The Integration of Germline Genetic Variations to Precision Medicine in Healthcare as applied to Screening and Treatment Paradigms
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Embargo End Date
2026-05-10
ICR Authors
Authors
Jones, A-B
Document Type
Thesis or Dissertation
Date
2025-11-10
Date Accepted
Abstract
In recent years, the ability to use an individual’s genetic information to predict, prevent, diagnose, and treat a wide range of conditions had grown substantially. Advances in genomic research, personalised medicine, and bioinformatics have enabled healthcare providers to give more accurate risk prediction, improve earlier detection, and customise targeted treatment strategies based on an individual’s genetic profile.
Applications of genomic medicine already span multiple healthcare domains, such as cancer diagnosis and management, cardiovascular disease, rare inherited disorders, and pharmacogenomics. Recent advances in genomics offer new opportunities to enhance traditional screening models through integration of genetic risk information , including both high-penetrance single gene variants and polygenic risk scores (PRS).
My MD(Res) investigates the use of germline genetic testing in two distinct settings: a feasibility study exploring the use of whole genome sequencing (WGS) in primary care among asymptomatic individuals, and the use of germline testing to guide treatment in men with metastatic castration resistant prostate cancer (mCRPC).
The 90S Study recruited individuals from a private general practice for germline genetic testing as an adjunct to medical screening. Results show that 22% (23/104) of participants had actionable germline genetics variants altering medical management or screening pathways. Ten of these (43%) had pathogenic variants in cancer predisposition genes, 60 (58%) participants harboured recessive alleles and 43 (41%) had pharmacogenetic variants. Participants who had a PRS above the 80th percentile may have a significantly increased risk of the associated cancer. This study shows how embedding germline WGS testing in a medical screening pathway is feasible in a community-based healthcare setting.
The BARCODE2 study is part of a clinical trial examining the use of a panel of DNA repair genes (DRG) to target therapy among men with mCRPC. This work includes analysis of 220 study
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participants. The pathogenic/likely pathogenic (P/LP) detection rate was 15.5%. Overall, carriers had higher Gleason scores (8-10) and higher PSA at diagnosis compared with non-carriers. Sub-analyses showed that BRCA2/ATM carriers had more aggressive disease at diagnosis compared with non-carriers. Time to onset of castration resistant disease was significantly shorter among BRCA2/ATM carriers (p=0.04).
These studies provide evidence to support broader use of genomically informed screening and treatment pathways.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Oncogenetics