HLA haplotypes and differential regional mortality caused by COVID-19 in Brazil: an ecological study based on a large bone marrow donor bank dataset.

The coronavirus disease 2019 (COVID-19) mortality rates varied among the states of Brazil during the course of the pandemics. The human leukocyte antigen (HLA) is a critical component of the antigen presentation pathway. Individuals with different HLA genotypes may trigger different immune responses against pathogens, which could culminate in different COVID-19 responses. HLA genotypes are variable, especially in the highly admixed Brazilian population. In this ecological study, we aimed to investigate the correlation between HLA haplotypes and the different regional distribution of COVID-19 mortality in Brazil. HLA data was obtained from 4,148,713 individuals registered in The Brazilian Voluntary Bone Marrow Donors Registry. COVID-19 data was retrieved from epidemiological bulletins issued by State Health Secretariats via Brazil's Ministry of Health from February/2020 to July/2022. We found a positive significant correlation between the HLA-A*01~B*08~DRB1*03 haplotype and COVID-19 mortality rates when we analyzed data from 26 states and the Federal District. This result indicates that the HLA-A*01~B*08~DRB1*03 haplotype may represent an additional risk factor for dying due to COVID-19. This haplotype should be further studied in other populations for a better understanding of the variation in COVID-19 outcomes across the world.

Neurodevelopment in Children Exposed to Zika in utero: Clinical and Molecular Aspects.

Five years after the identification of Zika virus as a human teratogen, we reviewed the early clinical manifestations, collectively called congenital Zika syndrome (CZS). Children with CZS have a very poor prognosis with extremely low performance in motor, cognitive, and language development domains, and practically all feature severe forms of cerebral palsy. However, these manifestations are the tip of the iceberg, with some children presenting milder forms of deficits. Additionally, neurodevelopment can be in the normal range in the majority of the non-microcephalic children born without brain or eye abnormalities. Vertical transmission and the resulting disruption in development of the brain are much less frequent when maternal infection occurs in the second half of the pregnancy. Experimental studies have alerted to the possibility of other behavioral outcomes both in prenatally infected children and in postnatal and adult infections. Cofactors play a vital role in the development of CZS and involve genetic, environmental, nutritional, and social determinants leading to the asymmetric distribution of cases. Some of these social variables also limit access to multidisciplinary professional treatment.

Fire association with respiratory disease and COVID-19 complications in the State of Pará, Brazil.

BACKGROUND: Brazil has faced two simultaneous problems related to respiratory health: forest fires and the high mortality rate due to COVID-19 pandemics. The Amazon rain forest is one of the Brazilian biomes that suffers the most with fires caused by droughts and illegal deforestation. These fires can bring respiratory diseases associated with air pollution, and the State of Pará in Brazil is the most affected. COVID-19 pandemics associated with air pollution can potentially increase hospitalizations and deaths related to respiratory diseases. Here, we aimed to evaluate the association of fire occurrences with the COVID-19 mortality rates and general respiratory diseases hospitalizations in the State of Pará, Brazil. METHODS: We employed machine learning technique for clustering k-means accompanied with the elbow method used to identify the ideal quantity of clusters for the k-means algorithm, clustering 10 groups of cities in the State of Pará where we selected the clusters with the highest and lowest fires occurrence from the 2015 to 2019. Next, an Auto-regressive Integrated Moving Average Exogenous (ARIMAX) model was proposed to study the serial correlation of respiratory diseases hospitalizations and their associations with fire occurrences. Regarding the COVID-19 analysis, we computed the mortality risk and its confidence level considering the quarterly incidence rate ratio in clusters with high and low exposure to fires. FINDINGS: Using the k-means algorithm we identified two clusters with similar DHI (Development Human Index) and GDP (Gross Domestic Product) from a group of ten clusters that divided the State of Pará but with diverse behavior considering the hospitalizations and forest fires in the Amazon biome. From the auto-regressive and moving average model (ARIMAX), it was possible to show that besides the serial correlation, the fires occurrences contribute to the respiratory diseases increase, with an observed lag of six months after the fires for the case with high exposure to fires. A highlight that deserves attention concerns the relationship between fire occurrences and deaths. Historically, the risk of mortality by respiratory diseases is higher (about the double) in regions and periods with high exposure to fires than the ones with low exposure to fires. The same pattern remains in the period of the COVID-19 pandemic, where the risk of mortality for COVID-19 was 80% higher in the region and period with high exposure to fires. Regarding the SARS-COV-2 analysis, the risk of mortality related to COVID-19 is higher in the period with high exposure to fires than in the period with low exposure to fires. Another highlight concerns the relationship between fire occurrences and COVID-19 deaths. The results show that regions with high fire occurrences are associated with more cases of COVID deaths. INTERPRETATION: The decision-make process is a critical problem mainly when it involves environmental and health control policies. Environmental policies are often more cost-effective as health measures than the use of public health services. This highlight the importance of data analyses to support the decision making and to identify population in need of better infrastructure due to historical environmental factors and the knowledge of associated health risk. The results suggest that The fires occurrences contribute to the increase of the respiratory diseases hospitalization. The mortality rate related to COVID-19 was higher for the period with high exposure to fires than the period with low exposure to fires. The regions with high fire occurrences is associated with more COVID-19 deaths, mainly in the months with high number of fires. FUNDING: No additional funding source was required for this study.

Investigating the role of EGF-CFC gene family in recurrent pregnancy loss through bioinformatics and molecular approaches.

Recurrent pregnancy loss (RPL) is the most common reproductive failure, reaching 1-5% of women throughout their lives, and having unknown etiology in 50% of the cases. In humans, EGF-CFC1 (Epidermal Growth Factors & Cripto/FRL-1/Cryptic) gene family is composed by TDGF1 and CFC1, two developmental genes. The aim of this study was to investigate the role of EGF-CFC on RPL. To this, multiple approaches were performed; we conducted an expression analysis of TDGF1 and CFC1 using publicly available data from Gene Omnibus Expression (GEO), systems biology analyses and functional prediction; and a molecular analysis carried out in a case-control study. Our GEO analysis showed a decrease in TDGF1 expression in the endometrium (p=0.049) and CFC1 expression in placenta (p=0.015) of women with RPL. Network analysis, gene ontology and literature pointed to a strong connection between EGF-CFC1 gene family to pathways that play key roles during pregnancy, including TGF-ß, c-Src/MAPK/AKT, Notch, TNFα, IFNγ and IL-6. A pathogenicity score developed for this gene family showed that the c.-14+1429T>C (rs3806702) variant in the TDGF1 and the p.Arg47Gln (rs201431919) variant in CFC1 gene would be the ones with the highest deleterious effect for RPL. In the case-control study, which involved 149 women with RPL and 159 controls, no statistical difference was observed in the allele and genotype distributions of the variants studied in the two groups. In this study, we performed extensive bioinformatics analysis for biomarker prioritization followed by experimental validation of proposed selected markers. Although there is no statistical difference in the frequencies of these variants between RPL and controls, the expression analysis results suggest that TDGF1 and CFC1 genes might play a role in RPL. In addition, systems biology analyzes raise the hypothesis that genes in other signaling pathways that may be related to RPL as good candidates for future studies.Abbreviations RPL: recurrent pregnancy loss; EGF-CFC1: Epidermal Growth Factors - Cripto/FRL-1; GEO: Gene Omnibus Expression; KEGG: Kyoto Encyclopedia of Genes and Genomes.

Molecular mechanisms of Zika virus teratogenesis from animal studies: a systematic review protocol.

BACKGROUND: Due to the diversity of studies in animal models reporting that molecular mechanisms are involved in the teratogenic effect of the Zika virus (ZIKV), the objective of the present study is to evaluate the methodological quality of these studies, as well as to demonstrate which genes and which molecular pathways are affected by ZIKV in different animal models. METHODS: This search will be performed in four databases: PubMed/MEDLINE, EMBASE, Web of Science, and Scopus, as well as in the grey literature. The studies selection process will be reported through the PRISMA Statement diagram model. All studies describing the molecular mechanisms possibly involved in the development of malformations caused by embryonic/fetal ZIKV exposure in animal models with an appropriate control group and methodology will be included (including, for instance, randomized and non-randomized studies). All animals used as experimental models for ZIKV teratogenesis may be included as long as exposure to the virus occurred during the embryonic/fetal period. From the selected studies, data will be extracted using a previously prepared standard form. Bias risk evaluation will be conducted following the SYRCLE's Risk of Bias tool. All data obtained will be tabulated and organized by outcomes (morphological and molecular). DISCUSSION: With the proposed systematic review, we expect to present results about the methodological quality of the published studies with animal models that investigated the molecular mechanisms involved in the teratogenic effect of ZIKV, as well as to show the studies with greater reliability. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019157316.

Prevalence of congenital anomalies at birth among live births in the state of Maranhão from 2001 to 2016: temporal and spatial analysis.

OBJECTIVES: To analyze the prevalence at birth and the spatial and temporal distribution of congenital anomalies (CAs) among live births in the state of Maranhão in 2001 to 2016. To describe demographic, gestational and neonatal variables of interest. METHODS: Ecological, population-based study, using secondary data from the Live Birth Information System (SINASC). Annual prevalence of total and per-group CAs was calculated. Spatial analyzes were based on the Local Indicators of Spatial Association (LISA) and the Moran I Index, and interactive maps were generated. Demographic, gestational and neonatal variables of interest available from SINASC were described in the group of newborns with CAs. RESULTS: 1,831,830 live births, 6,110 with CAs (33.4/10,000) were included. Higher frequencies occurred in more recent years. Spatial clusters have been observed in specific years. The prevalence of newborns with CAs was different between categories of variables considered as risk factors for this outcome. CONCLUSION: The prevalence at birth of total CAs was lower than expected for major human defects (3%). The temporal peak of records in 2015/2016 is probably related to the increase in CAs caused by gestational infection by the Zika virus. The spatial clusters were probably due to variations at random due to the small number of births as they are not repeated in other years. Studies like this are the basis for the establishment of CA surveillance programs.

Geographic distribution of live births and infant mortality from congenital anomalies in Brazil, 2012-2017.

In the 2010-2014 period, the mean prevalence of congenital anomalies (CA) in the world was estimated at 398/10,000 births. CA are an important cause of mortality, disability, and comorbidity. Thus, the present study aims to describe the geographical and temporal distributions of live births and infant mortality (IM) due CA (IM-CA) in Brazil, from 2012 to 2017. The data used in this study is available at the Department of Informatics of the Unified Health System (DATASUS). The prevalence of CA at birth was 81.67/10,000 (95% CI 80.46-82.88), and the IM-CA rate was 27.97/10,000 (95% CI 27.95-28.00) in the studied period. The five CA with the highest rates were polydactyly (9.66/10,000, 95% CI 6.10-9.82), Down syndrome (3.40/10,000, 95% CI 3.41-5.99), microcephaly (2.92/10,000, 95% CI 2.91-3.12), hydrocephalus (2.72/10,000, 95% CI 2.65-2.90), and spina bifida (2.44/10,000, 95% CI 2.43-2.64). São Paulo was the Brazilian state with the highest CA birth rate (119.3/10,000), and Amazonas was the state with the highest IM-CA rate (33.8/10,000). The description and data analyses such as those performed in this work are relevant for healthcare systems and can be very useful in the formulation of public health campaigns and policies, as well as informing and educating professionals and the population. The management of clinical actions should consider all social, economic, geographic, and epidemiological factors.

Prevalence of congenital anomalies at birth among live births in the state of Maranhão from 2001 to 2016: temporal and spatial analysis / Prevalências ao nascimento de anomalias congênitas entre nascidos vivos no estado do Maranhão de 2001 a 2016: análise temporal e espacial

ABSTRACT: Objectives: To analyze the prevalence at birth and the spatial and temporal distribution of congenital anomalies (CAs) among live births in the state of Maranhão in 2001 to 2016. To describe demographic, gestational and neonatal variables of interest. Methods: Ecological, population-based study, using secondary data from the Live Birth Information System (SINASC). Annual prevalence of total and per-group CAs was calculated. Spatial analyzes were based on the Local Indicators of Spatial Association (LISA) and the Moran I Index, and interactive maps were generated. Demographic, gestational and neonatal variables of interest available from SINASC were described in the group of newborns with CAs. Results: 1,831,830 live births, 6,110 with CAs (33.4/10,000) were included. Higher frequencies occurred in more recent years. Spatial clusters have been observed in specific years. The prevalence of newborns with CAs was different between categories of variables considered as risk factors for this outcome. Conclusion: The prevalence at birth of total CAs was lower than expected for major human defects (3%). The temporal peak of records in 2015/2016 is probably related to the increase in CAs caused by gestational infection by the Zika virus. The spatial clusters were probably due to variations at random due to the small number of births as they are not repeated in other years. Studies like this are the basis for the establishment of CA surveillance programs.

RESUMO: Objetivos: Analisar as prevalências ao nascimento e a distribuição espacial e temporal das anomalias congênitas (ACs) entre nascidos vivos no estado do Maranhão nos anos de 2001 a 2016; descrever variáves de interesse demográficas, gestacionais e neonatais. Métodos: Estudo ecológico, de base populacional, a partir de dados secundários do Sistema de Informações sobre Nascidos Vivos (SINASC). Foram calculadas prevalências ao nascimento anuais de ACs totais e por grupos. Análises espaciais utilizaram o cálculo de Indicadores Locais de Associação Espacial (LISA) e o Índice Global de Moran I, e mapas interativos foram gerados. Variáveis de interesse demográficos, gestacionais e neonatais disponíveis no SINASC foram descritas no grupo dos recém-nascidos com ACs. Resultados: Neste estudo, foram incluídos 1.831.830 nascidos vivos, 6.110 com ACs (33,4/10 mil). Maiores frequências ocorreram nos anos mais recentes. Aglomerados espaciais foram observados em anos específicos. As prevalências de nascidos vivos com anomalias foram diferentes entre categorias de variáveis consideradas como fatores de risco para esse desfecho. Conclusão: A prevalência ao nascimento de nascidos com ACs foi inferior ao esperado para defeitos maiores na espécie humana (3%). O pico temporal de registros em 2015/2016 está provavelmente relacionado ao aumento de microcefalia causada pela infecção gestacional por vírus Zika. Os aglomerados espaciais provavelmente se deveram a variações ao acaso pelo número pequeno de nascimentos, pois não se repetem em outros anos. Estudos como este são base para o estabelecimento de programas de vigilância de defeitos congênitos.

Prevalence at birth of congenital anomalies among live births in the state of Maranhão from 2001 to 2016: temporal and spatial analysis / Prevalências ao nascimento de anomalias congênitas entre nascidos vivos no estado do Maranhão de 2001 a 2016: análise temporal e espacial

Objectives: To analyze the prevalence at birth and the spatial and temporal distribution of congenital anomalies (CAs) among live births in the state of Maranhão in the years 2001 to 2016. To describe demographic, gestational and neonatal variables of interest. Methods: Ecological, population-based study, using secondary data from the Information System on Live Births (SINASC). Annual prevalence of total and per group CAs was calculated. Spatial analyzes used the calculation of Local Indicators of Spatial Association and the Moran I Index and interactive maps were generated. Demographic, gestational and neonatal variables of interest available at SINASC were described in the group of newborns with CAs. Results: 1,831,830 live births, 6,110 with CAs (33.4/10,000) were included. Higher frequencies have occurred in more recent years. Spatial clusters have been observed in specific years. The prevalence of births of babies with CAs was different between categories of variables considered as risk factors for this outcome. Conclusion: The prevalence at birth of total CAs was lower than expected for the human species for major defects (3%). The temporal peak of records in 2015/2016 is probably related to the increase in CAs caused by gestational infection by Zika virus. The spatial clusters were probably due to variations at random due to the small number of births as they are not repeated in other years. Studies like this are the basis for the establishment of CA surveillance programs.

Objetivos: Analisar as prevalências ao nascimento e a distribuição espacial e temporal das anomalias congênitas entre nascidos vivos no estado do Maranhão nos anos de 2001 a 2016. Descrever variáves de interesse demográficas, gestacionais e neonatais. Métodos: Estudo ecológico, de base populacional, a partir de dados secundários do Sistema de Informações sobre Nascidos Vivos. Foram calculadas prevalências ao nascimento anuais de ACs totais e por grupos. Análises espaciais utilizaram o cálculo de Indicadores de Associação Espacial Locais e o Índice de Moran I e mapas interativos foram gerados. Variáveis de interesse demográficos, gestacionais e neonatais disponíveis no SINASC foram descritas no grupo dos recém-nascidos com ACs. Resultados: Foram incluídos 1.831.830 nascidos vivos, 6.110 com anomalias congênitas (33,4/10.000). Maiores frequências ocorreram nos anos mais recentes. Aglomerados espaciais foram observados em anos específicos. As prevalências de nascidos vivos com anomalias foi diferente entre categorias de variáveis consideradas como fatores de risco para este desfecho. Conclusão: A prevalência ao nascimento de nascidos com anomalias congênitas  foi  inferior ao esperado para defeitos maiores na espécie humana (3%).  O pico temporal de registros em 2015/2016 está provavelmente relacionado ao aumento de microcefalia causada pela infecção gestacional por vírus Zika. Os aglomerados espaciais provavelmente se deveram a variações ao acaso pelo número pequeno de nascimentos pois não se repetem em outros anos. Estudos como este são base para o estabelecimento de programas de vigilância de defeitos congênitos.

Spatial analyzes of HLA data in Rio Grande do Sul, south Brazil: genetic structure and possible correlation with autoimmune diseases.

BACKGROUND: HLA genes are the most polymorphic of the human genome and have distinct allelic frequencies in populations of different geographical regions of the world, serving as genetic markers in ancestry studies. In addition, specific HLA alleles may be associated with various autoimmune and infectious diseases. The bone marrow donor registry in Brazil is the third largest in the world, and it counts with genetic typing of HLA-A, -B, and -DRB1. Since 1991 Brazil has maintained the DATASUS database, a system fed with epidemiological and health data from compulsory registration throughout the country. METHODS: In this work, we perform spatial analysis and georeferencing of HLA genetic data from more than 86,000 bone marrow donors from Rio Grande do Sul (RS) and data of hospitalization for rheumatoid arthritis, multiple sclerosis and Crohn's disease in RS, comprising the period from 1995 to 2016 obtained through the DATASUS system. The allele frequencies were georeferenced using Empirical Bayesian Kriging; the diseases prevalence were georeferenced using Inverse Distance Weighted and cluster analysis for both allele and disease were performed using Getis-Ord Gi* method. Spearman's test was used to test the correlation between each allele and disease. RESULTS: The results indicate a HLA genetic structure compatible with the history of RS colonization, where it is possible to observe differentiation between regions that underwent different colonization processes. Spatial analyzes of autoimmune disease hospitalization data were performed revealing clusters for different regions of the state for each disease analyzed. The correlation test between allelic frequency and the occurrence of autoimmune diseases indicated a significant correlation between the HLA-B*08 allele and rheumatoid arthritis. CONCLUSIONS: Genetic mapping of populations and the spatial analyzes such as those performed in this work have great economic relevance and can be very useful in the formulation of public health campaigns and policies, contributing to the planning and adjustment of clinical actions, as well as informing and educating professionals and the population.

Zika Virus as a Possible Risk Factor for Autism Spectrum Disorder: Neuroimmunological Aspects.

The recent outbreak of the Zika virus (ZIKV) and the discovery that perinatal Zika exposure can lead to the Congenital Zika Syndrome has promoted a call for prevention measures. Due to the increased number of babies born with microcephaly, structural brain abnormalities, and neurological alterations in regions affected by ZIKV, investigations were carried out in order to better understand this process. The maternal immune system directly influences the fetal central nervous system, and complications during pregnancy have been associated with neurodevelopmental disorders. Autism spectrum disorder (ASD), a neurodevelopmental disorder commonly manifested in the first years of life, is a disease with multifactorial etiology and is manifested typically by social and communication impairments, as well as stereotyped behaviors. Brain abnormalities, including both anatomically and functionally, can be observed in this disorder, suggesting delays in neuronal maturation and altered brain connectivity. It is known that some viral congenital infections, such as rubella, and cytomegalovirus can interfere with brain development, being associated with brain calcification, microcephaly, and ASD. Here, we reviewed a range of studies evaluating the aspects concerning brain development, immunological status during pregnancy, and neuroimmunomodulation in congenital viral infections, and we discuss if the fetal brain infection caused by ZIKV could predispose to ASD. Finally, we suggest a mechanism encompassing neurological and immunological pathways that could play a role in the development of ASD in infants after ZIKV infection in pregnancy.

Angiogenesis and oxidative stress-related gene variants in recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) affects ~3-5% of couples attempting to conceive and in around 50% of cases the aetiology remains unknown. Adequate vascularisation and placental circulation are indispensable for the development of a normal pregnancy. Prostaglandin-endoperoxide synthase 2 (PTGS2), vascular endothelial growth factor (VEGF) and the nitric oxide (NO) systems play important roles in reproductive physiology, participating in several steps including implantation and apoptosis of trophoblast cells. In this study we evaluated genetic polymorphisms in the inducible nitric oxide synthase (NOS2), PTGS2 and VEGFA genes as susceptibility factors for RPL. A case-control study was conducted in 149 women having two or more miscarriages and 208 controls. Allele and genotype distributions of the polymorphisms studied in the two groups were not statistically different. However, the dominant model showed that the presence of variant T (TT/GT) of rs2779249 (-1290G>T) of NOS2 was significantly associated with RPL (OR=1.58, CI 95%=1.03-2.44; P=0.037). The increased risk remained significant when adjusted for number of pregnancies, alcohol consumption and ethnicity (OR=1.92, CI95%=1.18-3.11; P=0.008). These results suggest that the variant genotypes of the functional polymorphism rs2779249 in the NOS2 promoter are a potential risk for RPL, possibly due to oxidative stress mechanisms.

Maternal SNPs in the p53 pathway: risk factors for trisomy 21?

The p53 family and its regulatory pathway play an important role as regulators of developmental processes, limiting the propagation of aneuploid cells. Its dysfunction or imbalance can lead to pathological abnormalities in humans. The aim of this study was to evaluate the effect of maternal polymorphisms TP53 c.215G>C (P72R), TP73 4 c.-30G>A and 14 c.-20C>T, MDM2 c.14+309T>G (SNP309), MDM4 c.753+572C>T and USP7 c.2719-234G>A as risk factors for Down Syndrome (DS) birth. A case-control study was conducted with 263 mothers of DS children and 196 control mothers. The distribution of these genotypic variants was similar between case and control mothers. However, the combined alleles TP53 C and MDM2 G, and P53 C and USP7 A increased the risk of having offspring with DS (OR=1.84 and 1.77; 95% CI; P < 0.007 and 0.018, respectively). These results suggest that, although the individual polymorphisms were not associated with DS birth, the effect of the combined genotypes among TP53, MDM2 and USP7 genes indicates a possible role of TP53 and its regulatory pathway as a risk factor for aneuploidy.

Aspectos biológicos e atividade tumorigênica da família proto-oncogênica Ras / Biological aspects and tumorigenic activity of the Ras proto-oncogenic Family

Os proto-oncogenes desempenham importante papel na regulação do ciclo celular, e são críticos à tumorigênese. Nessa categoria se encontra a família RAS, que, devido ao elevado potencial transformante dos genes que a compõem, é uma das mais bem descritas e estudadas. É formada pelos genes H-, K- e N-RAS, que codificam proteínas altamente relacionadas expressas em vários tipos de células, denominadas p21. Estas atuam na transdução de sinal da membrana ao núcleo, estão envolvidas no controle da proliferação, diferenciação e morte celular e são reguladas pela interação com GDP (inativa) e GTP (ativa). As proteínas p21 diferem em apenas 10-15% da sua estrutura primária, na porção C-terminal, denominada região hipervariante. Quando na forma oncogênica, permanecem ativas, e conferem estímulo contínuo à proliferação celular. Dentre os genes RAS, K-RAS tem sido o mais estudado, por apresentar mutações mais freqüentes e presentes em tumores mais agressivos, e implicar em menor sobrevida aos pacientes. Pelo importante papel já demonstrado na formação de tumores e relativa carência de bibliografia em língua portuguesa acerca dessa família gênica, apresentamos neste trabalho uma revisão sistematizada e atualizada sobre os proto-oncogenes RAS.

Proto-oncogenes play an important role in the regulation of the cellular cycle, being critical to the tumorigenesis. In this category we can find the RAS family. Due to the high transformation potential of these genes, this family is the best described and most studied one. It is formed by the H-, K- and the N-RAS genes, that codify highly related proteins expressed in several types of cells, denominated p21.These proteins act in the sign transduction from the membrane to the nucleus, as well as in the control of proliferation, differentiation and cellular death, and they are regulated by the interaction with GDP (inactive) and GTP (active). These proteins show variation in only 10 - 15% of the primary structure, in the C-terminal portion denominated hyper-variant region. When in the oncogenic form, the p21 proteins remain active, providing continuous stimuli to the cellular proliferation. Among the RAS genes, K-RAS ones have been the most studied for presenting more frequent mutations and for being present in more aggressive tumors, implying the patients’ shorter survival time. Due to these facts and relative bibliography lack in the Portuguese language on this family, we presented in this work a systematized and updated review on the RAS genes.