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2025 The John Black Charitable Foundation – PCF Young Investigator Award

The Impact of Tandem Repeats on the Evolution of Prostate Cancer: From Germline Features to Predicting Clinical Behavior

Gianmarco Leone, MD
University College London (UCL) Cancer Institute

Mentors: Gerhardt Attard, Andrea Alimonti, Francesca Demichelis

Description:

  • Tandem repeats are polymorphic DNA sequences in which a pattern of nucleotides is repeated a varying number of times – this can cause these DNA regions to take on alternate 3D structures that impact gene expression and DNA integrity. Despite representing around 10% of the human genome and having a well-defined role in the pathogenesis of several neurodegenerative conditions, the role of tandem repeats in cancer is understudied.
  • In cancer cells, genomic breaks occur more frequently near certain types of tandem repeats. The role of tandem repeats in causing DNA breaks or other genomic alterations such as copy number changes, is important for study in prostate cancer.
  • In this project, Dr. Gianmarco Leone will identify germline variable number tandem repeat variants in patients with prostate cancer and correlate these with emergence of specific genomic aberrations after exposure to treatment, including in patients with metastatic prostate cancer starting first-line hormone treatment.
  • New genome editing model systems will be developed to define the relationship between tandem repeats variants and prostate cancer structural genomic aberrations and for future research including development of new tandem repeat-directed therapeutic agents.
  • Whether tandem repeat genomic variants drive androgen receptor gene amplification as a mechanism of resistance to hormone treatment will be investigated.
  • If successful, this project will be the first to associate these germline DNA biomarkers with alterations selected during treatment for prostate cancer.

What this means to patients: Specific tandem repeat features in DNA predispose to altered DNA structures and DNA breakage; the role of these has been understudied in prostate cancer. Dr. Leone’s project will determine whether any tandem repeat features play a role in prostate cancer and clinical outcomes such as resistance to hormone therapy. This will lead to new understanding of prostate cancer biology and new biomarker tests that can be applied for risk stratification, personalized therapeutic approaches, and development of new cancer treatments.