Genetic investigation of prostate cancer: Evaluation of markers and relationship with Gleason score and metastasis.
Authors: Freitas Carla Simone Moreira , Silva Fabiana Rocha , Silva Thais Almeida Marques da , Soares Aleida Nazareth 
Published: June 2024

e17066 Background: The need to identify genetic, prognostic and predictive markers for prostate cancer (PC), metastatic or not, is fundamental for choosing the best treatment. Prevalence of pathogenic DNA damage repair (gDDR) mutations, mainly BRCA2 (gBRCA), was identified in Anglo-American populations with mPC (5.3%), Chinese (4.3%), Spanish (3.3%) and Italian (3%). In this sense, highlighting similarities or discrepancies in genetic changes in different populations is important for the development of therapeutic strategies. To evaluate the prevalence of gDDR, the understanding of gDDR in a Brazilian region and provide support for the development of personalized therapies. This research aims to fill gaps in current knowledge in the treatment of metastatic PC. Methods: Study approved by CONEP-SCBH-CAAE 42638620.3.0000.5138. A prospective observational trial was carried out, from 2020 to 2023, of 89 patients with CP who underwent screening for gDDR mutations in 16 genes evaluated by NGS. Firstly, the frequency of germline mutations in BRCA1, BRCA2, ATM, CDK12, CHECK1, CHECK2, FANCL2, PALB2, PPP2R2A, RAD51B, RAD51C and RAD51D, RAD54L and TP53 was determined. After that, the association of gDDR subgroups with metastasis and Gleason ≥8 was examined. Results: It was identified that 24.7% of patients (n=22) presented pathogenic variants. The most prevalent mutations with CP were: TP53 with 20.2% (n=18); BRCA2 with 5.6% of patients (n=5); BRCA1 with 4.5% (n=4); RAD54L with 3.4% (n=3); BARD1, CHECK2 and PALB2 with 2.2% (n=2; for each gene); followed by CDK12, FANCL, RAD51B, RAD52C with 1.1% of patients (n=1; for each gene). The prevalence of gBRCA2 in the studied population was 5.6%, similar to the Anglo-American population. Furthermore, a significant association was observed for Gleason≥8 (p<=0.05). In patients with metastatic PC, the most prevalent mutations were: TP53 with 26.7% of patients (n=8); BRCA1 with 6.8% (n=4); BRCA2 with 6.7% (n=3); 3.4 with PALB2 and FANCL (n=2; for each gene); followed by BARD1, CDK2, CHEC2, RAD51B, RADI51C, RAD 54L with 1.1% (n=1; for each gene). No mutations in BRIP, CHEC1, PPP2R2A, RAD51D were identified. In metastatic patients, no genetic changes were found in BRIP-1, CHEK1, PPP2R2A, RADD. Conclusions: The prevalence of gBRCA2 in the studied population was 5.6%, similar to the Anglo-American population. These genetic similarities suggest the existence of hereditary and genetic factors that transcend borders, highlighting the relevance of investigations into the origins and clinical implications of these specific mutations in the Brazilian population, and may have direct implications for the clinical approach, allowing the application of therapeutic strategies developed with based on already consolidated knowledge. Association of TP53 and Gleason score >=8 suggests a potential role for this gene in the manifestation of a more aggressive phenotype of the disease. Clinical trial information: CAAE42638620.3.0000.5138.