Publications by authors named "Patricia Ashton-Prolla"

127 Publications

Functional Polymorphisms in the p53 Pathway Genes on the Genetic Susceptibility to Zika Virus Teratogenesis.

Front Cell Infect Microbiol 2021 7;11:641413. Epub 2021 Jul 7.

Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

Congenital Zika Syndrome (CZS) occurs in up to 42% of individuals exposed to ZIKV prenatally. Deregulation in gene expression and protein levels of components of the p53 signaling pathway, such as p53 and MDM2, due to ZIKV infection has been reported. Here, we evaluate functional polymorphisms in genes of the p53 signaling pathway as risk factors to CZS. Forty children born with CZS and forty-eight children exposed to ZIKV, but born without congenital anomalies were included in this study. Gestational and sociodemographic information as well as the genotypic and allelic frequencies of functional polymorphisms in and genes were compared between the two groups. We found children with CZS exposed predominantly in the first trimester and controls in the third trimester (p<0.001). Moreover, children with CZS were predominantly from families with a lower socioeconomic level (p=0.008). We did not find a statistically significant association between the investigated polymorphisms and development of CZS; however, by comparing individuals with CZS and lissencephaly or without lissencephaly, we found a significative difference in the allelic frequencies of the rs1042522, which is associated with a more potent p53-induced apoptosis (p=0.007). Our findings suggest that the rs1042522 polymorphism should be better investigate as a genetic risk factor for the development of lissencephaly in children with CZS.
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http://dx.doi.org/10.3389/fcimb.2021.641413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294037PMC
July 2021

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of oesophageal cancer.

Ecancermedicalscience 2021 2;15:1195. Epub 2021 Mar 2.

Grupo Oncologia D'Or, 04535-110 São Paulo, Brazil.

Oesophageal cancer is among the ten most common types of cancer worldwide. More than 80% of the cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of oesophageal and oesophagogastric junction (OGJ) carcinomas. The Brazilian Group of Gastrointestinal Tumours invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy (including checkpoint inhibitors) and follow-up, which was followed by presentation, discussion and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of oesophageal and OGJ carcinomas in several scenarios and clinical settings.
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http://dx.doi.org/10.3332/ecancer.2021.1195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043684PMC
March 2021

The paradox of autophagy in Tuberous Sclerosis Complex.

Genet Mol Biol 2021 5;44(2):e20200014. Epub 2021 Apr 5.

Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Pesquisa Experimental, Laboratório de Medicina Genômica, Porto Alegre, RS, Brazil.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by germline mutations in TSC1 or TSC2 genes, which leads to the hyperactivation of the mTORC1 pathway, an important negative regulator of autophagy. This leads to the development of hamartomas in multiple organs. The variability in symptoms presents a challenge for the development of completely effective treatments for TSC. One option is the treatment with mTORC1 inhibitors, which are targeted to block cell growth and restore autophagy. However, the therapeutic effect of rapamycin seems to be more efficient in the early stages of hamartoma development, an effect that seems to be associated with the paradoxical role of autophagy in tumor establishment. Under normal conditions, autophagy is directly inhibited by mTORC1. In situations of bioenergetics stress, mTORC1 releases the Ulk1 complex and initiates the autophagy process. In this way, autophagy promotes the survival of established tumors by supplying metabolic precursors during nutrient deprivation; paradoxically, excessive autophagy has been associated with cell death in some situations. In spite of its paradoxical role, autophagy is an alternative therapeutic strategy that could be explored in TSC. This review compiles the findings related to autophagy and the new therapeutic strategies targeting this pathway in TSC.
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http://dx.doi.org/10.1590/1678-4685-GMB-2020-0014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022228PMC
April 2021

Prevalence of the Brazilian Founder c.1010G>A (p.Arg337His) in Lung Adenocarcinoma: Is Genotyping Warranted in All Brazilian Patients?

Front Genet 2021 2;12:606537. Epub 2021 Feb 2.

Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

In Southern and Southeastern Brazil, there is a germline pathogenic variant with incomplete penetrance located in the oligomerization domain of , c.1010G>A (p.Arg337His). Due to a founder effect, the variant is present in 0.3% of the general population of the region. Recently, this variant was identified in 4.4 and 8.9% of two apparently unselected, single center case series of Brazilian lung adenocarcinoma (LUAD) patients from the Southeastern and Central regions of the country, respectively. In the present study, our aim was to examine c.1010G>A allele and genotype frequencies in LUAD samples obtained from patients diagnosed in Southern Brazil. A total of 586 LUAD samples (tumor DNA) recruited from multiple centers in the region were tested, and the mutant allele was identified using TaqMan assays in seven cases (7/586, 1.2%) which were submitted to next generation sequencing analyses for confirmation. Somatic mutations were more frequent in c.1010G>A carriers than in non-carriers (57.1 vs. 17.6%, respectively). Further studies are needed to confirm if c.1010G>A is a driver in LUAD carcinogenesis and to verify if there is a combined effect of and germline c.1010G>A. Although variant frequency was higher than observed in the general population, it is less than previously reported in LUAD patients from other Brazilian regions. Additional data, producing regional allele frequency information in larger series of patients and including cost-effectiveness analyses, are necessary to determine if c.1010G>A screening in all Brazilian LUAD patients is justified.
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http://dx.doi.org/10.3389/fgene.2021.606537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885268PMC
February 2021

Tuberous Sclerosis Complex with rare associated findings in the gastrointestinal system: a case report and review of the literature.

BMC Gastroenterol 2020 Nov 23;20(1):394. Epub 2020 Nov 23.

Laboratório de Medicina Genômica - Centro de Pesquisa Experimental - Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil.

Background: Tuberous Sclerosis Complex (TSC) is a complex and heterogeneous genetic disease that has well-established clinical diagnostic criteria. These criteria do not include gastrointestinal tumors.

Case Presentation: We report a 45-year-old patient with a clinical and molecular diagnosis of TSC and a family history of cancer, presenting two rare associated findings: gastrointestinal polyposis and pancreatic neuroendocrine tumor. This patient was subjected to a genetic test with 80 cancer predisposing genes. The genetic panel revealed the presence of a large pathogenic deletion in the TSC2 gene, covering exons 2 to 16 and including the initiation codon. No changes were identified in the colorectal cancer and colorectal polyposis genes.

Discussion And Conclusions: We describe a case of TSC that presented tumors of the gastro intestinal tract that are commonly unrelated to the disease. The patient described here emphasizes the importance of considering polyposis of the gastrointestinal tract and low grade neuroendocrine tumor as part of the TSC syndromic phenotype.
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http://dx.doi.org/10.1186/s12876-020-01481-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682061PMC
November 2020

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of gastric cancer.

Ecancermedicalscience 2020 20;14:1126. Epub 2020 Oct 20.

Hospital Sírio Libanês, Brazil, 01308-050.

Gastric cancer is among the ten most common types of cancer worldwide. Most cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of gastric carcinomas. The Brazilian Group of Gastrointestinal Tumors (GTG) invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy and follow-up, which was followed by presentation, discussion, and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of gastric carcinomas in several scenarios and clinical settings.
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http://dx.doi.org/10.3332/ecancer.2020.1126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652540PMC
October 2020

Skin pigmentation polymorphisms associated with increased risk of melanoma in a case-control sample from southern Brazil.

BMC Cancer 2020 Nov 9;20(1):1069. Epub 2020 Nov 9.

Serviço de Pesquisa Experimental, Laboratório de Medicina Genômica, Hospital de Clínicas de Porto Alegre (HCPA), Rua Ramiro Barcelos, Porto Alegre, Rio Grande do Sul, 2350, Brazil.

Background: Melanoma is the most aggressive type of skin cancer and is associated with environmental and genetic risk factors. It originates in melanocytes, the pigment-producing cells. Single nucleotide polymorphisms (SNPs) in pigmentation genes have been described in melanoma risk modulation, but knowledge in the field is still limited.

Methods: In a case-control approach (107 cases and 119 controls), we investigated the effect of four pigmentation gene SNPs (TYR rs1126809, HERC2 rs1129038, SLC24A5 rs1426654, and SLC45A2 rs16891982) on melanoma risk in individuals from southern Brazil using a multivariate logistic regression model and multifactor dimensionality reduction (MDR) analysis.

Results: Two SNPs were associated with an increased risk of melanoma in a dominant model: rs1129038AA and rs1426654AA [OR = 2.094 (95% CI: 1.106-3.966), P = 2.3 10 and OR = 7.126 (95% CI: 1.873-27.110), P = 4.0 10, respectively]. SNP rs16891982CC was associated with a lower risk to melanoma development in a log-additive model when the allele C was inherited [OR = 0.081 (95% CI: 0.008-0.782), P = 3 10]. In addition, MDR analysis showed that the combination of the rs1426654AA and rs16891982GG genotypes was associated with a higher risk for melanoma (P = 3 10), with a redundant effect.

Conclusions: These results contribute to the current knowledge and indicate that epistatic interaction of these SNPs, with an additive or correlational effect, may be involved in modulating the risk of melanoma in individuals from a geographic region with a high incidence of the disease.
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http://dx.doi.org/10.1186/s12885-020-07485-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650158PMC
November 2020

Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia.

Breast Cancer Res 2020 10 21;22(1):108. Epub 2020 Oct 21.

Pontificia Universidad Católica de Chile, Santiago, Chile.

Background: The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry.

Methods: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia.

Results: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period.

Conclusions: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening.
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http://dx.doi.org/10.1186/s13058-020-01341-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579869PMC
October 2020

Pooling of samples to optimize SARS-CoV-2 diagnosis by RT-qPCR: comparative analysis of two protocols.

Eur J Clin Microbiol Infect Dis 2021 Apr 16;40(4):889-892. Epub 2020 Oct 16.

LABRESIS- Laboratório de Pesquisa em Resistência Bacteriana, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.

This study has aimed to evaluate the use pool of samples as a strategy to optimize the diagnostic of SARS-CoV-2 by RT-qPCR. A total of 220 naso/orofaryngeal swab samples were collected and tested using two different protocols of sample pooling. Results from protocol A were identical with the individual results. However, for results from protocol B, reduced agreement (91%) was observed in relation to individual testing. Inconsistencies observed were related to RT-qPCR results with higher cycle thresholds. These results suggest that pooling of samples before RNA extraction is preferable in terms of diagnostic for SARS-CoV-2.
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http://dx.doi.org/10.1007/s10096-020-04071-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561432PMC
April 2021

The role of genomics in global cancer prevention.

Nat Rev Clin Oncol 2021 02 24;18(2):116-128. Epub 2020 Sep 24.

International Agency for Research on Cancer, Lyon, France.

Despite improvements in the understanding of cancer causation, much remains unknown regarding the mechanisms by which genomic and non-genomic factors initiate carcinogenesis, drive cell invasion and metastasis, and enable cancer to develop. Technological advances have enabled the analysis of whole genomes, comprising thousands of tumours across populations worldwide, with the aim of identifying mutation signatures associated with particular tumour types. Large collaborative efforts have resulted in the identification and improved understanding of causal factors, and have shed light on new opportunities to prevent cancer. In this new era in cancer genomics, discoveries from studies conducted on an international scale can inform evidence-based strategies in cancer control along the cancer care continuum, from prevention to treatment. In this Review, we present the relevant history and emerging frontiers of cancer genetics and genomics from the perspective of global cancer prevention. We highlight the importance of local context in the adoption of new technologies and emergent evidence, with illustrative examples from worldwide. We emphasize the challenges in implementing important genomic findings in clinical settings with disparate resource availability and present a conceptual framework for the translation of such findings into clinical practice, and evidence-based policies in order to maximize the utility for a population.
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http://dx.doi.org/10.1038/s41571-020-0428-5DOI Listing
February 2021

Systems Biology Approaches Reveal Potential Phenotype-Modifier Genes in Neurofibromatosis Type 1.

Cancers (Basel) 2020 Aug 26;12(9). Epub 2020 Aug 26.

Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-007, Rio Grande do Sul, Brazil.

Neurofibromatosis type (NF1) is a syndrome characterized by varied symptoms, ranging from mild to more aggressive phenotypes. The variation is not explained only by genetic and epigenetic changes in the gene and the concept of phenotype-modifier genes in extensively discussed in an attempt to explain this variability. Many datasets and tools are already available to explore the relationship between genetic variation and disease, including systems biology and expression data. To suggest potential NF1 modifier genes, we selected proteins related to NF1 phenotype and gene ontologies. Protein-protein interaction (PPI) networks were assembled, and network statistics were obtained by using forward and reverse genetics strategies. We also evaluated the heterogeneous networks comprising the phenotype ontologies selected, gene expression data, and the PPI network. Finally, the hypothesized phenotype-modifier genes were verified by a random-walk mathematical model. The network statistics analyses combined with the forward and reverse genetics strategies, and the assembly of heterogeneous networks, resulted in ten potential phenotype-modifier genes: , and . Mathematical models using the random-walk approach suggested and as the main candidate genes for phenotype-modifiers.
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http://dx.doi.org/10.3390/cancers12092416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565824PMC
August 2020

XAF1 as a modifier of p53 function and cancer susceptibility.

Sci Adv 2020 Jun 24;6(26):eaba3231. Epub 2020 Jun 24.

School of Medicine, University of Sao Paulo, Sao Paulo, SP, Brazil.

Cancer risk is highly variable in carriers of the common R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma ( = 0.003) and subsequent malignancies ( = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic variants, whereas -E134* is markedly attenuated in this activity. We propose that cosegregation of E134* and R337H mutations leads to a more aggressive cancer phenotype than R337H alone, with implications for genetic counseling and clinical management of hypomorphic mutant carriers.
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http://dx.doi.org/10.1126/sciadv.aba3231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314530PMC
June 2020

Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact.

Cancers (Basel) 2020 Jun 30;12(7). Epub 2020 Jun 30.

Programa de Carcinogênese Molecular, Instituto Nacional de Câncer, Rio de Janeiro 20231-050, Brazil.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality rates. PDAC initiation and progression are promoted by genetic and epigenetic dysregulation. Here, we aimed to characterize the PDAC DNA methylome in search of novel altered pathways associated with tumor development. We examined the genome-wide DNA methylation profile of PDAC in an exploratory cohort including the comparative analyses of tumoral and non-tumoral pancreatic tissues (PT). Pathway enrichment analysis was used to choose differentially methylated (DM) CpGs with potential biological relevance. Additional samples were used in a validation cohort. DNA methylation impact on gene expression and its association with overall survival (OS) was investigated from PDAC TCGA (The Cancer Genome Atlas) data. Pathway analysis revealed DM genes in the calcium signaling pathway that is linked to the key pathways in pancreatic carcinogenesis. DNA methylation was frequently correlated with expression, and a subgroup of calcium signaling genes was associated with OS, reinforcing its probable phenotypic effect. Cluster analysis of PT samples revealed that some of the methylation alterations observed in the Calcium signaling pathway seemed to occur early in the carcinogenesis process, a finding that may open new insights about PDAC tumor biology.
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http://dx.doi.org/10.3390/cancers12071735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407273PMC
June 2020

Haplotypic characterization of BRCA1 c.5266dupC, the prevailing mutation in Brazilian hereditary breast/ovarian cancer.

Genet Mol Biol 2020 20;43(2):e20190072. Epub 2020 May 20.

Instituto Nacional de Câncer, Programa de Genética, Rio de Janeiro, RJ, Brazil.

Specific pathogenic mutations associated with breast cancer development can vary between ethnical groups. One example is BRCA1 c.5266dupC that was first described as a founder mutation in the Ashkenazi Jewish population, but was later also found in other populations. In Brazil, this mutation corresponds to 20% of pathogenic BRCA1 variants reported. Our objective was to investigate the haplotype component of a group of Brazilian families who inherited c.5266dupC in the BRCA1 gene and to verify the ancestry contribution from European, African, and Amerindian origins. Fourteen probands carrying c.5266dupC and 16 relatives (carriers and non-carriers) were investigated. The same haplotype was observed segregating within all the families analyzed, revealing no recombinants in a region of 0.68 Mb. Ancestry analysis demonstrated that the European component was predominant among probands. The BRCA1 c.5266dupC analysis indicates that there was a founder effect in the Brazilian population.
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http://dx.doi.org/10.1590//1678-4685-GMB-2019-0072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250276PMC
May 2020

Synchronous Periampullary Tumors in a Patient With Pancreas Divisum and Neurofibromatosis Type 1.

Front Genet 2020 28;11:395. Epub 2020 Apr 28.

Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

Introduction: In this study, we describe for the first time a Neurofibromatosis type 1 patient with pancreas divisum, multiple periampullary tumors and germline pathogenic variants in and genes.

Case Report: A 62-year-old female NF1 patient presented with weakness, choluria, nausea, and diffuse abdominal pain to an emergency room service. Magnetic resonance imaging revealed an abdominal mass involving the periampullary region and pancreas divisum. After surgical resection, three synchronous neoplasms were detected including two ampullary tumors (adenocarcinoma of the major ampulla and a neuroendocrine tumor of the minor ampulla) and a gastrointestinal stromal tumor (GIST). Germline multigene panel testing (MGPT) identified two pathogenic heterozygous germline variants: c.838del and c.1210-34TG[12]T[5].

Conclusion: This is the first report of a Neurofibromatosis type 1 patient with pancreas divisum and multiple periampullary tumors harboring pathogenic germline variants in and genes. The identification of two germline variants and a developmental anomaly in this patient may explain the unusual and more severe findings and underscores the importance of comprehensive molecular analyses in patients with complex phenotypes.
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http://dx.doi.org/10.3389/fgene.2020.00395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212385PMC
April 2020

Cancer-related worry and risk perception in Brazilian individuals seeking genetic counseling for hereditary breast cancer.

Genet Mol Biol 2020 22;43(2):e20190097. Epub 2020 Apr 22.

Universidade Federal do Rio Grande do Sul, Departamento de Genética, Porto Alegre, RS, Brazil.

In Brazil, the population in general has little knowledge about genetic risks, as well as regarding the role and importance of the Cancer Genetic Counseling (CGC). The goal of this study was to evaluate cancer-related worry and cancer risk perception during CGC sessions in Brazilian women at-risk for hereditary breast cancer. This study was performed in 264 individuals seeking CGC for hereditary breast cancer. Both cancer-affected and unaffected individuals were included. As results, individuals with and without cancer reported different motivations for seeking CGC and undergoing genetic testing. A correlation was observed between age at the first CGC session and age at which the closest relative was diagnosed with cancer. Multivariate analysis showed that educational level, cancer risk discussion within the family, and number of deaths by cancer among first-degree relatives influenced positively the cancer risk perception. In conclusion, the results of this study indicate that cancer-related worry and cancer risk perception are significant aspects of morbidity in individuals seeking CGC, whether they are cancer-affected or unaffected. CGC has an important role in health education and cancer prevention for its potential of promoting an accurate perception of the risk.
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http://dx.doi.org/10.1590/1678-4685-GMB-2019-0097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210979PMC
April 2020

Recommendations for Advancing the Diagnosis and Management of Hereditary Breast and Ovarian Cancer in Brazil.

JCO Glob Oncol 2020 03;6:439-452

Departmento de Genética, Universidade Federal do Rio Grande do Sul.

Purpose: The objective of this review was to address the barriers limiting access to genetic cancer risk assessment and genetic testing for individuals with suspected hereditary breast and ovarian cancer (HBOC) through a review of the diagnosis and management steps of HBOC.

Methods: A selected panel of Brazilian experts in fields related to HBOC was provided with a series of relevant questions to address before the multiday conference. During this conference, each narrative was discussed and edited by the entire group, through numerous drafts and rounds of discussion, until a consensus was achieved.

Results: The authors propose specific and realistic recommendations for improving access to early diagnosis, risk management, and cancer care of HBOC specific to Brazil. Moreover, in creating these recommendations, the authors strived to address all the barriers and impediments mentioned in this article.

Conclusion: There is a great need to expand hereditary cancer testing and counseling in Brazil, and changing current policies is essential to accomplishing this goal. Increased knowledge and awareness, together with regulatory actions to increase access to this technology, have the potential to improve patient care and prevention and treatment efforts for patients with cancer across the country.
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http://dx.doi.org/10.1200/JGO.19.00170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113069PMC
March 2020

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population.

BMC Med Genomics 2020 02 10;13(1):21. Epub 2020 Feb 10.

Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.

Background: The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20-30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants in ATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN, and TP53 genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients.

Methods: We systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways (ABRAXAS1, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53 and UIMC1). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions in BRCA1/BRCA2 genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms.

Results: We identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants in BRCA1, BRCA2 and TP53, a frequency higher than that identified among previous studies in Brazil. We identified a novel variant in ATR, which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants in ABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2, and PMS2 genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions in BRCA1/BRCA2 genes.

Conclusions: This study embodies the third report of a multi-gene analysis in the Brazilian population, and addresses the first report of many germline variants associated with HBOC in Brazil. Although further functional analyses are necessary to better characterize the contribution of those variants to the phenotype, these findings would improve the risk estimation and clinical follow-up of patients with HBOC clinical suspicion.
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http://dx.doi.org/10.1186/s12920-019-0652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011249PMC
February 2020

Genetic cancer risk assessment: A screenshot of the psychosocial profile of women at risk for hereditary breast and ovarian cancer syndrome.

Psychooncology 2020 04 6;29(4):681-687. Epub 2020 Feb 6.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Objective: There is a lack of information describing Brazilian women at risk of hereditary breast and ovarian cancer syndrome (HBOC) who undergo genetic cancer risk assessment (GCRA). This study aims to characterize the psychosocial profile of women at risk for HBOC at their first GCRA to obtain an overview of their families' profiles and the challenges of the oncogenetics setting.

Methods: This was a cross-sectional study in which interviews were conducted with 83 cancer-affected women at their first GRCA appointment after the pedigree draw. Tools to evaluate psychological outcomes were applied. The pedigree genogram and ecomap were constructed and analyzed with content analysis using the "life course perspective" theory.

Results: Individuals perceived their breast/ovarian cancer risk to be equal to that of the general population, although they were highly concerned about developing cancer. No evidence of anxiety or depressive symptoms was identified. Participants used the coping strategy of searching for religiosity. The genograms and ecomaps resulted in five major themes: support and social support; attitudes, feelings and emotions; cancer causes; communication; and relationships with relatives. Individuals between 20-29 years of age and those with no family history of cancer tended not to communicate with relatives, which may indicate future problems in the GCRA process regarding genetic testing.

Conclusions: This study demonstrated that knowing the families who undergo the GCRA process can help professionals provide more individualized and thorough attention during GCRA and genetic testing, which results in better follow-up and prevention strategies.
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http://dx.doi.org/10.1002/pon.5305DOI Listing
April 2020

MIR605 rs2043556 is associated with the occurrence of multiple primary tumors in TP53 p.(Arg337His) mutation carriers.

Cancer Genet 2020 01 20;240:54-58. Epub 2019 Nov 20.

Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil; Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil; Medical Genetics Service, HCPA, Porto Alegre, Rio Grande do Sul, Brazil; Department of Genetics, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil.

Li-Fraumeni and Li-Fraumeni-like (LFS/LFL) Syndrome are cancer predisposition syndromes caused by germline pathogenic variants in TP53 and are associated with an increased risk of multiple early-onset cancers. In Southern and Southeastern Brazil, a germline founder variant with partial penetrance located in the oligomerization domain of TP53, c.1010G>A p.(Arg337His, commonly known as R337H), has been detected in 0.3% of the general population. Recently, the functional MIR605 variant rs2043556 (A>G) has been identified as a novel LFS phenotype modifier in families with germline TP53 DNA binding variants. In this study, our goal was to verify MIR605 rs2043556 allele frequencies and further explore its possible effects on the phenotype of 238 Brazilian individuals carrying TP53 p.(Arg337His). The MIR605 rs2043556 G allele was detected in 136 (57.1%) individuals, including 25 homozygotes (10.5%), and although it had been previously associated with an earlier mean age of tumor onset, this effect was not observed in this study (p = 0.8). However, in p.(Arg337His) mutation carriers, the GG genotype was significantly associated with the occurrence of multiple primary tumors (p = 0.005). We provide further evidence of MIR605 rs2043556 G allele's effect as a phenotype modulator in carriers of germline TP53 pathogenic variants.
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http://dx.doi.org/10.1016/j.cancergen.2019.11.005DOI Listing
January 2020

The Role of Co-Deleted Genes in Neurofibromatosis Type 1 Microdeletions: An Evolutive Approach.

Genes (Basel) 2019 10 24;10(11). Epub 2019 Oct 24.

Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil.

Neurofibromatosis type 1 (NF1) is a cancer predisposition syndrome that results from dominant loss-of-function mutations mainly in the gene. Large rearrangements are present in 5-10% of affected patients, generally encompass neighboring genes, and are correlated with a more severe NF1 phenotype. Evident genotype-phenotype correlations and the importance of the co-deleted genes are difficult to establish. In our study we employed an evolutionary approach to provide further insights into the understanding of the fundamental function of genes that are co-deleted in subjects with microdeletions. Our goal was to access the ortholog and paralog relationship of these genes in primates and verify if purifying or positive selection are acting on these genes. Fourteen genes were analyzed in twelve mammalian species. Of these, four and ten genes showed positive selection and purifying selection, respectively. The protein, RNF135, showed three sites under positive selection at the RING finger domain, which may have been selected to increase efficiency in ubiquitination routes in primates. The phylogenetic analysis suggests distinct evolutionary constraint between the analyzed genes. With these analyses, we hope to help clarify the correlation of the co-deletion of these genes and the more severe phenotype of NF1.
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http://dx.doi.org/10.3390/genes10110839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896060PMC
October 2019

Analysis of Predictive Biomarkers in Patients With Lung Adenocarcinoma From Southern Brazil Reveals a Distinct Profile From Other Regions of the Country.

J Glob Oncol 2019 09;5:1-9

Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

Purpose: Adenocarcinoma is the most common histologic subtype of non-small-cell lung cancer, representing 40% of all diagnoses. Several biomarkers are currently used to determine patient eligibility for targeted treatments, including analysis of molecular alterations in and , as well as programmed death-ligand 1 (PD-L1) protein expression. Epidemiologic data reporting the frequency of these biomarkers in Brazilian patients with lung adenocarcinoma (LUAD) are limited, and existing studies predominantly included patients from the southeast region of the country.

Materials And Methods: The goal of this study was to investigate the frequency of somatic mutations in the and genes, ALK, and PD-L1 expression in a series of Brazilian patients diagnosed with LUAD predominantly recruited from centers in southern Brazil. Molecular analysis of the , and genes was performed by next-generation sequencing using DNA extracted from tumor tissue. Immunohistochemistry was used to detect ALK and PD-L1 expression.

Results: Analysis of 619 tumors identified mutations in 189 (30.2%), mutations in 120 (19.16%), and mutations in 19 (3%). Immunohistochemistry demonstrated ALK and PD-L1 expression in 4% and 35.1% of patients, respectively.

Conclusion: To our knowledge, this is the first study investigating the molecular epidemiology of patients with LUAD from southern Brazil and the largest assessing the frequency of multiple predictive biomarkers for this tumor in the country. The study also reveals a distinct mutation profile compared with data originating from other regions of Brazil.
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http://dx.doi.org/10.1200/JGO.19.00174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872182PMC
September 2019

TP53 variants of uncertain significance: increasing challenges in variant interpretation and genetic counseling.

Fam Cancer 2019 10;18(4):451-456

Programa de Pós-Graduação em Genética e Biologia Molecular (PPGBM), Universidade Federal do Rio Grande do Sul (UFRGS), Av. Bento Gonçalves, 9500 - Prédio 43323 M, Porto Alegre, RS, 91501-970, Brazil.

Li-Fraumeni syndrome (LFS) and Li-Fraumeni Like (LFL) are autosomal dominant cancer predisposition syndromes caused by pathogenic germline variants in the TP53 gene. Recent studies have shown that the incorporation of next-generation sequencing by using multigene panels in clinical practice has resulted in the frequent identification of variants of uncertain significance (VUS). Given that there is no established medical management for VUS carriers, the identification of these variants may cause confusion and anxiety for both patients and practitioners. Herein, we aimed to verify VUS frequency and review VUS classification and interpretation in 1844 patients submitted for comprehensive germline TP53 testing independent of clinical criteria. Variant characterization was done assessing clinical information whenever available, variant frequency in population databases, pathogenicity predictions using in silico tools and previous functional studies. All variants were classified based on the guidelines proposed by the American College of Medical Genetics and Genomics (2015) and by the Sherloc framework (2017). Of the twelve VUS (0.65%) identified in TP53, two were classified as likely pathogenic and two were classified as likely benign after re-evaluation, potentially resulting in significant management modification for the proband and relatives. This report cases highlights the challenges and impact of TP53 variant interpretation especially when there is no clear LFS/LFL phenotype.
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http://dx.doi.org/10.1007/s10689-019-00140-wDOI Listing
October 2019

A comprehensive analysis of core polyadenylation sequences and regulation by microRNAs in a set of cancer predisposition genes.

Gene 2019 Sep 21;712:143943. Epub 2019 Jun 21.

Programa de Pós-graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Laboratório de Medicina Genômica, Serviço de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Programa de Pós-graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.

Two core polyadenylation elements (CPE) located in the 3' untranslated region of eukaryotic pre-mRNAs play an essential role in their processing: the polyadenylation signal (PAS) AAUAAA and the cleavage site (CS), preferentially a CA dinucleotide. Herein, we characterized PAS and CS sequences in a set of cancer predisposition genes (CPGs) and performed an in silico investigation of microRNAs (miRNAs) regulation to identify potential tumor-suppressive and oncogenic miRNAs. NCBI and alternative polyadenylation databases were queried to characterize CPE sequences in 117 CPGs, including 81 and 17 known tumor suppressor genes and oncogenes, respectively. miRNA-mediated regulation analysis was performed using predicted and validated data sources. Based on NCBI analyses, we did not find an established PAS in 21 CPGs, and verified that the majority of PAS already described (74.4%) had the canonical sequence AAUAAA. Interestingly, "AA" dinucleotide was the most common CS (37.5%) associated with this set of genes. Approximately 90% of CPGs exhibited evidence of alternative polyadenylation (more than one functional PAS). Finally, the mir-192 family was significantly overrepresented as regulator of tumor suppressor genes (P < 0.01), which suggests a potential oncogenic function. Overall, this study provides a landscape of CPE in CPGs, which might be useful in development of future molecular analyses covering these frequently neglected regulatory sequences.
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http://dx.doi.org/10.1016/j.gene.2019.143943DOI Listing
September 2019

Information and Diagnosis Networks - tools to improve diagnosis and treatment for patients with rare genetic diseases.

Genet Mol Biol 2019 10;42(1 suppl 1):155-164. Epub 2019 Jun 10.

Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil.

Brazil is a country of continental dimensions and most genetic services are concentrated in the Southeast and South, including the Medical Genetics Service of the Hospital de Clínicas de Porto Alegre (MGS/HCPA). As many areas on the country do not have adequate medical genetics support, networks were designed to extend the service of the MGS/HCPA reference center. This paper presents the information and diagnosis networks that have their headquarters at MGS/HCPA: SIAT (National Information System on Teratogenic Agents), SIEM (Information Service on Inborn Errors of Metabolism), Alô Genética (Hello Genetics - Medical Genetics Information Service for Primary Health Care Professionals); Rede MPS Brasil (MPS-Mucopolysaccharidosis Brazil Network); Rede EIM Brasil (IEM-Inborn Errors of Metabolism Brazil Network), Rede NPC Brasil (Niemann-Pick C - NPC Brazil Network), Rede DLD Brasil (LSD-Lysosomal Storage Disorders Brazil Network), Rede DXB (MSUD-Maple Syrup Urine Disease Network), RedeBRIM (Brazilian Network of Reference and Information in Microdeletion Syndromes Project), Rede Neurogenética (Neurogenetics Network), and Rede Brasileira de Câncer Hereditário (Brazilian Hereditary Cancer Network). These tools are very useful to provide access to a qualified information and/or diagnostic service for specialized and non-specialized health services, bypassing difficulties that preclude patients to access reference centers.
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http://dx.doi.org/10.1590/1678-4685-GMB-2018-0214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687351PMC
June 2019

Performance of the Gail and Tyrer-Cuzick breast cancer risk assessment models in women screened in a primary care setting with the FHS-7 questionnaire.

Genet Mol Biol 2019 3;42(1 suppl 1):232-237. Epub 2019 Jun 3.

Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Breast cancer (BC) risk assessment models base their estimations on different aspects of a woman's personal and familial history. The Gail and Tyrer-Cuzick models are the most commonly used, and BC risks assigned by them vary considerably especially concerning familial history. In this study, our aim was to compare the Gail and Tyrer-Cuzick models after initial screening for familial history of cancer in primary care using the FHS-7 questionnaire. We compared 846 unrelated women with at least one positive answer to any of the seven FHS-7 questions (positive group) and 892 unrelated women that answered negatively (negative group). Concordance between BC risk estimates was compared by Bland-Altman graphics. Mean BC risk estimates were higher using the Tyrer-Cuzick Model in women from the positive group, while women from the negative group had higher BC risk estimates using the Gail model. With increasing estimates, discordance also increased, mainly in the FHS-7 positive group. Our results show that in women with a familial history of cancer, the Gail model underestimates risk and the Tyrer-Cuzick seems to be more appropriate. FHS-7 can be a useful tool for the identification of women with higher breast cancer risks in the primary care setting.
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http://dx.doi.org/10.1590/1678-4685-GMB-2018-0110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687344PMC
June 2019

Reviewing the characteristics of BRCA and PALB2-related cancers in the precision medicine era.

Genet Mol Biol 2019 29;42(1 suppl 1):215-231. Epub 2019 Apr 29.

Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.

Germline mutations in BRCA1 and BRCA2 (BRCA) genes confer high risk of developing cancer, especially breast and ovarian tumors. Since the cloning of these tumor suppressor genes over two decades ago, a significant amount of research has been done. Most recently, monoallelic loss-of-function mutations in PALB2 have also been shown to increase the risk of breast cancer. The identification of BRCA1, BRCA2 and PALB2 as proteins involved in DNA double-strand break repair by homologous recombination and of the impact of complete loss of BRCA1 or BRCA2 within tumors have allowed the development of novel therapeutic approaches for patients with germline or somatic mutations in said genes. Despite the advances, especially in the clinical use of PARP inhibitors, key gaps remain. Now, new roles for BRCA1 and BRCA2 are emerging and old concepts, such as the classical two-hit hypothesis for tumor suppression, have been questioned, at least for some BRCA functions. Here aspects regarding cancer predisposition, cellular functions, histological and genomic findings in BRCA and PALB2-related tumors will be presented, in addition to an up-to-date review of the evolution and challenges in the development and clinical use of PARP inhibitors.
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http://dx.doi.org/10.1590/1678-4685-GMB-2018-0104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687356PMC
April 2019

TULP3: A potential biomarker in colorectal cancer?

PLoS One 2019 14;14(1):e0210762. Epub 2019 Jan 14.

Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, PPGBM-UFRGS, Porto Alegre, Rio Grande do Sul, Brazil.

Colorectal cancer (CRC) is the second most common cancer in women and the third most common cancer in men globally. The identification of differentially expressed genes associated to patient's clinical data may represent a useful approach to find important genes in CRC carcinogenesis. Previously, the TULP3 transcription factor was identified as a possible prognostic biomarker in pancreatic ductal adenocarcinoma. Considering that pancreatic and colorectal tissues have the same embryonic origin, we investigated the profile of TULP3 expression in CRC hypothesizing that it may have a role in its development. We comparatively analysed TULP3 gene expression in CRC and normal adjacent colonic tissue and assessed association of expression profiles with survival and clinicopathological information, using publicly available datasets. TULP3 expression levels were increased in CRC when compared to the adjacent non-tumoral tissue. In addition, higher TULP3 gene expression was associated to lymphatic and vascular invasion in colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ), respectively. In summary, our results point to a possible role of TULP3 as a diagnostic and prognostic biomarker in CRC. Additional studies are necessary to confirm these preliminary findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210762PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331117PMC
November 2019

TP53 p.Arg337His germline mutation prevalence in Southern Brazil: Further evidence for mutation testing in young breast cancer patients.

PLoS One 2018 31;13(12):e0209934. Epub 2018 Dec 31.

Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

Premenopausal breast cancer (BC) is a core tumor of Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) Syndromes, predisposition disorders caused by germline mutations in TP53 gene. In the Southern and Southeastern regions of Brazil, a specific TP53 germline mutation, c.1010G>A (p.Arg337His), was identified at a population frequency of 0.3%, the highest value ever described for a TP53 germline variation. In Brazilian BC patients, carrier frequency can vary from 0.5% to 8.7%. The current study assessed carrier frequency by genotyping TP53 c.1010G>A in 2 BC groups: 1) 315 patients unselected for age of diagnosis and family history (FH) and 2) 239 patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. One carrier was identified in group 1 (0.3%; CI 95% 0.1-1.76%) and six carriers in group 2 (2.5%; CI 95% 0.93-5.39%). The frequencies differed significantly between groups (p = 0.04). The mutation carrier frequency observed in group 2 could justify mutation testing in BC patients diagnosed before 46 years and without Chompret criteria for LFS or LFL. Further studies in larger samples of BC patients of different ages and regions of the country are necessary to provide more definitive TP53 p.Arg337His carrier frequencies in different scenarios.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209934PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312227PMC
May 2019
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