Navegando por Autor "Ramalho, Rodrigo F."
Agora exibindo 1 - 2 de 2
- Resultados por página
- Opções de Ordenação
Artigo Complex landscape of germline variants in brazilian patients with hereditary and early onset breast cancer(2018-05-07) Torrezan, Giovana T.; Almeida, Fernanda G. dos Santos R. de; Figueiredo, Márcia C. P.; Barros, Bruna D. de Figueiredo; Paula, Cláudia A. A. de; Valieris, Renan; Souza, Jorge E. S. de; Ramalho, Rodrigo F.; Silva, Felipe C. C. da; Ferreira, Elisa N.; Nóbrega, Amanda F. de; Felicio, Paula S.; Achatz, Maria I.; Souza, Sandro José de; Palmero, Edenir I.; Carraro, Dirce M.Pathogenic variants in known breast cancer (BC) predisposing genes explain only about 30% of Hereditary Breast Cancer (HBC) cases, whereas the underlying genetic factors for most families remain unknown. Here, we used whole-exome sequencing (WES) to identify genetic variants associated to HBC in 17 patients of Brazil with familial BC and negative for causal variants in major BC risk genes (BRCA1/2, TP53, and CHEK2 c.1100delC). First, we searched for rare variants in 27 known HBC genes and identified two patients harboring truncating pathogenic variants in ATM and BARD1. For the remaining 15 negative patients, we found a substantial vast number of rare genetic variants. Thus, for selecting the most promising variants we used functional-based variant prioritization, followed by NGS validation, analysis in a control group, cosegregation analysis in one family and comparison with previous WES studies, shrinking our list to 23 novel BC candidate genes, which were evaluated in an independent cohort of 42 high-risk BC patients. Rare and possibly damaging variants were identified in 12 candidate genes in this cohort, including variants in DNA repair genes (ERCC1 and SXL4) and other cancer-related genes (NOTCH2, ERBB2, MST1R, and RAF1). Overall, this is the first WES study applied for identifying novel genes associated to HBC in Brazilian patients, in which we provide a set of putative BC predisposing genes. We also underpin the value of using WES for assessing the complex landscape of HBC susceptibility, especially in less characterized populations.Artigo Testing for Natural Selection in Human Exonic Splicing Regulators Associated with Evolutionary Rate Shifts(2013) Ramalho, Rodrigo F.; Gelfman, Sahar; Souza, Jorge E. de; Ast, Gil; Souza, Sandro José de; Meyer, DiogoDespite evidence that at the interspecific scale, exonic splicing silencers (ESSs) are under negative selection in constitutive exons, little is known about the effects of slightly deleterious polymorphisms on these splicing regulators. Through the application of a modified version of the McDonald–Kreitman test, we compared the normalized proportions of human polymorphisms and human/rhesus substitutions affecting exonic splicing regulators (ESRs) on sequences of constitutive and alternative exons. Our results show a depletion of substitutions and an enrichment of SNPs associated with ESS gain in constitutive exons. Moreover, we show that this evolutionary pattern is also present in a set of ESRs previously involved in the transition from constitutive to skipped exons in the mammalian lineage. The similarity between these two sets of ESRs suggests that the transition from constitutive to skipped exons in mammals is more frequently associated with the inhibition than with the promotion of splicing signals. This is in accordance with the hypothesis of a constitutive origin of exon skipping and corroborates previous findings about the antagonistic role of certain exonic splicing enhancers.