Identificação e análise de variantes do gene ATM (Ataxia-Telangiectasia Mutado) em pacientes portadoras de câncer de mama no estado da Bahia

Abstract

Introduction – Approximately 10% of new cases of breast cancer are related to hereditary factors, the main one being the hereditary predisposition syndrome, the hereditary breast and ovarian cancer syndrome, caused by mutations in the BRCA1 and BRCA2 genes (HBOC). However, only 10% of breast cancer patients show germline alterations in the BRCA1 or BRCA2 genes. Pathogenic variants in other genes known to have moderate penetrance, such as PALB2, CHEK2, and ATM, also increase the risk of breast cancer in 3% to 5% of women

referred for hereditary risk assessment of breast or ovarian cancer. The ATM (ataxia- telangiectasia mutated) gene is responsible for ataxia-telangiectasia (AT), a rare, autosomal

recessive disease characterized by progressive cerebellar degeneration, ocular and facial telangiectasias, a tendency to sinopulmonary infections, and a predisposition to cancer. Biallelic mutations in ATM cause ataxia-telangiectasia and heterozygous mutations in ATM are more common among individuals with breast cancer than in the general population. Women heterozygous for ATM mutations have a 2- to 5-fold increased risk of breast cancer. Objective – To investigate the mutational landscape of germline variants in the ATM gene related to breast cancer in a population of patients referred to a reference service of the public health system in the state of Bahia. Material and methods – Descriptive study with analysis of patients undergoing oncogenetic evaluation at a public reference service from 07/2007 to 06/2024 through next-generation sequencing (NGS) results analysis. Results – Fifteen pathogenic or likely pathogenic variants in the ATM gene and 31 variants of uncertain significance were identified in 874 patients evaluated for hereditary cancer predisposition syndromes. Among the patients with pathogenic variants, 12 had breast cancer, and 75% of them were under 50 years of age. Two pathogenic variants not reported in population databases were found. According to self-classification of race or color, 67% of the sample members identified themselves as Afro-descendants. More than one unrelated family shared the same variant. Consanguinity was reported in only one family. Deleterious nonsense and frameshift variants, which resulted in truncated proteins and loss of protein expression, were the majority of the variants found and justified the molecular basis for cancer development. Conclusion– This study identified ATM as the gene with moderate penetrance, most frequent in our population, affecting young women, with high prevalence in a population with a majority of Afro-descendants, with high variability of mutations and phenotypic expressions in the ATM gene, correlating the clinical and genomic findings that indicate the different contributions of European and African populations to the lineage of the Brazilian population.