Characterisation of ZFP36L1, a novel breast cancer predisposition gene

  • Timothy Winter

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Genetic susceptibility is a well-established risk factor for breast cancer. Several high and moderate penetrance predisposition genes have been identified to date including BRCA1, BRCA2, CHEK2, ATM, and PALB2.Mutations in any of these genes result in greater than two-fold increases in risk of breast cancer formation to an individual but, owing to their rarity within the population, they are predicted to account for less than 25% of the familial risk of breast cancer. It is now thought that the remaining genetic risk is attributable not to rare, high penetrance mutations but to more common single nucleotide polymorphisms (SNPs) with comparatively modest individual effect sizes. The dawn of genome wide association studies (GWAS) has resulted in an enormous wave of discovery of approximately 200 of these SNPs. However, the majority are found in non-coding DNA and so the functional causes underpinning their risk effects are mostly unknown. Recent work from our lab and others has demonstrated by capture Hi-C that one such risk locus, 14q24.1,interacts with the promoter of a nearby RNA binding protein encoding gene,ZFP36L1. Expression quantitative trait locus (eQTL) analysis using TCGA data revealed a statistically significant reduction in ZFP36L1 expression (P =0.003) in carriers of the risk allele of the lead SNP at this region. These findings suggest that one or more functional SNPs at 14q24.1 influence breast cancer risk by repressing the expression of ZFP36L1. The work presented in this thesis illuminates the impact of abrogated ZFP36L1 expression in non-cancerous human breast epithelial cells and proposes mechanisms by which this affects cancer risk. Using a profile of assays examining various hallmarks of cancer, this work identifies two novel cancer-relevant cellular processes impacted by loss of ZFP36L1, as well as one novel functional mechanism of action ofZFP36L1, and two critical cancer-relevant mRNA targets of repression byZFP36L1.

Thesis is embargoed until 31 July 2025.

Date of AwardJul 2023
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsNorthern Ireland Department for the Economy
SupervisorNick Orr (Supervisor) & Seyed Mehdi Jafarnejad (Supervisor)

Keywords

  • ZFP36L1
  • breast cancer
  • post-GWAS
  • GWAS
  • functional genomics
  • RNA binding protein
  • DNA damage
  • proliferation
  • MDM2
  • 14q24.1

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