Influence of somatic mutant allelic imbalance in breast cancer clinical characteristics

• Autor(a) principal: Correia, Lizelle Winkelströter
• Data de Publicação: 2019
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.1/15042
• topic: PIK3CA; TP53; Expressão diferencial de alelos; Cancro da mama; Cisregulação; Desequilíbrio alélico; Domínio/Área Científica::Ciências Médicas::Outras Ciências Médicas

Breast cancer is genomic and clinically heterogeneous, which represents a major challenge for treatment choice and has important consequences in survival rates. In the past decade studies profiled breast tumours, cataloguing somatic mutations and copy number alterations, which greatly improved prognosis and both expanded and facilitated treatment choices. In spite of this substantial progress, the current classification systems and biomarkers still do not encompass all breast cancer heterogeneity. Dosage changes of mutated allele has been associated with alterations in prognosis and in response to treatment. However, all studies examined the clinical association of somatic mutations and allelic imbalance solely at DNA level, leaving the contribution of gene expression regulation somewhat overlooked. Cis-regulatory variation is known to be a major determinant of allelic imbalance of expression, and a vast majority of the human genome is known to be affected by this. The most robust approach to detect the effect of, and map, cis-regulatory variation is to analyse differential allelic expression in heterozygotes. So, I hypothesised that differential allelic expression of mutated genes contributes to breast cancer biology and outcome, by creating imbalances in the allelic levels of gene expression (dosage) of somatic mutations. Using data from two independent sets of breast tumours, from METABRIC and TCGA projects, I studied the allelic imbalance of the two most mutated genes, PIK3CA and TP53. I show that preferential expression of the mutated allele presents positive selection, even more significantly that copy-number alterations. Also, I show that somatic mutations’ allelic imbalance resulting from cis-regulation impacts on the clinical characteristics of tumours, namely by showing association with known prognostic factors. Finally, tumours with differential allelic expression of PIK3CA’s mutated allele associated with poorer prognosis. The work presented in this thesis suggests that allelic imbalance generated by cis-regulation has an essential role in modulating of the effect of somatic mutations in tumours, as well as tumour clinical behaviour.