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Bladder cancer (BC) is the second most common type of cancer of the urinary system. Approximately 75% of the cases are non-muscle invasive bladder cancer (NMIBC), which has a high recurrence and progression rate. Current diagnosis and surveillance methods present challenges, including risks to the patients. For this reason, urinary biomarkers have been proposed as alternatives to the methods. The goal of this mini-review is to describe urinary mRNA-based biomarkers available in current literature for NMIBC tumors, using the PubMed database. The search included the following keywords: "biomarkers" AND "bladder cancer" AND "urine" and "RNA" and "non-muscle". The search yielded 11 original researchers utilizing mRNA-based urinary biomarkers. Although there is a wide variety of biomarkers described, the cohorts of the studies were not exclusively NMIBC, which is the subtype of BC that would mostly benefit from the introduction of a good follow-up biomarker, highlighting the need for randomized interventional trials for NMIBC.
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Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.
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Antígenos de Neoplasias , Carcinoma Ductal Pancreático , Metilação de DNA , Proteínas Ligadas por GPI , Predisposição Genética para Doença , Desequilíbrio de Ligação , Proteínas de Neoplasias , Neoplasias Pancreáticas , Polimorfismo de Nucleotídeo Único , Humanos , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Masculino , Proteínas Ligadas por GPI/genética , Antígenos de Neoplasias/genética , Proteínas de Neoplasias/genética , Estudos de Casos e Controles , População Branca/genética , Feminino , Locos de Características Quantitativas , Alelos , Povo Asiático/genética , Pessoa de Meia-IdadeRESUMO
Chronic myeloid leukemia (CML) is a type of leukemia whose main genetic marker is the reciprocal translocation that leads to the production of the BCR::ABL1 oncoprotein. The expression of some genes may interfere with the progression and development of leukemias. MicroRNAs are small non-coding RNAs that have the potential to alter the expression of some genes and may be correlated with some types of leukemia and could be used as biomarkers in the diagnosis and prognosis of patients. Therefore, this project carried out an analysis of microRNA-type plasma biomarkers in patients with chronic myeloid leukemia at unique points, including follow-up analysis of patients from the Erasto Gaertner Hospital. 35 microRNAs were analyzed in different cohorts. Inside those groups, 70 samples were analyzed at unique points and 11 patients in a follow-up analysis. Statistically different results were found for microRNA-7-5p, which was found to be upregulated in patients with high expression of the BCR::ABL1 transcript when compared to healthy controls. This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , MicroRNAs , Humanos , MicroRNAs/genética , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Translocação Genética , BiomarcadoresRESUMO
BACKGROUND: The median age for Prostate Cancer (PCa) diagnosis is 66 years, but 10% are diagnosed before 55 years. Studies on early-onset PCa remain both limited and controversial. This investigation sought to identify and characterize germline variants within Brazilian PCa patients classified as either early or later onset disease. METHODS: Peripheral blood DNA from 71 PCa patients: 18 younger (≤ 55 years) and 53 older (≥ 60 years) was used for Targeted DNA sequencing of 20 genes linked to DNA damage response, transcriptional regulation, cell cycle, and epigenetic control. Subsequent genetic variant identification was performed and variant functional impacts were analyzed with in silico prediction. RESULTS: A higher frequency of variants in the BRCA2 and KMT2C genes across both age groups. KMT2C has been linked to the epigenetic dysregulation observed during disease progression in PCa. We present the first instance of KMT2C mutation within the blood of Brazilian PCa patients. Furthermore, out of the recognized variants within the KMT2C gene, 7 were designated as deleterious. Thirteen deleterious variants were exclusively detected in the younger group, while the older group exhibited 37 variants. Within these findings, 4 novel variants emerged, including 1 designated as pathogenic. CONCLUSIONS: Our findings contribute to a deeper understanding of the genetic factors associated with PCa susceptibility in different age groups, especially among the Brazilian population. This is the first investigation to explore germline variants specifically in younger Brazilian PCa patients, with high relevance given the genetic diversity of the population in Brazil. Additionally, our work presents evidence of functionally deleterious germline variants within the KMT2C gene among Brazilian PCa patients. The identification of novel and functionally significant variants in the KMT2C gene emphasizes its potential role in PCa development and warrants further investigation.
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Neoplasias da Próstata , Masculino , Humanos , Idoso , Brasil , Neoplasias da Próstata/patologia , Mutação em Linhagem Germinativa , Mutação , Células Germinativas/patologia , Predisposição Genética para DoençaRESUMO
Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (Pâ =â 2.46â ×â 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (Pâ =â 1.53â ×â 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudos de Casos e Controles , Genoma Humano , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , DNA , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.
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Carcinoma Ductal Pancreático , Diabetes Mellitus Tipo 2 , Homem de Neandertal , Neoplasias Pancreáticas , Humanos , Animais , Homem de Neandertal/genética , Polimorfismo de Nucleotídeo Único , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genéticaRESUMO
Chronic myeloid leukemia (CML) is a well-characterized oncological disease in which virtually all patients possess a translocation (9;22) that generates the tyrosine kinase BCR::ABL1 protein. This translocation represents one of the milestones in molecular oncology in terms of both diagnostic and prognostic evaluations. The molecular detection of the BCR::ABL1 transcription is a required factor for CML diagnosis, and its molecular quantification is essential for assessing treatment options and clinical approaches. In the CML molecular context, point mutations on the ABL1 gene are also a challenge for clinical guidelines because several mutations are responsible for tyrosine kinase inhibitor resistance, indicating that a change may be necessary in the treatment protocol. So far, the European LeukemiaNet and the National Comprehensive Cancer Network (NCCN) have presented international guidelines on CML molecular approaches, especially those related to BCR::ABL1 expression. In this study, we show almost three years' worth of data regarding the clinical treatment of CML patients at the Erasto Gaertner Hospital, Curitiba, Brazil. These data primarily comprise 155 patients and 532 clinical samples. BCR::ABL1 quantification by a duplex-one-step RT-qPCR and ABL1 mutations detection were conducted. Furthermore, digital PCR for both BCR::ABL1 expression and ABL1 mutations were conducted in a sub-cohort. This manuscript describes and discusses the clinical importance and relevance of molecular biology testing in Brazilian CML patients, demonstrating its cost-effectiveness.
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Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Brasil , Proteínas de Fusão bcr-abl/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Translocação GenéticaRESUMO
Long noncoding RNAs (lncRNAs) are a class of non-coding RNAs that contain more than 200 nucleotides and exhibit a versatile regulatory capacity. Genomic alterations in lncRNAs have already been investigated in several complex diseases, including breast cancer (BC). BC is a highly heterogeneous disease and is the most prevalent cancer type among women worldwide. Single nucleotide polymorphisms (SNPs) in lncRNA regions appear to have an important role in BC susceptibility; however, little is known about lncRNA-SNPs in the Brazilian population. This study used Brazilian tumor samples to identify lncRNA-SNPs with a biological role in BC development. We applied a bioinformatic approach intersecting lncRNAs that are differentially expressed in BC tumor samples using The Cancer Genome Atlas (TCGA) cohort data and looked for lncRNAs with SNPs associated with BC in the Genome Wide Association Studies (GWAS) catalog. We highlight four lncRNA-SNPs-rs3803662, rs4415084, rs4784227, and rs7716600-which were genotyped in Brazilian BC samples in a case-control study. The SNPs rs4415084 and rs7716600 were associated with BC development at higher risk. These SNPs were also associated with progesterone status and lymph node status, respectively. The rs3803662/rs4784227 haplotype GT was associated with BC risk. These genomic alterations were also evaluated in light of the lncRNA's secondary structure and gain/loss of miRNA binding sites to better understand its biological functions. We emphasize that our bioinformatics approach could find lncRNA-SNPs with a potential biological role in BC development and that lncRNA-SNPs should be more deeply investigated in a highly heterogeneous disease population.
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Neoplasias da Mama , RNA Longo não Codificante , Humanos , Feminino , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Estudos de Casos e Controles , BrasilRESUMO
A lack of reliable early diagnostic tools represents a major challenge in the management of pancreatic cancer (PCa), as the disease is often only identified after it reaches an advanced stage. This highlights the urgent need to identify biomarkers that can be used for the early detection, staging, treatment monitoring, and prognosis of PCa. A novel approach called liquid biopsy has emerged in recent years, which is a less- or non-invasive procedure since it focuses on plasmatic biomarkers such as DNA and RNA. In the blood of patients with cancer, circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) have been identified such as DNA, mRNA, and non-coding RNA (miRNA and lncRNA). The presence of these molecules encouraged researchers to investigate their potential as biomarkers. In this article, we focused on circulating cfNAs as plasmatic biomarkers of PCa and analyzed their advantages compared to traditional biopsy methods.
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Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/genética , Fatores de Risco , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Early-onset pancreatic cancer (EOPC) represents 5-10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. METHODS: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. RESULTS: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69-5.04, P = 1.44 × 10-4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41-65.50, P = 3.58 × 10-4). CONCLUSION: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.
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Carcinoma Ductal Pancreático , Diabetes Mellitus Tipo 2 , Neoplasias Pancreáticas , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Estudo de Associação Genômica Ampla , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Fatores de Risco , Neoplasias PancreáticasRESUMO
Growing evidence suggests that metavirome changes could be associated increased risk for malignant cell transformation. Considering Viruses have been proposed as factors for prostate cancer induction. The objective of this study was to examine the composition of the plasma metavirome of patients with prostate cancer. Blood samples were obtained from 49 male patients with primary prostate adenocarcinoma. Thirty blood donors were included as a control group. The obtained next-generation sequencing data were analyzed using a bioinformatic pipeline for virus metagenomics. Viral reads with higher abundance were assembled in contigs and analyzed taxonomically. Viral agents of interest were also confirmed by qPCR. Anelloviruses and the Human Pegivirus-1 (HPgV-1) were the most abundant component of plasma metavirome. Clinically important viruses like hepatitis C virus (HCV), cytomegalovirus and human adenovirus type C were also identified. In comparison, the blood donor virome was exclusively composed of torque teno virus types (TTV) types. The performed HPgV-1 and HCV phylogeny revealed that these viruses belong to commonly detected in Brazil genotypes. Our study sheds light on the plasma viral abundance in patients with prostatic cancer. The obtained viral diversity allowed us to separate the patients and controls, probably suggesting that malignant processes may influence virome composition. More complex and multiple approach investigations are necessary to examine the likely causal relationship between metavirome and its nvolvement in prostate cancer.
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The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10-5) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Feminino , Humanos , Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Estrogênios/genética , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Pregnenolona , Neoplasias PancreáticasRESUMO
Seroconversion rates were compared between oncological and nononcological patients infected with SARS-CoV-2 during a 14-day hospitalization time. All COVID-19 non-oncological and solid malignancies patients reached 100% seroconversion at day 14, while less than half of the hematological patients were seroconverted at the same time point. Despite the limited number and variability of the patient's cohort, we conclude that there is a delayed seroconversion in the hematological malignancies group, which may be linked to changes in the hematological parameters, immune suppression and/or oncological treatments that are typically associated with these patients.
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COVID-19 , Neoplasias , Anticorpos Antivirais , Humanos , Imunidade , SARS-CoV-2RESUMO
Pancreatic cancer represents one of the leading causes of oncological death worldwide. A combination of pancreatic cancer aggressiveness and late diagnosis are key factors leading to a low survival rate and treatment inefficiency, and early diagnosis is pursued as a critical factor for pancreatic cancer. In this context, plasma microRNAs are emerging as promising players due to their non-invasive and practical usage in oncological diagnosis and prognosis. Recent studies have showed some miRNAs associated with pancreatic cancer subtypes, or with stages of the disease. Here we demonstrate plasma exosome-derived microRNA expression in pancreatic cancer patients and healthy individuals from Brazilian patients. Using plasma of 65 pancreatic cancer patients and 78 healthy controls, plasma exosomes were isolated and miRNAs miR-27b, miR-125b-3p, miR-122-5p, miR-21-5p, miR-221-3p, miR-19b, and miR-205-5p were quantified by RT-qPCR. We found that miR-125b-3p, miR-122-5p, and miR-205-5p were statistically overexpressed in the plasma exosomes of pancreatic cancer patients compared to healthy controls. Moreover, miR-205-5p was significantly overexpressed in European descendants, in patients with tumor progression and in those who died from the disease, and diagnostic ability by ROC curve was 0.86. Therefore, we demonstrate that these three microRNAs are potential plasma exosome-derived non-invasive biomarkers for the diagnosis and prognosis of Brazilian pancreatic cancer, demonstrating the importance of different populations and epidemiological bias.
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Exossomos , MicroRNAs , Neoplasias Pancreáticas , Biomarcadores/metabolismo , Biomarcadores Tumorais/metabolismo , Brasil , Detecção Precoce de Câncer , Exossomos/genética , Exossomos/metabolismo , Humanos , MicroRNAs/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Prognóstico , Neoplasias PancreáticasRESUMO
The detection of BCR-ABL1 mRNA transcripts is essential to molecular chronic myeloid leukemia (CML) diagnosis. In most cases, the RT-qPCR technique is performed as the gold standard diagnosis tool for clinical cases. However, this method requires expensive reagents and equipment, such as a real-time thermal cycler, probes and master mix. Consequently, the development and validation of simple and low-cost methods are essential for a rapid CML diagnosis in less specialized and equipped centers. In this study, we develop and demonstrate an accessible, rapid, and low-cost method using RT-LAMP for BCR-ABL1 detection in both cell lines and CML clinical samples, using fluorescent and colorimetric assays. Both methods demonstrated diagnostic specificity of 100% and while diagnostic sensitivity reaches more than 90% in samples with RT-qPCR cycle threshold above 31. The obtained data indicates that the proposed method here described is robust, specific and rapid approach for CML diagnosis with outstanding performance, especially for CML diagnostic procedure where present high BCR-ABL1 expression.
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Colorimetria , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Técnicas de Diagnóstico Molecular , Técnicas de Amplificação de Ácido Nucleico , Linhagem Celular Tumoral , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espectrometria de FluorescênciaRESUMO
Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10-5) compared with the additive effects (p>10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.
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Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, p = 3.03 × 10-6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.
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BACKGROUND: Pancreatic adenocarcinoma (PA) is a very aggressive cancer and has one of the poorest prognoses. Usually, the diagnosis is late and resistant to conventional treatment. Environmental and genetic factors contribute to the etiology, such as tobacco and alcohol consumption, chronic pancreatitis, diabetes and obesity. Somatic mutation in pancreatic cancer cells are known and SNP profile by GWAS could access novel genetic risk factors for this disease in different population context. Here we describe a SNP panel for Brazilian pancreatic cancer, together with clinical and epidemiological data. METHODS: 78 pancreatic adenocarcinoma and 256 non-pancreatic cancer subjects had 25 SNPs genotyped by real-time PCR. Unconditional logistic regression methods were used to assess the main effects on PA risk, using allelic, co-dominant and dominant inheritance models. RESULTS: 9 SNPs were nominally associated with pancreatic adenocarcinoma risk, with 5 of the minor alleles conferring protective effect while 4 related as risk factor. In epidemiological and clinical data, tobacco smoking, diabetes and pancreatitis history were significantly related to pancreatic adenocarcinoma risk. Polygenic risk scores computed using the SNPs in the study showed strong associations with PA risk. CONCLUSION: We could assess for the first time some SNPs related with PA in Brazilian populations, a result that could be used for genetic screening in risk population such as familial pancreatic cancer, smokers, alcohol users and diabetes patients.