Predisposición germinal en pacientes adultos diagnosticados de síndrome mielodisplásico a una edad temprana sin disfunción orgánica previa

Resumo

The last decade has witnessed how large-scale genomic studies have undercover most of the underpinning genetic variants in the most frequent types of cancer, including not only acquired lesions, but also the presence of predisposing germline variants, even when the diagnosis was beyond the pediatric age. Thus, the 2017 fourth revision of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues included a new category: myeloid neoplasms with germline predisposition. The WHO includes 3 categories of myeloid neoplasms with germline predisposition: neoplasms without preexisting conditions, neoplasms with a history of thrombocytopenia, and neoplasms with another organ dysfunction. In this thesis work, we have focused on the first group, neoplasms without preexisting conditions, which only included, in the WHO classification, one gene predisposing to myelodysplastic syndromes (MDS), DDX41. We included MDS patients diagnosed between 2014 and June 2021, from 28 centers, within the Spanish Group of MDS. Paired germinal-tumor tissue whole exome sequencing was performed. Variants were selected out of a list of predisposing candidate genes including: genes previously described as associated with (blood or solid) cancer predisposition, involved in the DNA repair response, and those described recurrently as affected by somatic variant in myeloid neoplasms. Variants detected were characterized following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations. Fifty four out of the 194 patients (27.8%) harbored, at least, a germline variant categorized as pathogenic o likely pathogenic. By functional groups, the DNA repair response pathway was the most frequently affected. Moreover, a significant association with the acquisition of TP53 mutations and a worse outcome could be noted regarding this functional group. A significant percentage of MDS with ring sideroblasts, diagnosed in the adult age, showed germline variants commonly considered causative of the congenital sideroblastic anemias, suggesting the existence of an incomplete penetrance. We found a relevant number of cases with low microsatellite instability in the germinal tissue. A fourth of these cases showed a germline variant in the mismatch repair genes, but also in other damage response genes. In summary, MDS in childhood is characterized by germline variants known for causing the classical congenital bone marrow failure syndromes, and the common sporadic MDS cases in the elderly that show a predominance of acquired mutations, in our early-onset cohort of adults with MDS, without previous organ dysfunction, germline variants segregate within the DNA repair response genes group.