previous girl with a (Y;9) derivative. Hence, these striking similarities point to a nonrandom Y;9 rearrangement in patients with either sex reversal or gonadal dysgenesis. Even if the present pseudodicentric derivative had inactivated the Y centromere, the existence of some variant cells points to functional dicentricity as it has been documented in other Y;autosome dicentric derivatives.

Macrophage migration inhibitory factor (MIF) promoter polymorphisms (-794 CATT5-8 and -173 G>C): association with MIF and TNFα in psoriatic arthritis.

Psoriatic arthritis (PsA) is an autoimmune disease with a complex interaction of gene and with a dysregulation of pro-inflammatory cytokine such as Macrophage migration Inhibitory Factor (MIF) and Tumor Necrosis Factor-alpha (TNFα). Two polymorphisms identified in the promoter region of the MIF gene have been described: the STR-794 CATT5-8 (rs5844572) and the SNP-173 G>C (rs755622), which are associated with increased MIF levels in circulation and with autoimmune diseases in several populations. In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with PsA susceptibility and clinical variables as well as with MIF and TNFα serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 and -173 G>C MIF polymorphisms was performed by PCR and PCR-RFLP respectively in 50 PsA patients and 100 healthy subjects (HS). MIF and TNFα serum levels were determined by ELISA. A significant increase of MIF (PsA: 7.8 vs. HS: 5.25 ng/mL; p < 0.001) and TNFα (PsA: 24.6 vs. HS: 9.9 pg/mL; p < 0.001) levels was found in PsA patients, a significant correlation was observed between MIF and TNFα (r = 0.41; p < 0.01). The 5,6 repeats genotype of the -794 CATT5-8 MIF was associated with protection to PsA (OR = 0.29; CI 0.77-0.98; p = 0.03), and the G/C genotype (OR = 7.5; CI 2.92-21.64; p < 0.001) and the -173*C allele (OR = 2.45; CI 1.43-4.20; p < 0.001) of the -173 G>C MIF were associated with susceptibility to PsA. In conclusion the -173*C allele is associated with susceptibility to PsA in Mexican-Mestizo population, whereas the correlation between MIF and TNFα soluble levels provided evidence that both cytokines are closely related in the pathophysiology of the PsA.

Role of toll-interacting protein gene polymorphisms in leprosy Mexican patients.

BACKGROUND: Leprosy is a debilitating infectious disease of human skin and nerves. Genetics factors of the host play an important role in the disease susceptibility. Toll-interacting protein (TOLLIP) is an inhibitory adaptor protein within the toll-like receptor (TLR) pathway, which recognizes structurally conserved molecular patterns of microbial pathogens, initiating immune responses. The objective of this study was to investigate the association of variants in the TOLLIP gene with susceptibility to leprosy in Mexican patients. METHODS: TOLLIP polymorphisms were studied using a case-control design of Mexican patients with lepromatous leprosy (LL). The polymorphisms of TOLLIP at loci -526 C>G (rs5743854), 1309956C>T (rs3750920), 1298430C>A (rs5744015), and 1292831 G>A (rs3750919) were analyzed by PCR, with sequence-specific primers in LL patients and healthy subjects (HS) as controls. RESULTS: Genotype distributions were in Hardy Weinberg equilibrium for all sites except for rs3750920. Neither genotype nor allele frequencies were statistically different between LL patients and controls (P > 0.05). The maximum pairwise D' coefficient reached was 0.44 of linkage (P = 0.01) for all the polymorphisms except for rs5743854. The three loci haplotype comparison yielded no significant differences between groups. CONCLUSIONS: Just the individuals with genotype C/C of rs3750920 have a trend of protective effect to developing LL.

The +49A>G CTLA-4 polymorphism is associated with rheumatoid arthritis in Mexican population.

BACKGROUND: The Cytotoxic T lymphocyte antigen (CTLA-4) is one of the major susceptibility genes associated with autoimmune diseases. Susceptibility to rheumatoid arthritis (RA) is determined by both environmental and genetic factors. The genetic contribution approaches 50-60%. The association between RA with the +49A>G CTLA-4 polymorphism in the Mexican population was investigated. METHODS: The polymerase chain reaction-restriction fragment was used to amplify the +49A>G CTLA-4 polymorphism in RA patients and healthy subjects (HS). RESULTS: We analyzed the association between the +49A>G CTLA-4 polymorphism and RA. The G allele frequency was higher in RA patients than HS (46.8 vs 37.7%, OR=1.45, p=0.01). RA patients carrying the A/G genotype were significantly more likely to be positive to CRP and RF. There was no evidence of an association between SNP genotypes and the clinical characteristics of rheumatoid arthritis. CONCLUSIONS: The +49A>G CTLA-4 polymorphism is a genetic marker of susceptibility for RA in western Mexican population.

Evaluación de cinco polimorfismos de genes trombofílicos en parejas con aborto habitual / Assessment of five thrombophilic genetic polymorphisms among couples with habitual abortion

Se han propuesto factores genéticos trombofílicos asociados con anormalidades obstétricas que implican la terminación temprana del embarazo. El propósito del estudio fue investigar la posible asociación de polimorfismos génicos trombofílicos con el aborto habitual (AH). Se analizaron muestras de dos grupos de personas que participaron voluntariamente en el estudio. El primero (n>100) consistió en mujeres atendidas en el Centro Médico de Occidente del Instituto Mexicano del Seguro Social y a sus parejas, por el antecedente reproductivo de por lo menos tres abortos idiopáticos (n>100). El grupo de referencia (n>200) lo formaron adultos sanos de ambos sexos residentes de Jalisco. El ADN se extrajo de una muestra de sangre periférica y se tipificaron, mediante PCR–RFLP o –SSP, los polimorfismos FII G20210A, FV G1691A, MTHFR C677T, ECA I/D y TNF G–308A. Las proporciones genotípicas en el grupo de referencia fueron similares a las predichas por la ley de Hardy–Weinberg y las comparaciones intergrupales alélicas, genotípicas y fenotípicas no mostraron diferencias significativas para ninguno de los polimorfismos estudiados. Estos resultados sugieren que los polimorfismos de los genes trombofílicos no representan un factor de riesgo para AH en nuestro medio.

An association between thrombophilic genes and obstetric conditions with early pregnancy termination has been previously proposed. In the present study we attempted to evaluate the possible association between thrombophilic genetic polymorphisms and habitual abortion (HA). Samples from two groups of volunteers were analyzed. The experimental group (n>100) was conformed by women attending the Centro Medico de Occidente, IMSS and their male couples, with a reproductive history ofat least three miscarriages. The reference group (n > 200) was composed by male and female healthy adults living in the state of Jalisco, Mexico. DNA was extracted from peripheral blood, and polymorphisms FII G20210A , FVG1691A, MTHFR C677T, ECA IID y TNF G-308A were typed by PCR-RFLP or -SSP. Genotype proportions in the reference group were in agreement with the HardyWeinberg expectations. Allele, genotype, and phenotype proportion inter-group comparisons did not show statistically significant differences. The present results could not demonstrate that thrombophilic polymorphisms constitute risk factors for HA in Jalisco.