Germline panel as standard method for investigating hereditary breast and ovarian cancer sundrome in the brazilian supplementary health system

• Autor(a) principal: João Paulo Gonzaga de Faria
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da UFMG
• Texto Completo: http://hdl.handle.net/1843/58933
• topic: Genetics; Breast neoplasms; Genetic counseling; Genes, BRCA1; Genes, BRCA2; Genetics; Genética; Breast Neoplasms; Neoplasias da Mama; Genetic Counseling; Aconselhamento Genético; Genes BRCA1; Genes BRCA2

Introduction: Approximately 10% of breast cancer cases are due to hereditary factors, according to data from the José de Alencar National Cancer Institute. In the Brazilian context, the incidence of breast cancer is approximately 59,000 new cases per year. Around 50 million Brazilians have private health insurance. In this population with supplementary health coverage, the molecular investigation of hereditary cancer for suspected cases of Hereditary Breast and Ovarian Cancer Syndrome is governed by the National Supplementary Health Agency through the Utilization Guidelines published in Annex II of the mandatory procedures list. The latest guidelines provide for a stepped investigation using next-generation sequencing and multiplex ligation-dependent probe amplification of the BRCA1 and BRCA2 genes, and in case of inconclusive results, performing germline panel testing through next-generation sequencing of the ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, TP53 genes, and in case of a new inconclusive result and if the panel in question is not validated for copy number analysis, performing multiplex ligation-dependent probe amplification of the same genes. Recent evidence suggests that this stepped investigation currently provided for by the National Supplementary Health Agency can be optimized by using only the germline panel with copy number analysis. This study evaluated 701 patients with criteria for molecular investigation of Hereditary Breast and Ovarian Cancer Syndrome according to the procedures list of the National Supplementary Health Agency. All patients were consulted by a geneticist and underwent testing using a germline panel through next-generation sequencing with copy number analysis. Methods: Between 2021 and 2022, 701 patients with criteria for Hereditary Breast and Ovarian Cancer Syndrome according to the criteria of the National Supplementary Health Agency were evaluated by a geneticist in Belo Horizonte, Minas Gerais, including 683 women and 18 men. All patients underwent testing at private laboratories using a germline panel with next-generation sequencing and copy number analysis using the NovaSeq Illumina platform. A subset of 348 patients was analyzed using a 40-gene panel, while another subset of 353 patients was analyzed using a 141-gene panel. Results: Pathogenic and likely pathogenic variants were identified in 19.54% of the patients. In the subset analyzed using 40 genes, the detection rate was 16.4% for one variant and 0.29% for two different variants, while in the subset analyzed using 141 genes, the detection rate was 22.7% for one variant and 2.27% for two variants. Nine percent of the patients had variants in autosomal dominant inheritance genes, 11% in recessive genes, and 2.2% in genes with both inheritance mechanisms. The incidence of variants with uncertain clinical significance was 47.12% in the 40-gene panels and 82.72% in the 141-gene panels. The results were subjected to statistical tests. The Mann-Whitney test was used between the female and male sample groups, with no significant difference between the results. The incidences of pathogenic and likely pathogenic variants between the 40-gene and 141-gene panels were subjected to the chi-square test, suggesting that tests with a larger number of genes are more likely to detect pathogenic and likely pathogenic variants. Conclusions: The results suggest that replacing the stepped investigation currently provided for by the National Supplementary Health Agency with the use of a germline panel with next-generation sequencing and copy number analysis as the initial method for patients with Hereditary Ovarian Cancer Syndrome criteria can detect up to a 22.7% incidence of pathogenic and likely pathogenic variants, representing a reduction in time and possibly the cost of investigation.