Hereditary Breast Cancer in a Brazilian Referral Cohort: Germline Diversity and Genotype–Phenotype Associations
7 affiliations
- 1Department of Medical Oncology, A.C. Camargo Cancer Center, São Paulo 01509-010, Brazil
- 2Department of Genetics, Institut Curie, Paris Sciences and Lettres (PSL) University, 75005 Paris, France
- 3Breast Cancer Reference Center , A.C. Camargo Cancer Center, São Paulo 01509-010, Brazil
- 4Department of Pathological Anatomy, A.C. Camargo Cancer Center, São Paulo 01509-010, Brazil
- 5Department of Oncogenetics, A.C. Camargo Cancer Center, São Paulo 01509-010, Brazil
- 6Department of Molecular Biology and Genetics, International Research Center (CIPE), A.C. Camargo Cancer Center, São Paulo 01509-010, Brazil
- 7Department of Oncogenetics, Hospital Sírio Libanês, São Paulo 01308-060, Brazil
Abstract
The germline landscape of hereditary breast cancer has been characterized predominantly in populations of European ancestry, with limited evidence from populations with different demographic histories. We investigated germline diversity and genotype–phenotype associations in a single-center ambispective cohort at a tertiary referral cancer center in Brazil. Among 10,098 individuals who underwent germline genetic testing, 503 adults with invasive or microinvasive breast cancer met the predefined eligibility criteria and carried 514 pathogenic or likely pathogenic germline variants. Analyses assessed gene distribution, recurrent and founder variants, ecological diversity metrics, and associations with clinicopathological characteristics and survival outcomes. BRCA1 (31.6%) and BRCA2 (21.7%) were the most frequently altered susceptibility genes, followed by TP53 (13.1%), including the Brazilian founder variant TP53 p.R337H (10.7%). Diversity analyses indicated substantial heterogeneity beyond BRCA1/2. In exploratory unadjusted analyses, BRCA1-associated tumors more frequently exhibited triple-negative phenotype, high histological and nuclear grade, elevated Ki-67, and increased tumor-infiltrating lymphocytes, whereas tumors associated with BRCA2, ATM, CHEK2, and mismatch repair genes more frequently exhibited luminal phenotypes. Recurrent variants included alleles previously reported in different geographic and population contexts. Exploratory survival analyses detected no statistically significant differences among genetic groups within a five-year analytical horizon. These findings describe a heterogeneous germline spectrum and exploratory genotype–phenotype associations in a Brazilian cohort. Heterogeneous genetic testing coverage and the absence of individual genomic ancestry assessment limit interpretation; the findings should not be considered ancestry-specific or nationally representative. Further studies with uniform genetic testing and genomic ancestry assessment are warranted in broader Brazilian and Latin American cohorts.
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BibTeX
@article{cicilini2026hereditary,
title = {{Hereditary Breast Cancer in a Brazilian Referral Cohort: Germline Diversity and Genotype–Phenotype Associations}},
author = {André Luiz Cicilini and Patrick Vinicius Cerqueira Batista and Sandrine M. Caputo and Viviane Primo Basilio de Souza and Solange Moraes Sanchez and Fabiana Baroni Makdissi and Marina de Brot and Marina de Assis da Escossia Fernandes and Beatriz Nelli Barbatto and Leticia Coelho de Mattos and Nathalia Machado Soldi and Flavia Cavalcanti Ballint and Débora Guilherme de Albuquerque e Rodrigues de Sousa and Eduarda Mirella da Silva Montiel and Lurick Rodrigues Soares and Thamilyn Yoshizaki Saruwatari and Sahlua Miguel Volc and Solange Maria Torchia Carvalho Castro and Giovana Tardin Torrezan and Dirce Maria Carraro and Alexandre Andre Balliero and Vladmir Cláudio Cordeiro de Lima and José Claudio Casali-da-Rocha and Elizabeth Santana dos Santos},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219686},
url = {https://www.mdpi.com/1422-0067/27/21/9686},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hereditary Breast Cancer in a Brazilian Referral Cohort: Germline Diversity and Genotype–Phenotype Associations
AU - André Luiz Cicilini
AU - Patrick Vinicius Cerqueira Batista
AU - Sandrine M. Caputo
AU - Viviane Primo Basilio de Souza
AU - Solange Moraes Sanchez
AU - Fabiana Baroni Makdissi
AU - Marina de Brot
AU - Marina de Assis da Escossia Fernandes
AU - Beatriz Nelli Barbatto
AU - Leticia Coelho de Mattos
AU - Nathalia Machado Soldi
AU - Flavia Cavalcanti Ballint
AU - Débora Guilherme de Albuquerque e Rodrigues de Sousa
AU - Eduarda Mirella da Silva Montiel
AU - Lurick Rodrigues Soares
AU - Thamilyn Yoshizaki Saruwatari
AU - Sahlua Miguel Volc
AU - Solange Maria Torchia Carvalho Castro
AU - Giovana Tardin Torrezan
AU - Dirce Maria Carraro
AU - Alexandre Andre Balliero
AU - Vladmir Cláudio Cordeiro de Lima
AU - José Claudio Casali-da-Rocha
AU - Elizabeth Santana dos Santos
PY - 2026
DA - 2026/10/29
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219686
UR - https://www.mdpi.com/1422-0067/27/21/9686
AB - The germline landscape of hereditary breast cancer has been characterized predominantly in populations of European ancestry, with limited evidence from populations with different demographic histories. We investigated germline diversity and genotype–phenotype associations in a single-center ambispective cohort at a tertiary referral cancer center in Brazil. Among 10,098 individuals who underwent germline genetic testing, 503 adults with invasive or microinvasive breast cancer met the predefined eligibility criteria and carried 514 pathogenic or likely pathogenic germline variants. Analyses assessed gene distribution, recurrent and founder variants, ecological diversity metrics, and associations with clinicopathological characteristics and survival outcomes. BRCA1 (31.6%) and BRCA2 (21.7%) were the most frequently altered susceptibility genes, followed by TP53 (13.1%), including the Brazilian founder variant TP53 p.R337H (10.7%). Diversity analyses indicated substantial heterogeneity beyond BRCA1/2. In exploratory unadjusted analyses, BRCA1-associated tumors more frequently exhibited triple-negative phenotype, high histological and nuclear grade, elevated Ki-67, and increased tumor-infiltrating lymphocytes, whereas tumors associated with BRCA2, ATM, CHEK2, and mismatch repair genes more frequently exhibited luminal phenotypes. Recurrent variants included alleles previously reported in different geographic and population contexts. Exploratory survival analyses detected no statistically significant differences among genetic groups within a five-year analytical horizon. These findings describe a heterogeneous germline spectrum and exploratory genotype–phenotype associations in a Brazilian cohort. Heterogeneous genetic testing coverage and the absence of individual genomic ancestry assessment limit interpretation; the findings should not be considered ancestry-specific or nationally representative. Further studies with uniform genetic testing and genomic ancestry assessment are warranted in broader Brazilian and Latin American cohorts.
SN - 1422-0067
ER -