Dados do Trabalho


Detection of germline pathogenic variants in early onset breast cancer patients using Whole Exome Sequencing


About 5 to 10% of breast cancer cases are hereditary (HBC). Several factors are associated with HBC, such as family history and early diagnosis. There are several high and moderate cancer predisposition genes known to be associated with the development of hereditary breast cancer. However, for a significant portion of the cases, the causal factor remains unknown.


In the present study we have performed comprehensive whole exome sequencing (WES) in order to identify germline pathogenic or likely pathogenic genetic alterations associated with the development of early breast cancer (EBC).


DNA constitutive samples from breast cancer patients(n=70) diagnosed under 35 years of age and without any pathogenic variants in BRCA1/2 and TP53 genes were retrospectively included. This study was approved by the local ethics committee (Barretos Cancer Hospital (approval number: 56164716.9.0000.5437)). The whole exome sequencing was performed by Sophia Genetics using Illumina platform and our study group developed a pipeline for data analysis and the curation of the variants following the ACMG criteria were performed by two independent researchers.


The mean age of the patients was 27.6 years (SD=3.37). Variants identified were classified following the ACMG/AMP criteria and were classified as Pathogenic (P), Likely Pathogenic (LP), Variants of Uncertain Significance (VUS), Likely Benign (LB) and Benign (B). Twenty-seven unrelated patients (38,57% of our cohort) were carriers of a P/LP (29 unique variants and 28 genes). A total of 750 variants classified as VUS were also identified. Among the 29 P/LP variants identified, 10 were located in genes associated with hereditary cancer and several repair pathways, one of these genes is involved in homologous recombination repair such as ATM. Besides, other genes involved in DNA repair pathways and cancer were also mutated in our cohort. We highlight EXO1 involved in mismatch repair, both ATM and EXO1 were related to breast cancer. This patients with variants IV and V, 63% are the luminal molecular subtype, 22.2% of the triple-negative molecular subtype and 14.8% of the HER2 molecular subtype.


These findings may contribute to new genes associated with the risk of early breast cancer, contributing to the fact that WES studies are a good tool for understanding HBC.


Hereditary breast cancer, whole-exome sequencing, DNA repair genes.

Financiador do resumo

National Oncology Care Support Program (PRONON, Grant number (25000.056766/2015-64)) from the Ministry of Health, Barretos Cancer Hospital and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior).


Estudo Clínico - Tumores de Mama


CINTIA REGINA NIEDERAUER RAMOS, Felipe Antônio Oliveira Garica, Edilene Santos Andrade, Natalia Campacci, Cristina Silva Sábato, Matias Eliseo Melendez, Rui Manuel Reis, Henrique Campos Galvão, Augusto Perazzolo Antoniazzi, Cristiano Pádua Souza, Edenir Inêz Palmero