Dados do Resumo

Título

Novel candidate genes for breast cancer predisposition uncovered in Brazilian families

Introdução

It is estimated that 5 to 10% of breast cancer cases have a strong hereditary component. At present, women diagnosed with breast cancer and increased risk of hereditary predisposition typically undergo testing to assess germline variants in BRCA1, BRCA2, and a few other predisposing genes. However, only around 30% of this group carry a germline pathogenic variant in well-established predisposing genes, while the majority lack a clear genetic etiology.

Objetivo

We aim to identify novel breast cancer predisposing genes through whole exome sequencing (WES) of families with multiple affected women and unknown genetic etiology.

Métodos

As inclusion criteria, we recruited patients from families with at least three unilateral and/or two bilateral breast cancer cases, within a maximum of three generations. All investigated patients had negative results for pathogenic variants in the main BC susceptibility genes. The study involved 29 affected individuals from eight families, and WES was performed using genomic DNA from either saliva or blood samples. The IDT xGen Exome v2 kit was used for the sequencing library preparation, followed by the Illumina HiSeq platform sequencing. Candidate variant prioritization was based on read quality, population frequencies, predicted impact on protein function, and segregation analysis among the affected women within the families. This study was approved by the Ethics Committee of the Institute of Biosciences - University of São Paulo (CAAE: 25325019.5.0000.5464).

Resultados

We uncovered 18 variants predicted to be pathogenic in 18 candidate genes that completely segregate with breast cancer in one of the eight families studied. Among these, the tumor suppressor gene RAD54L2 emerged as the most promising candidate due to its interaction with canonical cancer genes and its role in the homologous recombination DNA repair pathway. This pathway includes several well-characterized breast cancer predisposing genes, such as BRCA1 and BRCA2. Notably, analysis of three tumors from affected relatives revealed loss of heterozygosity (LOH) of the wild-type allele in one case, which could facilitate tumorigenesis by serving as a somatic second hit in the context of the two-hit hypothesis.

Conclusões

Our results contribute to characterizing the genetic background of familial breast cancer patients without a determined etiology. It also supports further analyses of the impact of RAD54L2 on breast cancer susceptibility and holds the potential for improving genetic tests and informed clinical management.

Financiador do resumo

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Palavras Chave

Breast Cancer Predisposition; novel candidate genes; whole exome sequencing (WES)