Deciphering the genetic basis of Spanish familial testicular cancer
- Autores: Beatriz Paumard Hernández
- Directores de la Tesis: Javier Benítez (dir. tes.)
- Lectura: En la Universidad Autónoma de Madrid ( España ) en 2017
- Idioma: inglés
- Número de páginas: 242
- Tribunal Calificador de la Tesis: José Fernández Piqueras (presid.), Karen Elise Heath (secret.), Juan Francisco Rodríguez Moreno (voc.), Beatriz Martínez Delgado (voc.), Ana Isabel González Neira (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: Biblos-e Archivo
- Resumen
Testicular cancer is a frequently occurring disease among adult males, and it accounts for 1-2% of all male tumors. It can be classified into different types of cancer: germ cell tumors (GCT), which represent 98% of all cases, and tumors involving the gonadal stromal tumors and secondary tumors of the testes. The incidence of Testicular Germ Cell Tumors (TGCTs) has been increasing for the past decades, although the etiology of the disease and the reasons of its increased incidence remain unknown. Environmental factors, in particular exposure to endocrine disruptors during embryogenesis and perinatal life are suspected culprits. It is likely that genetic factors also play an important role in TGCT formation, as the estimated heritability, 48.9%, is the third highest among all cancers, and the Familial Testicular Germ Cell Tumor (FTGCT) risk is 2-fold higher than what is typical for more common cancers such as breast, colorectal and prostate cancer. Several candidate gene approaches failed to identify high susceptibility genes. In fact, in the last years scientists have come to believe that a polygenic model fits better with the genetic landscape of the disease, although the idea of polygenic susceptibility does not fit in with a history of familial aggregations in a disease. Due to the absence of information about the genetic basis of this disease, our objective was to identify high/moderate or low susceptibility genes using whole exome sequencing (WES) and case-control studies considering both monogenic and polygenic models of inheritance. These studies will help to increase our knowledge about the genetic basis of the disease and may have a significant impact on its prevention, early diagnosis and a possible treatment.
The hypothesis of the monogenic model was tested using a pipeline previously described by our group, while the polygenic model was studied by performing family-based association tests in which we evaluated the level of additive and cumulative effects our variants could have in the familial aggregation of the disease. DNA of a group of 19 families (71 individuals) was sequenced with an Illumina HiSeq 2000 sequencer. Based on the analysis assuming both patterns of inheritance, a total of 120 candidate variants were evaluated in the case-control study performed in 391 sporadic cases and 382 healthy Spanish controls. In order to increase the size sample, we used data from the public database of the Spanish Center for Biomedical Research on Rare Diseases (CIBERER), which contains WES data of 788 unaffected individuals, and to perform statistical analysis. In this discovery analysis, 27 variants gave significant results and two of them (located in the VNN1 and SLC22A16 genes, which are both involved in spermatogenesis) were later on replicated in a large series studied in the English population. Moreover, the variant of the SLC22A16 gene appears to be specifically associated with the development of Seminoma germ cell tumors.
In summary, our results present two new susceptibility risk genes whose variants are potential candidates for being associated with the development of familial testicular cancer.
