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Tytuł pozycji:

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

Tytuł:
Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population.
Autorzy:
da Costa E Silva Carvalho S; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.; Center for Medical Genomics at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.; Regional Blood Center at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
Cury NM; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.; Regional Blood Center at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
Brotto DB; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.; Regional Blood Center at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
de Araujo LF; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.; Regional Blood Center at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
Rosa RCA; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.; Center for Medical Genomics at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
Texeira LA; Division of Internal Medicine and Geriatrics, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Plaça JR; Regional Blood Center at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
Marques AA; Regional Blood Center at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
Peronni KC; Regional Blood Center at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
Ruy PC; Center for Medical Genomics at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
Molfetta GA; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.; Center for Medical Genomics at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.
Moriguti JC; Division of Internal Medicine and Geriatrics, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Carraro DM; International Research, Center/CIPE, AC Camargo Cancer Center, Sao Paulo, SP, Brazil.
Palmero EI; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.
Ashton-Prolla P; Laboratório de Medicina Genômica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
de Faria Ferraz VE; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.; Center for Medical Genomics at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil.; Department of Medical Genetics, University Hospital of the Ribeirão Preto Medical School, Ribeirão Preto, Brazil.
Silva WA Jr; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil. .; Center for Medical Genomics at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil. .; Regional Blood Center at University Hospital of the Ribeirão Preto Medical School of University of São Paulo, Ribeirão Preto, SP, Brazil. .
Źródło:
BMC medical genomics [BMC Med Genomics] 2020 Feb 10; Vol. 13 (1), pp. 21. Date of Electronic Publication: 2020 Feb 10.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: London : BioMed Central
MeSH Terms:
Algorithms*
Computer Simulation*
Germ-Line Mutation*
INDEL Mutation*
Hereditary Breast and Ovarian Cancer Syndrome/*genetics
Neoplasm Proteins/*genetics
Adult ; Aged ; Brazil ; Female ; Humans ; Male ; Middle Aged
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Contributed Indexing:
Keywords: BRCA1; BRCA2; DNA repair genes; HBOC; Molecular diagnosis; Multi-gene panel screening; Next-generation sequencing
Substance Nomenclature:
0 (Neoplasm Proteins)
Entry Date(s):
Date Created: 20200211 Date Completed: 20201216 Latest Revision: 20201216
Update Code:
20240105
PubMed Central ID:
PMC7011249
DOI:
10.1186/s12920-019-0652-y
PMID:
32039725
Czasopismo naukowe
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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