Genetic counseling for identification of at-risk individuals for hereditary cancer syndromes

Keywords

oncogenetics - hereditary cancer syndromes - breast cancer - Li-Fraumeni syndrome - Lynch syndrome

Introduction: Hereditary cancer syndromes (HCSs) represent approximately 10% of all cancer cases, despite being frequently underdiagnosed. Advances in the next-generation sequencing and the recent discovery of the new genes associated with cancer became genetic testing a crucial step in routine diagnosis for HCSs.

Objective: To evaluate the occurrence of germline mutations in genes related to HCSs in risk patients.

Method: The cohort included 200 individuals with family history suggestive of predisposition to hereditary cancer, that sought genetic counseling service in Campos dos Goytacazes-RJ from July 2020 to July 2024. The genetic tests performed comprised multigene panels that the pathogenicity of the variants detected by next-generation sequencing was established according to the American College of Medical Genetics criteria.

Results: The hereditary origin of malignant neoplasia was confirmed in 24% of the tested patients. Breast cancer was the most frequent type, with pathogenic mutations detected mainly in the BRCA1 gene, followed by a missense mutation in the TP53 gene [c.1010G>A: p.(Arg337His)], associated to Li-Fraumeni syndrome. The second most frequent type of hereditary cancer was colorectal, with mutations related to Familial Adenomatous Polyposis (APC and MUTYH genes), Lynch and Muir-Torre syndromes (MLH1 and MSH2 genes). It is imperative to highlight that pathogenic variants related to HCSs were detected in 8% of individuals without previously malignant neoplasia, including an Ashkenazi Jewish male descendant with pathogenic mutation in the BRCA1 gene [c.68_69del.(Glu23Valfs*17)], which allowed the establishment of personalized preventive programs and familial cascade testing. Moreover, variants of uncertain clinical significance (VUS) were reported in 50,5% of the tested individuals, comprehending 68 different genes.

Conclusion: The results indicated that genetic testing for HCSs allowed patients with an increased risk of familial cancer to receive appropriate therapeutic management that may reduce risk for themselves and their family members. Additionally, expanded multigene testing enables the identification of pathogenic variants in rare and non-classical genes, besides the most frequent HCSs-related genes.

Corresponding author: Gustavo Antonio Mesquita Drumond Lopes (e-mail: [e-mail]).