Genomic alterations in familial and sporadic epithelial ovarian carcinomas and their clinical relevance

• Autores: Marta Kamieniak
• Directores de la Tesis: Javier Benítez Ortiz (dir. tes.), María José García (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2014
• Idioma: inglés
• Tribunal Calificador de la Tesis: José Fernández Piqueras (presid.), María Belén Pérez González (secret.), Sara Alvarez De Andrés (voc.), Ahmed Ahmed (voc.), José Palacios Calvo (voc.)
• Materias:
  • Ciencias médicas
    • Ciencias clínicas
      • Oncología
      • Genética clínica
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • 1. Our results indicate that sporadic and familiar EOCs exhibit a similar global pattern of DNA copy number changes as reflected by comparable frequency plots and lack of stratification by unsupervised hierarchical clustering. Overall, high levels of genomic instability and greater contribution of losses versus gains was a common feature in EOCs.

    2. We defined a set of recurrent DNA copy number changes shared by sporadic and familial EOCs that encompassed known and putative cancer-related genes. These commonly altered regions and genes would point to key events in ovarian carcinogenesis in general, regardless the existence of germinal mutations in the BRCA1 or BRCA2 genes.

    3. Despite general similarity between sporadic and hereditary EOCs, we found that extensive genomic loss was significantly higher in tumors from BRCA1 and BRCA2 mutation carriers. In addition we could also define a few, but potentially specific, BRCA1- associated alterations. These hallmark features might be clinically relevant as it could help to identify BRCA-related patients, who present better prognosis when treated with standard regimes and are likely to respond to PARP inhibitors.

    4. DNA copy number profiles of BRCAX cases presented the lowest total number of alterations overall and in particular of losses resembling more sporadic than BRCA1/2 tumors. Also, the greater involvement of losses compared to gains was less marked in this tumor group and similar to that observed in sporadic cases, supporting that prominent genomic loss is particularly related to BRCA1 and BRCA2 dysfunctions.

    5. Groups of EOCs defined based on their DNA copy number profiles showed an association with histotype, FIGO stage and proliferation-related markers. In particular we found that EOCs of greater genomic instability are more likely to be of higher FIGO stage, serous subtype and show increased expression of TP53, Ki-67 and survivin.

    6. Deletion at 6q24-q26 was found to be an independent prognostic marker for overall and 5yrs survival in patients with EOC. In particular, our results indicate prognostic utility in high grade serous ovarian carcinomas, the most common and aggressive subtype. This marker has a potential clinical value, as it can be analyzed by FISH on tumor sections and guide selection of patients towards more conservative therapeutic strategies in order to reduce side-effects and to improve quality of life.