Characterization of genetic predisposition to molecular subtypes of breast cancer in Brazilian patients

Daniele Paixão; Giovana Tardin Torrezan; Karina Miranda Santiago; Maria Nirvana Formiga; Samuel Terkper Ahuno; Emmanuel Dias-Neto; Israel Tojal da Silva; William D Foulkes; Paz Polak; Dirce Maria Carraro

doi:10.3389/fonc.2022.976959

Characterization of genetic predisposition to molecular subtypes of breast cancer in Brazilian patients

Front Oncol. 2022 Aug 31:12:976959. doi: 10.3389/fonc.2022.976959. eCollection 2022.

Authors

Affiliations

¹ Oncogenetics Department, A.C.Camargo Cancer Center, São Paulo, SP, Brazil.
² Clinical and Functional Genomics Group, International Research Center/CIPE, A.C.Camargo Cancer Center, São Paulo, SP, Brazil.
³ National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation (INCITO), São Paulo, SP, Brazil.
⁴ Tri-Institutional PhD Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY, United States.
⁵ Genomic Medicine Group, - International Research Center/CIPE, A.C.Camargo Cancer Center, São Paulo, SP, Brazil.
⁶ Bioinformatics and Computational Biology Group, - International Research Center/CIPE, A.C.Camargo Cancer Center, São Paulo, SP, Brazil.
⁷ Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, QC, Canada.
⁸ Computational Biology, C2i Genomics, New York, NY, United States.

Abstract

Introduction: BRCA1 and BRCA2 germline pathogenic variants (GPVs) account for most of the 5-10% of breast cancer (BC) that is attributable to inherited genetic variants. BRCA1 GPVs are associated with the triple negative subtype, whereas BRCA2 GPVs are likely to result in higher grade, estrogen-receptor positive BCs. The contribution of other genes of high and moderate risk for BC has not been well defined and risk estimates to specific BC subtypes is lacking, especially for an admixed population like Brazilian.

Objective: The aim of this study is to evaluate the value of a multigene panel in detecting germline mutations in cancer-predisposing genes for Brazilian BC patients and its relation with molecular subtypes and the predominant molecular ancestry.

Patients and methods: A total of 321 unrelated BC patients who fulfilled NCCN criteria for BRCA1/2 testing between 2016-2018 were investigated with a 94-genes panel. Molecular subtypes were retrieved from medical records and ancestry-specific variants were obtained from off-target reads obtained from the sequencing data.

Results: We detected 83 GPVs in 81 patients (positivity rate of 25.2%). Among GPVs, 47% (39/83) were identified in high-risk BC genes (BRCA1/2, PALB2 and TP53) and 18% (15/83) in moderate-penetrance genes (ATM, CHEK2 and RAD51C). The remainder of the GPVs (35% - 29/83), were identified in lower-risk genes. As for the molecular subtypes, triple negative BC had a mutation frequency of 31.6% (25/79), with predominance in BRCA1 (12.6%; 10/79). Among the luminal subtypes, except Luminal B HER2-positive, 18.7% (29/155) had GPV with BRCA1/2 genes contributing 7.1% (11/155) and non-BRCA1/2 genes, 12.9% (20/155). For Luminal B HER2-positive subtype, 40% (16/40) had GPVs, with a predominance of ATM gene (15% - 6/40) and BRCA2 with only 2.5% (1/40). Finally, HER2-enriched subtype presented a mutation rate of 30.8% (4/13) with contribution of BRCA2 of 7.5% (1/13) and non-BRCA1/2 of 23% (3/13). Variants of uncertain significance (VUS) were identified in 77.6% (249/321) of the patients and the number of VUS was increased in patients with Asian and Native American ancestry.

Conclusion: The multigene panel contributed to identify GPVs in genes other than BRCA1/2, increasing the positivity of the genetic test from 9.6% (BRCA1/2) to 25.2% and, considering only the most clinically relevant BC predisposing genes, to 16.2%. These results indicate that women with clinical criteria for hereditary BC may benefit from a multigene panel testing, as it allows identifying GPVs in genes that directly impact the clinical management of these patients and family members.

Keywords: breast cancer; cancer genetics; hereditary cancer; molecular subtype of breast cancer; multigene panel.