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The mucin (MUC) family includes several genes aberrantly expressed in multiple carcinomas and mediates diverse pathways essentials for oncogenesis, in both solid and hematological malignancies. Acute Lymphoblastic Leukemia (ALL) can have its course influenced by genetic variants, and it seems more frequent in the Amerindian population, which has been understudied. Therefore, the present work aimed to investigate the MUC family exome in Amerindian individuals from the Brazilian Amazon, in a sample containing healthy Native Americans (NAMs) and indigenous subjects with ALL, comparing the frequency of polymorphisms between these two groups. The population was composed of 64 Amerindians from the Brazilian Amazon, from 12 different isolated tribes, five of whom were diagnosed with ALL. We analyzed 16 genes from the MUC family and found a total of 1858 variants. We compared the frequency of each variant in the ALL vs. NAM group, which led to 77 variants with a significant difference and, among these, we excluded those with a low impact, resulting in 63 variants, which were distributed in nine genes, concentrated especially in MUC 19 (n = 30) and MUC 3A (n = 18). Finally, 11 new variants were found in the NAM population. This is the first work with a sample of native Americans with cancer, a population which is susceptible to ALL, but remains understudied. The MUC family seems to have an influence on the development of ALL in the Amerindian population and especially MUC19 and MUC3A are shown as possible hotspots. In addition, the 11 new variants found point to the need to have their clinical impact analyzed.

Identifying a microbiome pattern in gastric cancer (GC) is hugely debatable due to the variation resulting from the diversity of the studied populations, clinical scenarios, and metagenomic approach. H. pylori remains the main microorganism impacting gastric carcinogenesis and seems necessary for the initial steps of the process. Nevertheless, an additional non-H. pylori microbiome pattern is also described, mainly at the final steps of the carcinogenesis. Unfortunately, most of the presented results are not reproducible, and there are no consensual candidates to share the H. pylori protagonists. Limitations to reach a consistent interpretation of metagenomic data include contamination along every step of the process, which might cause relevant misinterpretations. In addition, the functional consequences of an altered microbiome might be addressed. Aiming to minimize methodological bias and limitations due to small sample size and the lack of standardization of bioinformatics assessment and interpretation, we carried out a comprehensive analysis of the publicly available metagenomic data from various conditions relevant to gastric carcinogenesis. Mainly, instead of just analyzing the results of each available publication, a new approach was launched, allowing the comprehensive analysis of the total sample amount, aiming to produce a reliable interpretation due to using a significant number of samples, from different origins, in a standard protocol. Among the main results, Helicobacter and Prevotella figured in the “top 6” genera of every group. Helicobacter was the first one in chronic gastritis (CG), gastric cancer (GC), and adjacent (ADJ) groups, while Prevotella was the leader among healthy control (HC) samples. Groups of bacteria are differently abundant in each clinical situation, and bacterial metabolic pathways also diverge along the carcinogenesis cascade. This information may support future microbiome interventions aiming to face the carcinogenesis process and/or reduce GC risk.

Given the role of pharmacogenomics in the large variability observed in drug efficacy/safety, an assessment about the pharmacogenomic profile of patients prior to drug prescription or dose adjustment is paramount to improve adherence to treatment and prevent adverse drug reaction events. A population commonly underrepresented in pharmacogenomic studies is the Native American populations, which have a unique genetic profile due to a long process of geographic isolation and other genetic and evolutionary processes. Here, we describe the pharmacogenetic variability of Native American populations regarding 160 pharmacogenes involved in absorption, distribution, metabolism, and excretion processes and biological pathways of different therapies. Data were obtained through complete exome sequencing of individuals from 12 different Amerindian groups of the Brazilian Amazon. The study reports a total of 3311 variants; of this, 167 are exclusive to Amerindian populations, and 1183 are located in coding regions. Among these new variants, we found non-synonymous coding variants in the DPYD and the IFNL4 genes and variants with high allelic frequencies in intronic regions of the MTHFR, TYMS, GSTT1, and CYP2D6 genes. Additionally, 332 variants with either high or moderate (disruptive or non-disruptive impact in protein effectiveness, respectively) significance were found with a minimum of 1% frequency in the Amazonian Amerindian population. The data reported here serve as scientific basis for future design of specific treatment protocols for Amazonian Amerindian populations as well as for populations admixed with them, such as the Northern Brazilian population.

Introdução: A mucosite oral (MO) consiste em uma reação inflamatória aguda na mucosa bucal sendo uma das complicações mais comuns do tratamento com o quimioterápico 5-Fluorouracil (5-FU), podendo levar a várias complicações incluindo dor intensa, diarreia e desnutrição. Essas complicações, além de comprometer a qualidade de vida do paciente oncológico, podem levar a interrupções no tratamento quimioterápico, o que pode reduzir sua sobrevida. Objetivos: Determinar a prevalência de MO em pacientes com diagnóstico de câncer gástrico e colorretal, tratados com o quimioterápico 5-FU, isolado ou em combinação, entre os anos de 2017 e 2018, em dois hospitais de referência no tratamento oncológico localizados na cidade de Belém- PA (Unidade de Alta Complexidade em Oncologia-UNACON e Ophir Loyola-HOL). Material e Métodos: O estudo tem caráter transversal, descritivo e quantitativo e foi aprovado pelo comitê de ética em pesquisa (protocolo 231.244/2013). Dados epidemiológicos e clínicos foram coletados dos prontuários médicos de 216 pacientes e posteriormente foram analisados no programa estatístico SPSS v.25. Resultados: Entre os pacientes incluídos no estudo, 92 (42,6%) tinha o diagnóstico de câncer gástrico e 124 (57,4%) de câncer colorretal, 112 (51,8%) pacientes eram do gênero masculino e 104 (48,2%) do feminino. A média de idade dos participantes foi de 54 anos. Todos os pacientes receberam 5-FU, isoladamente (7,4%) ou em associação com outros fármacos, sendo o esquema de tratamento mais frequente 5-FU combinado a leucovorin (41,2%), seguido por FOLFOX (5-FU, leucovorin, oxaliplatina) 40,3% e FOLFIRI (5-FU, irinotecano e leucovorin) 11,1%. A maioria dos pacientes analisados possuíam estadiamento tumoral avançado grau III (42, 6%) e IV (39, 8%). Durante o tratamento, 50 pacientes (23, 1%) apresentaram MO, a maior parte desses pacientes apresentavam câncer colorretal (66%) e eram gênero feminino (24%). A média de idade entre os pacientes com MO foi de 54,3 anos e a maioria recebeu o esquema terapêutico FOLFOX (40%). Conclusão: Foi observado no estudo uma alta prevalência de MO em pacientes portadores de câncer gastrointestinal tratado com 5-FU. Esses dados servem de alerta para elaboração de abordagens preventivas e terapêutica para a MO, a fim de melhorar a qualidade de vida dos pacientes oncológicos.

Genetic factors associated with COVID-19 disease outcomes are poorly understood. This study aimed to associate genetic variants in the SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1, and ABO genes with the risk of severe forms of COVID-19 in Amazonian Native Americans, and to compare the frequencies with continental populations. The study population was composed of 64 Amerindians from the Amazon region of northern Brazil. The difference in frequencies between the populations was analyzed using Fisher’s exact test, and the results were significant when p ≤ 0.05. We investigated 64 polymorphisms in 7 genes; we studied 47 genetic variants that were new or had impact predictions of high, moderate, or modifier. We identified 15 polymorphisms with moderate impact prediction in 4 genes (ABO, CXCR6, FYCO1, and SLC6A20). Among the variants analyzed, 18 showed significant differences in allele frequency in the NAM population when compared to others. We reported two new genetic variants with modifier impact in the Amazonian population that could be studied to validate the possible associations with COVID-19 outcomes. The genomic profile of Amazonian Native Americans may be associated with protection from severe forms of COVID-19. This work provides genomic data that may help forthcoming studies to improve COVID-19 outcomes.

Genetic variations in PCLO have been associated with different pathologies in global literature, but there are no data regarding this gene in Native American populations. The Amazonian Native American populations have lower genetic diversity and are more different from other continental groups. We investigated 18 genetic variants in the PCLO gene in Amazonian indigenous and compared our results with the ones found in global populations, which were publicly available in the 1000 Genomes Project, gnmAD and ABraOM databases. The results demonstrated that the variants of the PCLO, especially rs17156844, rs550369696, rs61741659 and rs2877, have a significantly higher frequency in Amerindian populations in comparison with other continental populations. These data outline the singular genetic profile of the Native American population from the Brazilian Amazon region.

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, representing about 30–35% of cases. Its etiology is complex and not fully understood. ALL is influenced by genetic variants, and their frequencies (Fq) vary in different ethnic groups, which consequently could influence the epidemiology of this cancer worldwide. The aim of this study was to investigate the correlation between the genetic variants and their impacts on incidence (IC), mortality (MT), and prevalence (PV) rates of ALL in different world populations. Methods: Sixty variants were selected from the literature with Genome Wide Association studies (GWAS). Information regarding allele Fq was selected from the 1000 Genomes platform. Epidemiological data were taken from the Global Burden of disease visualisations (GBD) Compare website. Statistical analyses were calculated in RStudio v.3.5.1 software. Results: Four variants demonstrated significant results in correlations with epidemiological data for ALL. The PAX5 gene variant (rs2297105) had an indirect relationship with PV and IC of ALL, showing that an increased Fq of this variant is related to low rates of both. An increased Fq of rs915172 in EPB4IL2 gene was also correlated with a lower IC of ALL. The rs1048943 of the CYP1A1 gene and the rs3088440 polymorphism of the CDKN2A gene were shown to have a direct proportional relationship with MT rate, showing that an increased Fq of these variants correlates with a worse prognosis worldwide. Conclusion: Our study points out four important variants for understanding the IC, PV, and MT rates for ALL. The ascertainment of these data may help to choose molecular markers to investigate the susceptibility and prognosis of ALL.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm derived from the balanced reciprocal translocation of chromosomes 9 and 22 t (9q34 and 22q11), which leads to the formation of the Philadelphia chromosome and fusion of the BCR-ABL genes. The first-line treatment for CML is imatinib, a tyrosine kinase inhibitor that acts on the BCR-ABL protein. However, even though it is a target-specific drug, about 25% of patients do not respond to this treatment. The resistance mechanisms involved in this process have been investigated and studies have shown that germinal alterations can influence this mechanism. The aim of this work was to investigate 32 polymorphisms in 24 genes of carcinogenic pathway to verify the influence of these genetic variants on the response to treatment with imatinib. Our results demonstrated that individuals with the recessive GG genotype for the rs2372536 variant in the ATIC gene are approximately three times more likely to experience treatment failure with imatinib (p = 0.045, HR = 2.726, 95% CI = 0.9986–7.441), as well as individuals with the TT genotype for the rs10821936 variant in the ARID5B gene, who also have a higher risk for treatment failure with imatinib over time (p = 0.02, HR = 0.4053, IC 95% = 0.1802–0.911). In conclusion, we show that variants in the ATIC and ARIDB5 gene, never screened in previous studies, could potentially influence the therapeutic response to imatinib in patients treated for CML.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the world. Single nucleotide variants (SNVs) in miRNA and genes encoding proteins of the miRNA synthesis complex (SC) may affect the processing of drugs used in the treatment of ALL, resulting in treatment-related toxicities (TRTs). We investigated the role of 25 SNVs in microRNA genes and genes encoding proteins of the miRNA SC, in 77 patients treated for ALL-B from the Brazilian Amazon. The 25 SNVs were investigated using the TaqMan® OpenArray™ Genotyping System. SNVs rs2292832 (MIR149), rs2043556 (MIR605), and rs10505168 (MIR2053) were associated with an increased risk of developing Neurological Toxicity, while rs2505901 (MIR938) was associated with protection from this toxicity. MIR2053 (rs10505168) and MIR323B (rs56103835) were associated with protection from gastrointestinal toxicity, while DROSHA (rs639174) increased the risk of development. The rs2043556 (MIR605) variant was related to protection from infectious toxicity. SNVs rs12904 (MIR200C), rs3746444 (MIR499A), and rs10739971 (MIRLET7A1) were associated with a lower risk for severe hematologic toxicity during ALL treatment. These findings reveal the potential for the use of these genetic variants to understand the development of toxicities related to the treatment of ALL in patients from the Brazilian Amazon region.

Gastric cancer (GC) is the fifth most common type of cancer and the fourth leading cause of cancer death. In Brazil, GC has a high incidence and mortality rates, and it is highly variable by region. The Amazon region has significant rising rates among all Brazil regions. Only very few studies have evaluated the association between genetic variants and the risk of gastric cancer in the Brazilian Amazon population. Therefore, this study aimed to investigate associations between single nucleotide polymorphisms of miRNA processing genes and the risk for GC in this population. Potentially functional single nucleotide polymorphisms from miRNA processing genes were genotyped in 159 cases and 193 healthy controls by QuantStudio Real Time PCR. According to our findings, the genotype GG of the variant rs10739971 presents a lower risk to the development of GC in comparison to the remaining genotypes (p = 0.000016; OR = 0.055; 95% CI = 0.015–0.206). This is the first study to report the association of pri-let-7a-1 rs10739971 with GC in the Brazilian Amazon population, which is a highly mixed population with a unique genetic constitution that is different from other populations that are studied in the vast majority of scientific research.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm derived from the balanced reciprocal translocation of chromosomes 9 and 22 t (9q34 and 22q11), which leads to the formation of the Philadelphia chromosome and fusion of the

Due to their continuing geographic isolation, the Amerindian populations of the Brazilian Amazon present a different genetic profile when compared to other continental populations. Few studies have investigated genetic variants present in these populations, especially in the context of next-generation sequencing. Knowledge of the molecular profile of a population is one of the bases for inferences about human evolutionary history, in addition, it has the ability to assist in the validation of molecular biomarkers of susceptibility to complex and rare diseases, and in the improvement of specific precision medicine protocols applied to these populations and to populations with high Amerindian ancestry, such as Brazilians. DNA polymerases play essential roles in DNA replication, repair, recombination, or damage repair, and their influence on various clinical phenotypes has been demonstrated in the specialized literature. Thus, the aim of this study is to characterize the molecular profile of POLA1, POLE, POLG, POLQ, and REV3L genes in Amerindian populations from the Brazilian Amazon, comparing these findings with genomic data from five continental populations described in the gnomAD database, and with data from the Brazilian population described in ABraOM. We performed the whole exome sequencing (WES) of 63 Indigenous individuals. Our study described for the first time the allele frequency of 45 variants already described in the other continental populations, but never before described in the investigated Amerindian populations. Our results also describe eight unique variants of the investigated Amerindians populations, with predictions of moderate, modifier and high clinical impact. Our findings demonstrate the unique genetic profile of the Indigenous population of the Brazilian Amazon, reinforcing the need for further studies on these populations, and may contribute to the creation of public policies that optimize not only the quality of life of this population, but also of the Brazilian population.

Native American populations from the Brazilian Amazon have a low genetic diversity and a different genetic profile when compared to people from other continents. Despite this, few studies have been conducted in this group, and there is no description of their genetic data in the various currently existent international databases. The characterization of the genomic profile of a population not only has an impact in studies of population genetics, but also helps to advance diagnostic and therapeutic response studies, leading to the optimization of clinical applicability. Genetic variations in DNA repair genes have been associated with the modulation of susceptibility to various pathologies, as well as in their prognosis and therapy. This is the first study to investigate DNA repair genes in Amerindians from the Brazilian Amazon region. We investigated 13 important DNA repair genes in the exome of 63 Native Americans, comparing our results with those found in 5 continental populations, whose data are available in the Genome Aggregation Database. Our results showed that 57 variants already described in literature were differentially distributed in the Amerindian populations in relation to the continental populations, 7 of which have significant clinical relevance. In addition, 9 new variants were described, suggesting that they are unique to these populations. Our study reinforces the understanding that the Amazonian Native American population presents a unique genetic profile, and our findings may collaborate with the creation of public policies that optimize the quality of life of these groups as well as the Brazilian population, which presents a high degree of interethnic mixing with Amerindian groups.

Genetic variations in

Background Susceptibility to Chronic Myeloid Leukemia (CML) may be modulated by genetic variables. However, the majority of previous investigations have focused on genetically homogeneous populations, resulting in a lack of evidence on how genetic factors may influence the development of CML in miscegenated populations. We analyzed 30 polymorphisms in genes related to DNA repair, folate metabolism, transmembrane transport, xenobiotic metabolism, and pyrimidine synthesis in relation to their potential role in the susceptibility of the individual to CML. Methods This case‐control study included 126 healthy individuals and 143 patients diagnosed with CML from the admixed population of the Brazilian Amazon. The samples were genotyped by real‐time PCR and the genetic ancestry analysis was based on a panel of 61 ancestry informative markers. Results The results indicated a protective effect against the development of CML in carriers of the C allele of the rs28399433 (CYP2A6) gene and the CC genotype of the rs3742106 (ABCC4) gene. Conclusion Our findings suggest that the rs3742106 (ABCC4) and rs28399433 (CYP2A6) polymorphisms may modulate susceptibility to CML in a population of the Brazilian Amazon region., Susceptibility to chronic myeloid leukemia may be modulated by genetic variables. The accumulated evidence of genetic players in CML development may not be applied to highly admixed populations since their allelic frequencies vary widely between groups with distinct ancestry backgrounds. Thus, we analyzed 30 polymorphisms in genes involved in transport and metabolism pathways in patients with CML from the Brazilian Amazon, one of the most genetically heterogeneous population worldwide.

Background: Tuberculosis is a global public health issue. Recent studies suggested association of host genetic factors to tuberculosis susceptibility in many populations. Polymorphisms can influence the host immune responses to tuberculosis. This study was designed to investigate the association of seventeen genetic polymorphisms with susceptibility and severity to tuberculosis in a sample of Brazilian population. Methods: This case-control study encompassed 283 active tuberculosis patients and 145 healthy subjects that had contact with the bacillus. Genotyping of 13 INDELs polymorphisms and 4 SNPs was achieved using Multiplex PCR method and TaqMan SNP Genotyping Assays. Results: Of the 17 investigated markers, only the ACE marker (rs4646994) showed significant differences between cases and controls. Conclusions: The DEL/DEL (deletion /deletion) genotype of the ACE marker configured a protection factor for the development of tuberculosis. As there is no data in the recent literature relating this polymorphism with tuberculosis in a Brazilian population, our study has become unprecedented.

Leprosy is a chronic neurodermatological disease caused by the bacillus Mycobacterium leprae. Recent studies show that SNPs in genes related to miRNAs have been associated with several diseases in different populations. This study aimed to evaluate the association of twenty-five SNPs in genes encoding miRNAs related to biological processes and immune response with susceptibility to leprosy and its polar forms paucibacillary and multibacillary in the Brazilian Amazon. A total of 114 leprosy patients and 71 household contacts were included in this study. Genotyping was performed using TaqMan Open Array Genotyping. Ancestry-informative markers were used to estimate individual proportions of case and control groups. The SNP rs2505901 (pre-miR938) was associated with protection against the development of paucibacillary leprosy, while the SNPs rs639174 (DROSHA), rs636832 (AGO1), and rs4143815 (miR570) were associated with protection against the development of multibacillary leprosy. In contrast, the SNPs rs10739971 (pri-let-7a1), rs12904 (miR200C), and rs2168518 (miR4513) are associated with the development of the paucibacillary leprosy. The rs10739971 (pri-let-7a1) polymorphism was associated with the development of leprosy, while rs2910164 (miR146A) and rs10035440 (DROSHA) was significantly associated with an increased risk of developing multibacillary leprosy.

Fluoropyrimidines are one of the most used drug class to treat cancer patients, although they show high levels of associated toxicity. This study analyzed 33 polymorphisms in 17 pharmacogenes involved with the pharmacogenomics of fluoropyrimidines, in gastrointestinal cancer patients undergoing fluoropyrimidine-based treatment in the Brazilian Amazon.The study population was composed of 216 patients, 92 of whom have an anatomopathological diagnosis of gastric cancer and 124 of colorectal cancer. The single nucleotide polymorphisms (SNP) were genotyped by allelic discrimination using the TaqMan OpenArray Genotyping technology, with a panel of 32 customized assays, run in a QuantStudio ™ 12K Flex Real-Time PCR System (Applied Biosystems, Life Technologies, Carlsbad USA). Ancestry analysis was performed using 61 autosomal ancestry informative markers (AIMs).The study population show mean values of 48.1% European, 31.1% Amerindian, and 20.8% African ancestries. A significant risk association for general and severe toxicity was found in the rs4451422 of FPGS (p = 0.001; OR 3.40; CI 95% 1.65-7.00 and p = 0.006; OR 4.63; CI 95% 1.56-13.72, respectively) and the rs9524885 of ABCC4 (p = 0.023; OR 2.74; CI 95% 1.14-6.65 and p = 0.024; OR 5.36; IC 95% 1.24-23.11, respectively) genes. The rs760370 in the SLC29A1 gene (p = 0.009; OR 6.71; CI 95% 1.16-8.21) and the rs1801133 in the MTHFR toxicity (p = 0.023; OR 3.09; CI 95% 1.16-8.21) gene also demonstrated to be significant, although only for severe toxicity. The results found in this study did not have statistics analysis correction.Four polymorphisms of the ABCC4, FPGS, SLC29A1, and MTHFR genes are likely to be potential predictive biomarkers for precision medicine in fluoropyrimidine-based treatments in the population of the Brazilian Amazon, which is constituted by a unique genetic background.

Estimates show that 5&ndash, 10% of breast cancer cases are hereditary, caused by genetic variants in autosomal dominant genes, of these, 16% are due to germline mutations in the BRCA1 and BRCA2 genes. The comprehension of the mutation profile of these genes in the Brazilian population, particularly in Amazonian Amerindian groups, is scarce. We investigated fifteen polymorphisms in the BRCA1 and BRCA2 genes in Amazonian Amerindians and compared the results with the findings of global populations publicly available in the 1000 Genomes Project database. Our study shows that three variants (rs11571769, rs144848, and rs11571707) of the BRCA2 gene, commonly associated with hereditary breast cancer, had a significantly higher allele frequency in the Amazonian Amerindian individuals in comparison with the African, American, European, and Asian groups analyzed. These data outline the singular genetic profiles of the indigenous population from the Brazilian Amazon region. The knowledge about BRCA1 and BRCA2 variants is critical to establish public policies for hereditary breast cancer screening in Amerindian groups and populations admixed with them, such as the Brazilian population.

Marianne Rodrigues Fernandes,1,2 Juliana Carla Gomes Rodrigues,1 Olalla Maroñas,3 Ana Latorre-Pellicer,3,4 Raquel Cruz,5 João Farias Guerreiro,6 Rommel Mario Rodriguez Burbano,1,2 Paulo Pimentel de Assumpção,1 Andrea Ribeiro-dos-Santos,1,6 Sidney Emanuel Batista dos Santos,1,6 Angel Carracedo,3,5,7 Ney Pereira Carneiro dos Santos1 1Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, Brazil; 2Departamento de ensino e pesquisa, Hospital Ophir Loyola, Belém, Pará, Brazil; 3Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3), Universidade de Santiago de Compostela, Santiago de Compostela, España; 4Unidad de Genética Clínica y Genómica Funcional, Departamento de Farmacología-Fisiología, Escuela de Medicina, Universidad de Zaragoza, IIS-Aragón, E-50009 Zaragoza, España; 5Centro de Investigación Biomédica en Enfermedades Raras (CIBERER), Grupo de Medicina Genómica, CIMUS, Universidad de Santiago de Compostela, Santiago de Compostela, España; 6Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém, Pará, Brazil; 7Fundación Pública de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), Universidade de Santiago de Compostela, Santiago de Compostela, EspañaCorrespondence: Ney Pereira Carneiro dos SantosHospital Universitário João de Barros Barreto, Núcleo de Pesquisa em Oncologia, 2º Floor of the Unidade de Alta Complexidade em Oncologia. Av. Mundurucus, 4487, Guamá, Belém 66073-005, PA, BrazilTel +55 (91) 99113-9221Email npcsantos.ufpa@gmail.comIntroduction: The genetic admixture of the Brazilian population has considerable relevance to the implementation of the principles of pharmacogenomics (PGx), as it may compromise the extrapolation of data obtained in more homogeneous world populations.Purpose: This study aims to investigate a panel of 117 polymorphisms in 35 pharmacogenes, which contains label recommendations or clinical evidence by international drug regulatory agencies, in Amazonian Native American populations, and compare the results obtained with continental population data from the 1000 Genomes Project Consortium.Patients and Methods: The study population is composed of 109 Native American individuals from three Brazilian Amazon groups. The genotyping of the PGx polymorphisms was performed by allelic discrimination using TaqMan® OpenArray Genotyping with a panel of 120 customized assays on the QuantStudio™ 12K Flex Real-Time PCR System.Results: Statistical differences within the Native American populations were observed regarding both genotypes and phenotypes of some genes of the CYP family. The discriminant analysis of principal components (DAPCs) between the NAM group and the continental populations of the 1000 Genomes Project resulted in the clustering of the three Native American populations. Additionally, in general, the NAM group was determined to be closely situated between East Asia, America, and South Asia groups, which enabled us to infer a genetic similarity between these populations. The DAPC analysis further demonstrated that eight polymorphisms and six polymorphisms were more relevant in differentiating the NAM from the continental populations and the NAM populations among themselves, respectively.Conclusion: Some investigated polymorphisms show differences among world populations, particularly with populations of European origin, for whom precision medicine protocols are primarily designed. The accumulated knowledge regarding these variations may assist in the design of specific protocols for Native American populations and populations admixed with them.Keywords: Native Americans, pharmacogenomics, polymorphisms, population, genetic admixture, Brazil

Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient&rsquo, s genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population.

Acute Lymphoblastic Leukemia (ALL) is the most common type of cancer in children. Polymorphisms that alter the normal function of the microRNAs involved in the development of ALL have been widely investigated, although published data on these polymorphisms in admixed populations are scarce. We investigated the role of 10 polymorphisms in the microRNA and protein-coding genes of the microRNA synthesis complex in susceptibility to pediatric B-cell ALL. The study includes 100 pediatric ALL patients and 180 healthy individuals. The statistical analyses were run in SPSS v.25.0. In the case of the microRNA synthesizing genes, a significant pattern was found in only gene, that is, the rs3805500 polymorphism of DROSHA, in which the homozygous mutant (AA) genotype was associated with a threefold increase in the risk of developing ALL when compared to other genotypes (P=0.004, OR=2.913, CI=1.415-5.998). In the microRNA coding genes, the homozygous mutant rs3746444 genotype of the MIR499A gene was associated with a 17-fold increase in the risk of development of ALL (P

Colorectal (CRC) and gastric (GC) cancers are associated with increased morbidity and mortality. Single nucleotide polymorphisms (SNPs) of xenobiotic metabolism and transporter genes may play a role in the individual responses to exposure to substances implicated in susceptibility to cancer. The investigation of the genetic variation related to the activation and detoxification of xenobiotics may thus help to clarify the prevalence of neoplasms. We analyzed the role of 30 SNPs in xenobiotic-metabolizing and transporter genes in susceptibility to CRC and GC. The study included individuals diagnosed with CRC (n = 121) and GC (n = 95), and 141 controls (non-cancer patients) from the population of Belém, in the Brazilian Amazon. The results indicated an association between the polymorphisms rs2231142 (P = 0.013; OR = 3.01; 95% CI = 1.26-7.13), in the ABCG2 gene, and rs1801159 (P = 0.03; OR = 2.35; 95% CI = 1.14-5.05), in DPYD gene, with the risk of developing GC. The polymorphism rs17116806 of the DPYD gene was found to be associated with a lower risk of developing gastric (P≤0.0001; OR = 0.043; 95% CI = 0.015-0.12) or colorectal (P≤0.0001; OR = 0.076; 95% CI = 0.33-0.18) cancers, indicating that the same variant may play a similar role in different types of cancer tissue. Additionally, the carriers of the TT genotype of the polymorphism in the ABCB1 gene (rs1128503) presented a reduced probability of developing CRC (P = 0.0001; OR = 0.16; 95% CI = 0.06-0.41) as well as GC (P = 0.007; OR = 0.27; 95% CI = 0.1-0.7). Our findings indicate that polymorphisms in xenobiotic-metabolizing and transporter genes may modulate susceptibility to colorectal and gastric cancers.

In recent years, the incidence of tuberculosis (TB) has declined worldwide, although this disease still occurs at relatively high rates in Amerindian populations. This suggests that the genetic ancestry of Amerindians may be an important factor in the development of infections, and may account for at least some of the variation in infection rates in the different populations. The present study investigated the potential influence of Amerindian genetic ancestry on susceptibility to tuberculosis in an Amazon population. The study included 280 patients diagnosed with tuberculosis and 138 asymptomatic hospital employees with no history of TB, but who were in contact with bacterially active TB patients. Ancestry analysis was run on a set of 61 Ancestry-Informative Markers to estimate European, African, and Amerindian genetic ancestry using STRUCTURE v2.2. The TB group had significantly higher Amerindian ancestry in comparison with the control group, and significantly lower European ancestry. Amerindian ancestry in the 20-60% range was found to be the principal risk factor for increased susceptibility to TB. The results of the study indicate that Amerindian ancestry is an important risk factor for susceptibility to TB in the admixed population of the Brazilian Amazon region.

The manifestation of the COVID-19 varies from absence of symptoms to Severe Acute Respiratory Syndrome. The epidemiological data indicate that infection and mortality rates are greater in European populations in comparison with eastern Asians. To test if epidemiological patterns may be partly determined by human genetic variation, we investigated, by exomic and databank analyses, the variability found in the TMPRSS2 gene in populations from different continents, since this gene is fundamental to virus access into human cells. The functional variants revealed low diversity. The analyses of the variation in the modifiers of gene expression indicate that the European populations may have much higher levels of pulmonary expression of the TMPRSS2 gene and would be more vulnerable to infection by SARS-CoV-2. By contrast, the pulmonary expression of the TMPRSS2 may be reduced in the populations from East Asia, which implies that they are less susceptible to the virus infection and, these genetic features might also favor their better outcomes. The presented data, if confirmed, indicates a potential genetic contribution of TMPRSS2 to individual susceptibility to viral infection, and might also influence COVID-19 outcome.

Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children. Differences are found among ethnic groups in the results of the treatment of pediatric ALL. In general, children with a high level of native American ancestry tend to respond less positively to ALL treatments, which may be related to specific genomic variants found in native American groups. Despite the evidence, few data are available on the distribution of the pharmacogenomic variants relevant to the treatment of ALL in traditional Amerindian populations, such the those of the Amazon region. Given this, the present study investigated 27 molecular markers related to the treatment of ALL in Amerindians from Brazilian Amazonia and compared the frequencies with those recorded previously on five continents, that are available in the 1,000 Genomes database. The variation in the genotype frequencies among populations was evaluated using Fisher’s exact test. The False Discovery Rate method was used to correct the results of the multiple analyses. Significant differences were found in the frequencies of the majority of markers between the Amerindian populations and those of other regions around the world. These findings highlight the unique genetic profile of the indigenous population of Brazilian Amazonia, which may reflect a distinct therapeutic profile for the treatment of ALL in these populations.

IntroductionThe nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil.MethodsThe entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa® (Viewer of Variants) software.ResultsFour NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high frequencies in both our study populations in comparison with other populations catalogued in the 1000 Genomes database. We also identified the NUDT15*4 haplotype in our study populations, at frequencies similar to those reported in other populations from around the world.ConclusionOur findings indicate that Amerindian and admixed populations from northern Brazil have high frequencies of the NUDT15 haplotypes that alter the metabolism profile of thiopurines.

e15532 Background: Fluoropyrimidine-based treatments are still considered challenging due to the wide variability in efficacy and toxicity rates presented by patients. This variability can be explained, partially, by individual genetic differences that contribute significantly to the response of the drug, with 30% of patients experiencing severe toxicity related to dihydropyrimidine dehydrogenase (DPD) deficiency and 5-Fluorouracil (5-FU) metabolism. Methods: This study analyzed the exome of the main genes involved in the fluoropyrimidine metabolism pathway ( DPYD, TYMS / ENOSF1, MTHFR, CDA, CES2, and UGT1A1) in seven patient who developed fatal 5-FU toxicity diagnosed with gastric or colorectal adenocarcinoma and underwent fluoropyrimidine-based cancer treatment. The genotyping service was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. Results: A total of 74 genetic polymorphisms were identified, 25 of which stand out due to their potential role in the safety of 5-FU administration. Eight variants are exclusive of the studied population (two found in the DPYD gene, two in the MHFR, one in the CES2, and three in the UGT1A1 gene) and 17 have already been associated with fluoropyrimidine efficacy and/or toxicity events: 10 of them are located in the DPYD gene (rs1801159, rs2297595, rs72728438, rs17376848, rs1801160, rs1801265, rs22447512, rs5568, rs56038477, rs56276561, and rs56293913), two in the intergenic region of the TYMS/ ENOSF1 genes (rs11280056 and rs699517), two in the MTHFR gene (rs1801131 and rs1801133) and three in the CDA gene (rs1048977, rs2072671, and rs3215400). Conclusions: The current study has allowed us to obtain a global profile of genetic variants in the pharmacokinetic and pharmacodynamic pathways of fluoropyrimidines in patients with high genetic miscegenation in the northern region of Brazil who have evolved to death due to the fatal toxicity resulting from 5-FU-based therapies. Keywords: Pharmacogenomics; Exome; 5-Fluorouracil; Drug toxicity; Brazil.

e15082 Background: Adverse drug reactions are an important cause of morbidity and mortality commonly found in different therapeutic regimens, particularly in oncologic. About 20-30% of these reactions are due to the individual genetic variability of patients. Pharmacogenomics focuses on the identification of genetic variants that influence drug efficacy, response, and/or toxicity by changes in pharmacokinetics/pharmacodynamics. Pharmacogenomic investigations are known to have a population bias. There is a gap in the accumulated about pharmacogenomic variants in poorly studied populations, such as the Amerindian population from the Brazilian Amazon region. The objective of this work is to describe the pharmacogenetic variability regarding 160 pharmacogenes involved in pharmacokinetic processes and biological pathways of different therapies, including oncology treatments, based on data obtained through complete exome sequencing of 64 individuals from different Amerindian groups of the Brazilian Amazon. Methods: The present study was approved by the National Committee for Ethics in Research and the Research Ethics Committee of the UFPA Tropical Medicine Center, under CAAE number 20654313.6.0000.5172. All participants signed a free-informed consent. The DNA extraction was performed using phenol-chloroform. Libraries were prepared using the Nextera Rapid Capture Exome and SureSelect Human All Exon V6 kits. Bioinformatic analysis was performed by ViVa software. Results: Our results show a total of 3,311 variants found in the study subjects. Of this, 167 are exclusive variants found in the Amerindians. Among these new variants, we found a non-synonymous coding variant in the DPYD gene with an allelic frequency of 3%, and variants with high allelic frequencies in intronic regions, which may regulate gene expression: MTHFR (5.56%), TYMS (11.5%) GSTT1 (54.1%), and three variants in the CYP2D6 gene with frequencies of 54%, 62.3%, and 65.6%. The DPYD is a pivotal gene involved with the efficacy of fluoropyrimidine-based treatment; the MTHFR and TYMS genes also participate in the biological pathways of these drugs, responsible for variation in response rates. The GSTT1 is a gene associated with platinum-based treatments, such as carboplatin and cisplatin. And, finally, CYP2D6 is one of the main pharmacogene described, involved in several drug schemes, including tamoxifen and gefitinib, used to treat breast and lung cancer, respectively. Conclusions: Understanding the diversity of genetic markers in Amazonian Amerindian is crucial to the implementation of pharmacogenomic-guided oncology treatment protocols, since pharmacogenomic data validated in other ancestral groups may not be fully applicable in these populations due to their unique genetic profile. Keywords: Exome, Native American populations, fluoropyrimidine, platinum-based drugs, tamoxifen, gefitinib.

e19025 Background: The MUC family includes several genes previously associated with carcinogenesis and it is associated with solid neoplasms such as those of the gastrointestinal tract. As far as we are aware, there are no studies relating MUC genes to acute lymphoblastic leukemia (ALL), and this type of cancer is more frequent in the Amerindian population, which has been understudied. Therefore, the present work aimed to investigate the MUC family exome in Amerindian individuals from Brazilian Amazon, in a sample containing healthy Native Americans (NAM) and indigenous with ALL, comparing the frequency of polymorphisms between these two groups. Methods: The population was formed by 64 Amerindians from the Brazilian Amazon from 12 different ethnic groups, 5 of whom were diagnosed with ALL. We analyzed 16 genes from the MUC family (MUC1, MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC12, MUC13, MUC15, MUC16, MUC17, MUC19, MUC20, MUC21) and found a total of 1858 variants. Results: After the quality filter, only 743 variants remained. Among them, we compared the frequency of each polymorphism in the LLA vs NAM group, which led to 77 variants with a significant difference, and, among these, we excluded those with LOW impact, resulting in 63. The 63 polymorphisms were distributed in 9 genes, concentrated especially in MUC 19 (n = 30) and MUC 3A (n = 18). Finally, 11 new variants were found in the NAM population. Conclusions: This is the first work with a sample of native americans with cancer, a population which is susceptible to ALL, but remains understudied. The MUC family seems to have an influence on the development of ALL in the Amerindian population, and especially MUC19 and MUC3A are shown as possible hotspots. In addition, the 11 new variants found point to the need to have their clinical impact analyzed. Keywords: MUC family; ALL; Susceptibility; Native American Populations; Brazil.

e20538 Background: Lung cancer is one of the most frequent neoplasms in the world, representing 11.4% of all registered cancers, and is responsible for 18% of cancer deaths. It is divided into two categories, small cell lung cancer, responsible for 15% of cases; and non-small cell lung cancer (NSCLC), which represents 85% of cases. The most well-known risk factor for the development of lung cancer is smoking, due to substances contained in tobacco associated with inflammation and carcinogenesis. Pulmonary carcinogenesis is a complex and gradual process, with synergistic and complex interactions between environmental risk factors and individual genetic susceptibility. The aim of this study was to investigate possible associations between TP53, PAR1, and CCR5 gene polymorphism for susceptibility to NSCLC in the Amazon. Methods: This is a pilot, case-control study, which included 263 subjects, 67 patients with NSCLC and 196 healthy subjects. The samples were analyzed for TP53 (rs17880560), PAR1 (rs11267092), and CCR5 (rs333) gene polymorphism, genotyped in PCR, followed by fragment analysis. To avoid misinterpretation due to population substructure, we applied a previously developed set of 61 informative ancestral markers that were genotyped by multiplex PCR. We used logistic regression to identify differences in genotypic frequencies between individuals with and without lung cancer. Results: We observed that some genotypes were associated with protection for NSCLC: TP53 gene LED/DEL genotype (p = 0.041, OR: 0.510, 95%CI: 0.267-0.974); DEL/DEL genotype of the PAR1 gene (p = 0.023, OR: 0.471, 95%CI: 0.247-0.971); and also the INS/INS genotype of the CCR5 gene (p = 0.033, OR: 0.331, 95%CI: 0.120-0.917). Conclusions: TP53 (rs17880560), PAR1 (rs11267092) and CCR5 (rs333) gene variants were significantly associated with NSCLC in patients from the Amazon. The validation of these findings may favor, in the future, the screening of individuals, facilitating the institution of preventive measures personalized, early diagnosis, consequently reducing the cost for health services and mortality from this malignant neoplasm. Keywords: Genetic Polymorphism; TP53; PAR1; CCR5; Biomarker; Non-Small Cell Lung Cancer.

Estimates of different ancestral proportions in admixed populations are very important in population genetics studies, especially for the detection of population substructure effects in studies of case-control associations. Brazil is one of the most heterogeneous countries in the world, both from a socio-cultural and a genetic point of view. In this work, we investigated a previously developed set of 61 ancestry informative markers (AIM), aiming to estimate the proportions of four different ancestral groups (African, European, Native American and Asian) in Brazilian populations. To the best of our knowledge, this is the first study to use a set of AIM to investigate the genetic contribution of all four main parental populations to the Brazilian population, including Asian contribution. All selected markers were genotyped through multiplex PCR and capillary electrophoresis. The set was able to successfully differentiate the four ancestral populations (represented by 939 individuals) and identify their genetic contributions to the Brazilian population. In addition, it was used to estimate individual interethnic admixture of 1050 individuals from the Southeast region of Brazil and it showed that these individuals present a higher European ancestry contribution, followed by African, Asian and Native American ancestry contributions. Therefore, the 61 AIM set has proved to be a valuable tool to estimate individual and global ancestry proportions in populations mainly formed by these four groups. Our findings highlight the importance of using sets of AIM to evaluate population substructure in studies carried in admixed populations, in order to avoid misinterpretation of results.