sábado, 7 de diciembre de 2019

Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico. - PubMed - NCBI

Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico. - PubMed - NCBI



 2019 Nov 28;9(1):17769. doi: 10.1038/s41598-019-54170-6.

Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico.

Author information


1
Cancer Biology Division, Ponce Research Institute, Ponce Health Sciences University, Ponce, PR, USA. jdutil@psm.edu.
2
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
3
Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
4
Molecular Genomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
5
University of South Florida Morsani College of Medicine, Tampa, FL, USA.
6
Cancer Biology Division, Ponce Research Institute, Ponce Health Sciences University, Ponce, PR, USA.
7
Ambry Genetics, Aliso Viejo, CA, USA.
8
Auxilio Cancer Center, Auxilio Mutuo Hospital, San Juan, PR, USA.

Abstract

Inherited pathogenic variants in genes that confer moderate to high risk of breast cancer may explain up to 50% of familial breast cancer. This study aimed at identifying inherited pathogenic variants in breast cancer cases from Puerto Rico that were not linked to BRCA1 or BRCA2. Forty-eight breast cancer patients that met the clinical criteria for BRCA testing but had received a negative BRCA1/2 result were recruited. Fifty-three genes previously implicated in hereditary cancer predisposition were captured using the BROCA Agilent cancer risk panel followed by massively parallel sequencing. Missense variants of uncertain clinical significance in CHEK2 were evaluated using an in vitro kinase assays to determine their impact on function. Pathogenic variants were identified in CHEK2, MUTYH, and RAD51B in four breast cancer patients, which represented 8.3% of the cohort. We identified three rare missense variants of uncertain significance in CHEK2 and two variants (p.Pro484Leu and p.Glu239Lys) showed markedly decreased kinase activity in vitro comparable to a known pathogenic variant. Interestingly, the local ancestry at the RAD51B locus in the carrier of p.Arg47* was predicted to be of African origin. In this cohort, 12.5% of the BRCA-negative breast cancer patients were found to carry a known pathogenic variant or a variant affecting protein activity. This study reveals an unmet clinical need of genetic testing that could benefit a significant proportion of at-risk Latinas. It also highlights the complexity of Hispanic populations as pathogenic factors may originate from any of the ancestral populations that make up their genetic backgrounds.

PMID:
 
31780696
 
DOI:
 
10.1038/s41598-019-54170-6
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