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Oral squamous cell carcinoma (OSCC) has a poor prognosis and the treatment employed generates significant physical deformity in patients. In recent years, an increase in the incidence of cases of OSCC has been observed in adult patients up to 45 years old in several genetic underrepresented and underserved countries. The increase in OSCC cases in young people is very relevant because it shows that OSCC does not make exceptions and hereditarily must play an important role. This fact has not been associated with an evident biological basis, and a large majority of these patients do not present the classic principal risk factors association. OSCC is the result of accumulation of genetic and epigenetic alterations and this information is still fragmented in the literature, mainly in the young group. Conducting studies with a comprehensive analysis of genetic and epigenetic data is crucial, to provide greater understanding of the underlying biology of OSCC, because this information can be decisive to determine targets for therapeutic treatment. We review the main germline and somatic aspects of genetic and genomic variation in OSCC considering the absence of genomic data from developing countries such as Chile and the rest of Hispano-America.
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Fission yeast ribosomal protein genes (RPGs) contain a HomolD box as a core promoter element required for transcription. Some of the RPGs also contain a consensus sequence named HomolE, located upstream of the HomolD box. The HomolE box acts as an upstream activating sequence (UAS), and it is able to activate transcription in RPG promoters containing a HomolD box. In this work, we identified a HomolE-binding protein (HEBP) as a polypeptide of 100 kDa, which was able to bind to the HomolE box in a Southwestern blot assay. The features of this polypeptide were similar to the product of the fhl1 gene of fission yeast. The Fhl1 protein is the homolog of the FHL1 protein of budding yeast and possesses fork-head-associated (FHA) and fork-head (FH) domains. The product of the fhl1 gene was expressed and purified from bacteria, and it was demonstrated that is able to bind the HomolE box in an electrophoretic mobility assay (EMSA), as well as being able to activate in vitro transcription from an RPG gene promoter containing HomolE boxes upstream of the HomolD box. These results indicate that the product of the fhl1 gene of fission yeast can bind to the HomolE box, and it activates the transcription of RPGs.
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Schizosaccharomyces , Proteínas Portadoras/metabolismo , Regiones Promotoras Genéticas , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Transcripción GenéticaRESUMEN
Breast cancer (BC) is the most common cancer among women worldwide. BRCA1/2 are responsible for 16-20% of the risk for hereditary BC. Other susceptibility genes have been identified; Fanconi Anemia Complementation Group M (FANCM) being one of these. Two variants in FANCM, rs144567652 and rs147021911, are associated with BC risk. These variants have been described in Finland, Italy, France, Spain, Germany, Australia, the United States, Sweden, Finnish, and the Netherlands, but not in the South American populations. Our study evaluated the association of the SNPs rs144567652 and rs147021911 with BC risk in non-carriers of BRCA1/2 mutations from a South American population. The SNPs were genotyped in 492 BRCA1/2-negative BC cases and 673 controls. Our data do not support an association between FANCM rs147021911 and rs144567652 SNPs and BC risk. Nevertheless, two BC cases, one with a family history of BC and the other with sporadic early-onset BC, were C/T heterozygotes for rs144567652. In conclusion, this is the first study related contribution of FANCM mutations and BC risk in a South American population. Nevertheless, more studies are necessary to evaluate if rs144567652 could be responsible for familial BC in BRCA1/2-negatives and for early-onset non-familial BC in Chilean BC cases.
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Neoplasias de la Mama , ADN Helicasas , Predisposición Genética a la Enfermedad , Femenino , Humanos , Neoplasias de la Mama/genética , Chile/epidemiología , ADN Helicasas/genética , Mutación , Edad de InicioRESUMEN
Cancer is a genomic disease, with driver mutations contributing to tumorigenesis. These potentially heritable variants influence risk and underlie familial breast cancer (BC). This study evaluated associations between BC risk and 13 SNPs in driver genes MAP3K1, SF3B1, SMAD4, ARID2, ATR, KMT2C, MAP3K13, NCOR1, and TBX3, in BRCA1/2-negative Chilean families. SNPs were genotyped using TaqMan Assay in 492 cases and 1285 controls. There were no associations between rs75704921:C>T (ARID2); rs2229032:A>C (ATR); rs3735156:C>G (KMT2C); rs2276738:G>C, rs2293906:C>T, rs4075943T:>A, rs13091808:C>T (MAP3K13); rs178831:G>A (NCOR1); or rs3759173:C>A (TBX3) and risk. The MAP3K1 rs832583 A allele (C/A+A/A) showed a protective effect in families with moderate BC history (OR = 0.7 [95% CI 0.5-0.9] p = 0.01). SF3B1 rs16865677-T (G/T+T/T) increased risk in sporadic early-onset BC (OR = 1.4 [95% CI 1.0-2.0] p = 0.01). SMAD4 rs3819122-C (A/C+C/C) increased risk in cases with moderate family history (OR = 2.0 [95% CI 1.3-2.9] p ≤ 0.0001) and sporadic cases diagnosed ≤50 years (OR = 1.6 [95% CI 1.1-2.2] p = 0.006). SMAD4 rs12456284:A>G increased BC risk in G-allele carriers (A/G + G/G) in cases with ≥2 BC/OC cases and early-onset cases (OR = 1.2 [95% CI 1.0-1.6] p = 0.04 and OR = 1.4 [95% CI 1.0-1.9] p = 0.03, respectively). Our study suggests that specific germline variants in driver genes MAP3K1, SF3B1, and SMAD4 contribute to BC risk in Chilean population.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Proteína BRCA1/genética , Chile/epidemiología , Predisposición Genética a la Enfermedad , Proteína BRCA2/genética , Mutación de Línea Germinal , Células Germinativas , Polimorfismo de Nucleótido SimpleRESUMEN
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.
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Neoplasias de la Mama , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Chile/epidemiología , Femenino , Predisposición Genética a la Enfermedad/genética , Genómica , HumanosRESUMEN
The interaction between malignant cells and the tumor microenvironment is critical for tumor progression, and the chemokine ligand/receptor axes play a crucial role in this process. The CXCR4/CXCL12 and CCR5/CCL5 axes, both related to HIV, have been associated with the early (epithelial-mesenchymal transition and invasion) and late events (migration and metastasis) of cancer progression. In addition, these axes can also modulate the immune response against tumors. Thus, antagonists against the receptors of these axes have been proposed in cancer therapy. Although preclinical studies have shown promising results, clinical trials are needed to include these drugs in the oncological treatment protocols. New alternatives for these antagonists, such as dual CXCR4/CCR5 antagonists or combined therapy in association with immunotherapy, need to be studied in cancer therapy.
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Antagonistas de los Receptores CCR5 , Carcinoma , Receptores CXCR4 , Humanos , Carcinoma/tratamiento farmacológico , Quimiocina CXCL12 , Receptores CCR5 , Receptores CXCR4/antagonistas & inhibidores , Transducción de Señal , Microambiente Tumoral , Antagonistas de los Receptores CCR5/uso terapéuticoRESUMEN
Recently, the combination of chemotherapy plus nivolumab (chemo-immunotherapy) has become the standard of care for advanced-stage gastric cancer (GC) patients. However, despite its efficacy, up to 40% of patients do not respond to these treatments. Our study sought to identify variations in gene expression associated with primary resistance to chemo-immunotherapy. Diagnostic endoscopic biopsies were retrospectively obtained from advanced GC patients previously categorized as responders (R) or non-responders (NR). Thirty-four tumor biopsies (R: n = 16, NR: n = 18) were analyzed by 3' massive analysis of cDNA ends (3'MACE). We found >30 differentially expressed genes between R and NRs. Subsequent pathway enrichment analyses demonstrated that angiogenesis and the Wnt-ß-catenin signaling pathway were enriched in NRs. Concomitantly, we performed next generation sequencing (NGS) analyses in a subset of four NR patients that confirmed alterations in genes that belonged to the Wnt/ß-catenin and the phosphoinositide 3-kinase (PI3K) pathways. We speculate that angiogenesis, the Wnt, and the PI3K pathways might offer actionable targets. We also discuss therapeutic alternatives for chemo-immunotherapy-resistant advanced-stage GC patients.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , beta Catenina/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Estudios Retrospectivos , Vía de Señalización Wnt/genética , Inmunoterapia , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
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.
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Neoplasias de la Mama , MicroARNs , Femenino , Humanos , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , MicroARNs/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
MicroRNA-423 (miR-423) is highly expressed in breast cancer (BC). Previously, our group showed that the SNP rs6505162:C>A located in the pre-miR-423 was significantly associated with increased familial BC risk in patients with a strong family history of BC. Therefore, in this study, we evaluated the functional role of rs6505162 in mammary tumorigenesis in vitro to corroborate the association of this SNP with BC risk. We found that rs6505162:C>A upregulated expression of both mature miR-423 sequences (3p and 5p). Moreover, pre-miR-423-A enhanced proliferation, and promoted cisplatin resistance in BC cell lines. We also showed that pre-miR-423-A expression decreased cisplatin-induced apoptosis, and increased BC cell migration and invasion. We propose that the rs6505162-A allele promotes miR-423 overexpression, and that the rs6505162-A allele induces BC cell proliferation, viability, chemoresistance, migration, and invasion, and decreases cell apoptosis as a consequence. We suggest that rs6505162:C>A is a functional SNP site with potential utility as a marker for early diagnosis, prognosis, and treatment efficacy monitoring in BRCA1/2-negative BC patients, as well as a possible therapeutic target.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Movimiento Celular/genética , Resistencia a Antineoplásicos/genética , Variación Genética , MicroARNs/metabolismo , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , MicroARNs/genética , Invasividad Neoplásica , Polimorfismo de Nucleótido Simple/genética , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry. METHODS: To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni's multiple adjustment tests determined statistical differences between allele frequencies. RESULTS: Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031-0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations. CONCLUSIONS: This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.
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Aging is a complex biological process accompanied by a progressive decline in the physical function of the organism and an increased risk of age-related chronic diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. Studies have established that there exist nine hallmarks of the aging process, including (i) telomere shortening, (ii) genomic instability, (iii) epigenetic modifications, (iv) mitochondrial dysfunction, (v) loss of proteostasis, (vi) dysregulated nutrient sensing, (vii) stem cell exhaustion, (viii) cellular senescence, and (ix) altered cellular communication. All these alterations have been linked to sustained systemic inflammation, and these mechanisms contribute to the aging process in timing not clearly determined yet. Nevertheless, mitochondrial dysfunction is one of the most important mechanisms contributing to the aging process. Mitochondria is the primary endogenous source of reactive oxygen species (ROS). During the aging process, there is a decline in ATP production and elevated ROS production together with a decline in the antioxidant defense. Elevated ROS levels can cause oxidative stress and severe damage to the cell, organelle membranes, DNA, lipids, and proteins. This damage contributes to the aging phenotype. In this review, we summarize recent advances in the mechanisms of aging with an emphasis on mitochondrial dysfunction and ROS production.
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This study aimed to analyze the molecular characteristics of oral epithelial dysplasia (OED), highlighting the pathways and variants of genes that are frequently mutated in oral squamous cell carcinoma (OSCC) and other cancers. Ten archival OED cases were retrieved for retrospective clinicopathological analysis and exome sequencing. Comparative genomic analysis was performed between high-grade dysplasia (HGD) and low-grade dysplasia (LGD), focusing on 57 well-known cancer genes, of which 10 were previously described as the most mutated in OSCC. HGD cases had significantly more variants; however, a similar mutational landscape to OSCC was observed in both groups. CASP8+FAT1/HRAS, TP53, and miscellaneous molecular signatures were also present. FAT1 is the gene that is most affected by pathogenic variants. Hierarchical divisive clustering showed division between the two groups: "HGD-like cluster" with 4HGD and 2LGD and "LGD-like cluster" with 4 LGD. MLL4 pathogenic variants were exclusively in the "LGD-like cluster". TP53 was affected in one case of HGD; however, its pathway was usually altered. We describe new insights into the genetic basis of epithelial malignant transformation by genomic analysis, highlighting those associated with FAT1 and TP53. Some LGDs presented a similar mutational landscape to HGD after cluster analysis. Perhaps molecular alterations have not yet been reflected in histomorphology. The relative risk of malignant transformation in this molecular subgroup should be addressed in future studies.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/genética , Estudios Retrospectivos , Neoplasias de la Boca/genética , Mapeo Cromosómico , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Chagas disease is caused by the protozoan Trypanosoma cruzi and is endemic to Central and South America. However, it has spread around the world and affects several million people. Treatment with currently available drugs cause several side effects and require long treatment times to eliminate the parasite, however, this does not improve the chronic effects of the disease such as cardiomyopathy. A therapeutic vaccine for Chagas disease may be able to prevent the disease and improve the chronic effects such as cardiomyopathy. This vaccine would be beneficial for both infected people and those which are at risk in endemic and non-endemic areas. In this article, we will review the surface antigens of T. cruzi, in order to choose those that are most antigenic and least variable, to design effective vaccines against the etiological agent of Chagas disease. Also, we discuss aspects of the design of nucleic acid-based vaccines, which have been developed and proven to be effective against the SARS-CoV-2 virus. The role of co-adjuvants and delivery carriers is also discussed. We present an example of a chimeric trivalent vaccine, based on experimental work, which can be used to design a vaccine against Chagas disease.
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Transcriptional coactivators play a key role in RNA polymerase II transcription and gene regulation. One of the most important transcriptional coactivators is the Mediator (MED) complex, which is an evolutionary conserved large multiprotein complex. MED transduces the signal between DNA-bound transcriptional activators (gene-specific transcription factors) to the RNA polymerase II transcription machinery to activate transcription. It is known that MED plays an essential role in ER-mediated gene expression mainly through the MED1 subunit, since estrogen receptor (ER) can interact with MED1 by specific protein-protein interactions; therefore, MED1 plays a fundamental role in ER-positive breast cancer (BC) etiology. Additionally, other MED subunits also play a role in BC etiology. On the other hand, microRNAs (miRNAs) are a family of small non-coding RNAs, which can regulate gene expression at the post-transcriptional level by binding in a sequence-specific fashion at the 3' UTR of the messenger RNA. The miRNAs are also important factors that influence oncogenic signaling in BC by acting as both tumor suppressors and oncogenes. Moreover, miRNAs are involved in endocrine therapy resistance of BC, specifically to tamoxifen, a drug that is used to target ER signaling. In metazoans, very little is known about the transcriptional regulation of miRNA by the MED complex and less about the transcriptional regulation of miRNAs involved in BC initiation and progression. Recently, it has been shown that MED1 is able to regulate the transcription of the ER-dependent miR-191/425 cluster promoting BC cell proliferation and migration. In this review, we will discuss the role of MED1 transcriptional coactivator in the etiology of BC and in endocrine therapy-resistance of BC and also the contribution of other MED subunits to BC development, progression and metastasis. Lastly, we identified miRNAs that potentially can regulate the expression of MED subunits.
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Neoplasias de la Mama , MicroARNs , Neoplasias de la Mama/patología , Femenino , Humanos , Complejo Mediador/genética , MicroARNs/genética , ARN Polimerasa II/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Trypanosomatids are a group of primitive unicellular eukaryotes that can cause diseases in plants, insects, animals, and humans. Kinetoplast genome integrity is key to trypanosomatid cell survival and viability. Kinetoplast DNA (kDNA) is usually under attack by reactive oxygen and nitric species (ROS and RNS), damaging the DNA, and the cells must remove and repair those oxidatively generated lesions in order to survive and proliferate. Base excision repair (BER) is a well-conserved pathway for DNA repair after base damage, single-base loss, and single-strand breaks, which can arise from ROS, RSN, environmental genotoxic agents, and UV irradiation. A powerful BER system has been described in the T. cruzi kinetoplast and it is mainly carried out by DNA polymerase ß (pol ß) and DNA polymerase ß-PAK (pol ß-PAK), which are kinetoplast-located in T. cruzi as well as in other trypanosomatids. Both pol ß and pol ß-PAK belong to the X-family of DNA polymerases (pol X family), perform BER in trypanosomatids, and display intrinsic 5-deoxyribose phosphate (dRP) lyase and DNA polymerase activities. However, only Pol ß-PAK is able to carry out trans-lesion synthesis (TLS) across 8oxoG lesions. T. cruzi cells overexpressing pol ß are more resistant to ROS and are also more efficient to repair 8oxoG compared to control cells. Pol ß seems to play a role in kDNA replication, since it associates with kinetoplast antipodal sites in those development stages in trypanosomatids which are competent for cell replication. ROS treatment of cells induces the overexpression of pol ß, indicating that plays a role in kDNA repair. In this review, we will summarize the main features of trypanosomatid minicircle kDNA replication and the biochemical characteristics of pol ß-like enzymes and their involvement in BER and kDNA replication. We also summarize key structural features of trypanosomatid pol ß compared to their mammalian (human) counterpart.
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ADN Polimerasa beta , Animales , ADN , Daño del ADN , ADN Polimerasa beta/genética , ADN Polimerasa beta/metabolismo , Reparación del ADN , Replicación del ADN , HumanosRESUMEN
Multi-subunit enzymes are protein biopolymers that are involved in many cellular processes. The enzyme that carries out the process of transcription of mRNAs is RNA polymerase II (RNAPII), which is a multi-subunit enzyme in eukaryotes. This protein biopolymer starts the transcription from specific sites and is positioned by transcription factors, which form a preinitiation complex (PIC) on gene promoters. To recognize and position the RNAPII and the transcription factors on the gene promoters are needed specific DNA sequences in the gene promoters, which are named promoter elements. Those gene promoter elements can vary and therefore several kinds of promoters exist, however, it appears that all promoters can use a similar pathway for PIC formation. Those pathways are discussed in this review. The in vitro transcribed mRNA can be used as vaccines to fight infectious diseases, e.g., in immunotherapy against cancer and in nanotechnology to deliver mRNA for a missing protein into the cell. We have outlined a procedure to produce an mRNA vaccine against the SARS-CoV-2 virus, which is the causing agent of the big pandemic, COVID-19, affecting human beings all over the world. The potential advantages of using eukaryotic RNAPII to synthetize large transcripts are outlined and discussed. In addition, we suggest a method to cap the mRNA at the 5' terminus by using enzymes, which might be more effective than cap analogs. Finally, we suggest the construction of a future multi-talented RNAPII, which would be able to synthetize large mRNA and cap them in the test tube.
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Abstract This study aimed to analyze the molecular characteristics of oral epithelial dysplasia (OED), highlighting the pathways and variants of genes that are frequently mutated in oral squamous cell carcinoma (OSCC) and other cancers. Ten archival OED cases were retrieved for retrospective clinicopathological analysis and exome sequencing. Comparative genomic analysis was performed between high-grade dysplasia (HGD) and low-grade dysplasia (LGD), focusing on 57 well-known cancer genes, of which 10 were previously described as the most mutated in OSCC. HGD cases had significantly more variants; however, a similar mutational landscape to OSCC was observed in both groups. CASP8+FAT1/HRAS, TP53, and miscellaneous molecular signatures were also present. FAT1 is the gene that is most affected by pathogenic variants. Hierarchical divisive clustering showed division between the two groups: "HGD-like cluster" with 4HGD and 2LGD and "LGD-like cluster" with 4 LGD. MLL4 pathogenic variants were exclusively in the "LGD-like cluster". TP53 was affected in one case of HGD; however, its pathway was usually altered. We describe new insights into the genetic basis of epithelial malignant transformation by genomic analysis, highlighting those associated with FAT1 and TP53. Some LGDs presented a similar mutational landscape to HGD after cluster analysis. Perhaps molecular alterations have not yet been reflected in histomorphology. The relative risk of malignant transformation in this molecular subgroup should be addressed in future studies.
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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.
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Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Chile/epidemiología , Predisposición Genética a la Enfermedad/genética , GenómicaRESUMEN
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.