Abordaje de estudio genético del cáncer de ovario epitelial de alto grado sensible a derivados del platino mediante técnicas de secuenciación masiva con un amplio panel de genes

Résumé

Ovarian cancer is the gynecological cancer with the highest mortality, with high-grade serous ovarian cancer accounting for 75% of this pathology, characterized by having an aggressive course and being diagnosed in advanced stages. One of the inclusion criteria according to the Spanish Society of Medical Oncology for high-risk hereditary breast and ovarian cancer syndrome (HOCCOS) is the diagnosis of non-mucinous high-grade epithelial ovarian cancer. SCMOH has an autosomal dominant inheritance pattern in cancer susceptibility genes. Historically, the risk of SCMOH has been mainly linked to germline mutations in BRCA1/2. However, it is now also associated with tumor suppressor genes involved in DNA repair. High-grade ovarian cancer is evidenced by being genetically unstable and approximately 50% of these tumors are deficient in DNA repair mechanisms by homologous recombination. The diagnostic yield obtained in the CO genetic study was 22% in the BRCA population. This data justifies the importance of including this phenotype in the SEOM selection criteria for the study of hereditary breast and ovarian cancer syndrome. The genetic study of OC, through a panel of clinical action genes related to various hereditary syndromes, manages to increase the diagnostic yield with respect to the study of the BRCA1 and BRCA2 genes alone. Therefore, its inclusion in clinical practice is necessary. From a clinical point of view, 52% of the variants obtained have been classified as VP and 48% as VUS. When extending the genetic study to a panel of genes, the number of VUS obtained increases and may even exceed the number of VP. For this reason, the laboratory must have an updated registry of the VUS obtained and reevaluate them periodically in order to achieve their clinical classification unequivocally. From the molecular point of view, and in agreement with the literature, 65% of the VP obtained were frameshift variants. With respect to the VUS obtained, 87% were missense or frameshift variants, which makes their clinical classification difficult in those cases where insufficient information is available. Survival analysis of OC, as a function of response to first-line treatment with platinum derivatives, shows a better prognosis in the sensitive phenotype with respect to the partially sensitive or resistant phenotypes. This sensitive phenotype behaves the same in the presence or absence of VP in the BRCA1/2 genes, so it should share similar biological characteristics regardless of BRCA genotype. The use of NGS techniques to sequence a large panel of genes generates a large number of VUS. To facilitate and optimize the management of these variants, the use of VUS prioritization algorithms is indispensable. Thanks to this algorithm it has been possible to reclassify 8% of the VUS obtained as prioritized according to evidence of pathogenicity, making it an essential tool in healthcare practice.