Background: Breast cancer (BC) is one of the leading neoplasms among women worldwide, with the luminal subtype (LBC) being the most prevalent.However, Brazilian genomic data remains scarce, limiting precision oncology approaches, especially among women who do not carry pathogenic or likely pathogenic (P/LP) genetic variants (GVs) in genes related to hereditary breast-ovarian cancer (HBOC) syndromes.This study aimed to characterize the germline genomic profile of an unselected cohort of LBC in Parana, Brazil, using whole-exome sequencing (WES) data, and compared it with controls. Methods:We analyzed germline WES data from 73 women with LBC and 177 controls from Curitiba, Brazil.Data processing followed GATK Best Practices and stringent filtering (VQSR and CEGH Filter) to identify high-confidence GVs.Annotation was carried out on ANNOVAR.We assessed the presence of P/LP GVs in BC susceptibility genes (BCSGs) in both groups.Cases were also clinically reclassified based on the identification of moderate-to high-penetrance P/LP GVs in HBOC genes. Results:We identified 350,686 high-confidence GVs in the LBC cohort, including 13,020 novel variants absent from major public databases (gnomAD, 1kGP, ABraOM).The frequency of carriers of P/LP GVs in BCSGs was significantly higher in cases (17.8%) compared to controls (7.9%) (OR: 2.59; p=0.02), and carrier status was strongly associated with relevant cancer family history (OR: 4.29; p=0.02).Notable findings included the BRCA2 c.475+1G>A GV in a patient of Japanese descentlikely the first report in Braziland the BRCA2 c.6656C>G GVrecurrent in Brazil, yet not reported in Paran.WES data led to the reclassification of 8 cases previously stratified as familial or sporadic BC.The proportion of HBOC syndrome in the LBC cohort increased from 5.5% to 16.4% after reclassification.Notably, four clinically sporadic cases were reclassified as HBOC syndrome.
Galasso et al. (Fri,) studied this question.