Utilidad del estudio genético, mediante un amplio panel de genes clínicamente accionables, en el síndrome de cáncer de mama y ovario hereditario

Abstract

Hereditary breast and ovarian cancer syndrome (HBOC) has always been linked to pathogenic variants in the BRCA1 and BRCA2 genes; however, nowadays, it is known that there are other genes involved in this syndrome. In this work, thanks to the massive next-generation sequencing (NGS) technique, the genetic study of HBOC has been performed on a cohort of 414 index cases, previously selected by the genetic counseling consultation of the region of Murcia, according to the SEOM 2019 criteria, applying a panel of 50 genes, of which 20 clinically actionable recommended by the NCCN. In this study, a diagnostic yield obtained of 15.22% confirms the need to incorporate in the genetic analysis the panel of clinically actionable genes recommended by the NCCN clinical guideline, , through a genetic counseling consultation in hereditary cancer in which an appropriate selection of patients who are candidates for study is done. The high-grade epithelial ovarian cancer phenotype is the one with the highest diagnostic yield within the HBOC, thus confirming the importance of selecting this group of patients regardless of their family history. However, the use of the individual selection criteria of the SEOM 2019, related to breast cancer is a limiting factor when detecting patients with HBOC cancer carrying a VP/VPP. In this study, and in agreement with that described in the literature, the VP/VPP detected in the BRCA genes present a greater contribution in HBOC than the VP/VPP of the non-BRCA genes, with 56.9% versus 43.1%, respectively. However, the contribution of the latter is considerable, highlighting in our study the high contribution of the ATM gene, which was higher than the rest of the European and world studies, due to the VP c.8251_8254del, where its founder effect has been previously demonstrated in the Murcian population. There is a statistically significant association between triple-negative breast cancer and the BRCA1 gene, and bilateral breast cancer and the BRCA1 and CHEK2 genes. With respect to the mean age at diagnosis of unilateral breast cancer, this is lower in those patients carrying a VP/VPP in BRCA2. The re-evaluation of VUS considerably reduces the number of VUS, and it is recommended that laboratories use this re-evaluation strategy periodically. In addition, the VUS prioritization algorithm allows clinical laboratories to manage their resources more efficiently and to cope with the high number of VUS detected daily after gene panel analysis in clinical practice. The methodology based on the RT-PCR technique is a fundamental tool in the classification of those genetic variants susceptible to generate an aberrant splicing according to bioinformatics prediction programs. In fact, this technique has served to demonstrate that the genetic variant c.375+2T>C in the TP53 gene produces an aberrant maturation of the transcript that, in the case of protein synthesis, would generate a truncated protein. In the study of candidate genes for HBOC, the VP obtained in the low penetrance genes MRE11, RAD50 and XRCC2 should be highlighted. However, and according to current evidence, in these cases it is only possible to follow up index cases and family members carrying the VP/VPP detected. Therefore, these genes should only be used for research purposes until there is more scientific evidence. In the meantime, in healthcare practice it is advisable to use only panels that incorporate all the clinically actionable genes described by the scientific societies for each hereditary syndrome.