Characterization of PCLO Gene in Amazonian Native American Populations.

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.

Polymorphisms of xenobiotic-metabolizing and transporter genes, and the risk of gastric and colorectal cancer in an admixed population from the Brazilian Amazon.

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.

Characterization of pharmacogenetic markers related to Acute Lymphoblastic Leukemia toxicity in Amazonian native Americans population.

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.

Influence of variants of the drosha, mir499a, and mir938 genes on susceptibility to acute lymphoblastic leukemia in an admixed population from the brazilian amazon.

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<0.001, OR=17.797, CI=5.55-57.016). A protective effect against the development of ALL was also observed in the carriers of the wild homozygous rs2505901 genotype in the MIR938 gene. Our findings highlight the potential of these polymorphisms in the genes involving in the coding of microRNAs for the evaluation of the risk of contracting ALL in the population of the Brazilian Amazon region. These findings contribute to a more complete understanding of the complex etiology of ALL.

Pharmacogenomics and variations in the risk of toxicity during the consolidation/maintenance phases of the treatment of pediatric B-cell leukemia patients from an admixed population in the Brazilian Amazon.

The treatment of Acute Lymphoblastic Leukemia (ALL) in children has a high clinical success rate, although toxicological complications are frequent, and often result in the interruption of the treatment. Various studies have shown that toxicities resulting from the treatment are influenced by pharmacogenetic variants. Most of this research has focused on relatively homogeneous populations, and the influence of these variants in highly admixed populations, such as that of Brazil, is still poorly understood. The present study investigated the association between pharmacogenetic variants and severe toxicities in pediatric B-cell ALL patients from an admixed population of the Brazilian Amazon. The rs2306283 (of SLCO1B1) mutant allele increased the risk of neurotoxicity threefold, and the homozygous mutant rs9895420 (of ABCC3) genotype was associated with a fivefold increase in protection against severe gastrointestinal toxicity. This indicates that the rs2306283 and rs9895420 polymorphisms may be relevant to the prediction of severe toxicity in pediatric ALL patients.

Correction to: Effect of genetic ancestry to the risk of susceptibility to gastric cancer in a mixed population of the Brazilian Amazon.

Following publication of the original article [1], the authors requested a correction to the name of one of the co-authors. The correct name Marianne Rodrigues Fernandes, not Marianne Fernandes Rodrigues.

Effect of genetic ancestry to the risk of susceptibility to gastric cancer in a mixed population of the Brazilian Amazon.

BACKGROUND: Global literature describes differences in the incidence of gastric cancer among populations. For instance, Europeans have lower incidence rates of gastric cancer in relation to Latin and Asian populations, particularly Korean and Japanese populations. However, only a few studies have been able to verify the occurrence of gastric cancer in admixed populations with high interethnic degree mix, such as the Brazilian Amazon region. RESULTS: We observed an increase in European ancestry in the control group compared to the case group (47% vs. 41%). Using increments of 10%, compared to categorical distribution of European ancestry in the sample, we found a difference in the contribution between cases and controls (p = 0.03). Multiple logistic regression was performed to determine the influence of European ancestry in susceptibility to gastric cancer in the sample. According to the adopted model, for each 10% increase in European ancestry, there is a 20% decrease chance of developing gastric cancer (P = 0.0121; OR = 0.81; 95% CI 0.54-0.83). CONCLUSION: Overall, the results suggest that a greater contribution of European ancestry can be a protective factor for the development of gastric cancer in the studied Amazon population. It can help to establish protocols able to predict susceptibility to gastric cancer in admixed populations.

Investigation of Potentially Deleterious Alleles for Response to Cancer Treatment with 5-Fluorouracil.

AIM: To investigate polymorphisms that are probable indicators of response variability during cancer treatment with 5-fluorouracil (rs16430, rs2279198, rs1801159 and rs17878362). MATERIALS AND METHODS: We investigated 1,038 individuals regarding allele distribution from different populations, out of which we genotyped 127 individuals from a Brazilian admixed population. Similarity analyses with parental populations were performed. Prevalence of potentially deleterious alleles was also evaluated. RESULTS: Thirty-seven percent of the population had at least three potentially deleterious alleles and 38.6% had at least one potentially deleterious allele in homozygosis. CONCLUSION: Potentially deleterious alleles are present under diverse frequencies in different populations. Therefore, genotyping prior to 5-fluorouracil administration should be recommended.

Association of slow acetylation profile of NAT2 with breast and gastric cancer risk in Brazil.

BACKGROUND: The N-acetyltransferase 2 (NAT2) gene is a marker for the study of interindividual susceptibility to developing neoplasias. The purpose of this study was to verify a possible association between single nucleotide polymomorphisms (SNPs) of NAT2 and the susceptibility to gastric cancer (GC) and breast cancer (BC) in patients from the North region of Brazil. MATERIALS AND METHODS: Five SNPs of the NAT2 gene were investigated by direct sequencing. Ancestry was estimated by analysis of a panel with 48 ancestry-informative markers (AIM). RESULTS: Individuals with slow acetylation profile had an increased risk of developing neoplasias up to three times when compared to controls. CONCLUSION: In this study, slow acetylation profile was found to strongly influence susceptibility to GC and BC.