Navegando por Autor "Krepischi, Ana Cristina Victorino"
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Artigo Family-based whole-exome sequencing identifies rare variants potentially related to cutaneous melanoma predisposition in Brazilian melanoma-prone families(Public Library of Science (PLoS), 2022-01-27) Fidalgo, Felipe; Torrezan, Giovana Tardin; Sá, Bianca Costa Soares de; Barros, Bruna Durães de Figueiredo; Moredo, Luciana Facure; Valieris, Renan; Souza, Sandro José de; Duprat, João Pereira; Krepischi, Ana Cristina Victorino; Carraro, Dirce MariaGenetic predisposition accounts for nearly 10% of all melanoma cases and has been associated with a dozen moderate- to high-penetrance genes, including CDKN2A, CDK4, POT1 and BAP1. However, in most melanoma-prone families, the genetic etiology of cancer predisposition remains undetermined. The goal of this study was to identify rare genomic variants associated with cutaneous melanoma susceptibility in melanoma-prone families. Whole-exome sequencing was performed in 2 affected individuals of 5 melanoma-prone families negative for mutations in CDKN2A and CDK4, the major cutaneous melanoma risk genes. A total of 288 rare coding variants shared by the affected relatives of each family were identified, including 7 loss-of-function variants. By performing in silico analyses of gene function, biological pathways, and variant pathogenicity prediction, we underscored the putative role of several genes for melanoma risk, including previously described genes such as MYO7A and WRN, as well as new putative candidates, such as SERPINB4, HRNR, and NOP10. In conclusion, our data revealed rare germline variants in melanoma-prone families contributing with a novel set of potential candidate genes to be further investigated in future studiesArtigo A genomic case study of desmoplastic small round cell tumor: comprehensive analysis reveals insights into potential therapeutic targets and development of a monitoring tool for a rare and aggressive disease(2016) Ferreira, Elisa Napolitano; Barros, Bruna Durães Figueiredo; Souza, Jorge Estefano de; Almeida, Renan Valieris; Torrezan, Giovana Tardin; Garcia, Sheila; Krepischi, Ana Cristina Victorino; Mello, Celso Abdon Lopes de; Cunha, Isabela Werneck da; Pinto, Clóvis Antonio Lopes; Soares, Fernando Augusto; Dias-Neto, Emmanuel; Lopes, Ademar; Souza, Sandro José de; Carraro, Dirce MariaBackground: Genome-wide profiling of rare tumors is crucial for improvement of diagnosis, treatment, and, consequently, achieving better outcomes. Desmoplastic small round cell tumor (DSRCT) is a rare type of sarcoma arising from mesenchymal cells of abdominal peritoneum that usually develops in male adolescents and young adults. A specific translocation, t(11;22)(p13;q12), resulting in EWS and WT1 gene fusion is the only recurrent molecular hallmark and no other genetic factor has been associated to this aggressive tumor. Here, we present a comprehensive genomic profiling of one DSRCT affecting a 26-year-old male, who achieved an excellent outcome. Methods: We investigated somatic and germline variants through whole-exome sequencing using a family based approach and, by array CGH, we explored the occurrence of genomic imbalances. Additionally, we performed mate-paired whole-genome sequencing for defining the specific breakpoint of the EWS-WT1 translocation, allowing us to develop a personalized tumor marker for monitoring the patient by liquid biopsy. Results: We identified genetic variants leading to protein alterations including 12 somatic and 14 germline events (11 germline compound heterozygous mutations and 3 rare homozygous polymorphisms) affecting genes predominantly involved in mesenchymal cell differentiation pathways. Regarding copy number alterations (CNA) few events were detected, mainly restricted to gains in chromosomes 5 and 18 and losses at 11p, 13q, and 22q. The deletions at 11p and 22q indicated the presence of the classic translocation, t(11;22)(p13;q12). In addition, the mapping of the specific genomic breakpoint of the EWS-WT1 gene fusion allowed the design of a personalized biomarker for assessing circulating tumor DNA (ctDNA) in plasma during patient follow-up. This biomarker has been used in four post-treatment blood samples, 3 years after surgery, and no trace of EWS-WT1 gene fusion was detected, in accordance with imaging tests showing no evidence of disease and with the good general health status of the patient. Conclusions: Overall, our findings revealed genes with potential to be associated with risk assessment and tumorigenesis of this rare type of sarcoma. Additionally, we established a liquid biopsy approach for monitoring patient follow-up based on genomic information that can be similarly adopted for patients diagnosed with a rare tumor.