RT info:eu-repo/semantics/doctoralThesis
T1 Genomic, predictive, and personalised medicine for aggressive thyroid tumours. Identification of diagnostic, prognostic, and therapeutic biomarkers.
A1 Gil Bernabé, Sara
A2 Universidad de Valladolid. Escuela de Doctorado
K1 Biomarcadores
K1 Thyroid cancer
K1 Cáncer de tiroides
K1 Biomarkers
K1 Biomarcadores
K1 Personalised medicine
K1 Medicina personalizada
K1 2410.02 Anatomía Humana
AB Thyroid cancer (TC) is one of the cancers that has increased in prevalence worldwide during the last decades. Although most cases are indolent, the increasing number of aggressive TCs has made this an urgent issue for study. To identify distinctive genomic alterations among patients with aggressive thyroid cancer (advanced stage, radioiodine resistant, PTCs with paired synchronous and/or metachronous DM, PDTCs and ATCs), and to detect reliable diagnostic, prognostic and therapeutic molecular biomarkers that can be easily analysed in daily clinical practice, using non-invasive tools and procedures will mean a pivotal improvement in the diagnosis and treatment of these patients. 112 patients with TC (21 PTCs with LNM, 20 PTCs with DM, 35 PDTCs and 36 ATCs) and 272 areas with different characteristics were analysed in several genes through direct sequencing and multiplex ligation-dependent probe amplification. Clonality and the spread of mutations during tumour progression and across primary tumour to metastasis were determined. EP300 alterations were not present in ATCs. EIF1AX mutations have been observed in PDTCs and ATCs, not in PTCs. TP53 and KIT mutations are present at low prevalence in aggressive PTCs. CTNNB1, PLEKSH1, and TBC1D12 are not biomarkers of aggressive PTCs. MED12 mutations are not present in TC. The other alterations analysed were present in all the aggressive histotypes, showing associations between them. RAS mutations and TERT amplifications significantly correlate with PTCs with DM. Most genetic events tend to spread with metastatic PTC cells to LNMs and DMs and can emerge “de novo” in metastases. Genetic events among PDTCs and ATCs spread with tumour dedifferentiation. All the alterations can appear as subclonal events. Therapies directed at mutations in only a subset of tumour cells (subclonal mutations) may exclusively affect that subclone, resulting in limited therapeutic efficacy. Molecular genetic heterogeneity increases with tumour progression. Several associations are made between genetic alterations and clinicopathological tumour features. Targeting subclonal events alone is insufficient to prevent tumour progression. Nowadays clinicians opt for targeted therapy based on a single biopsy, which may not accurately represent the clonal status of the targeted gene. Multiregional sequencing will help to determine an effective treatment that will attack several alterations to avoid drug resistance.
YR 2025
FD 2025
LK https://uvadoc.uva.es/handle/10324/75895
UL https://uvadoc.uva.es/handle/10324/75895
LA eng
NO Escuela de Doctorado
DS UVaDOC
RD 10-jun-2025