The use of germline genetic profiles to guide prostate cancer targeted screening and cancer care
Thesis or Dissertation
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The genetic heritability of prostate cancer is contributed to by rarely occurring but high penetrant genetic variants, and moderate to commonly occurring variants conferring lower risks. Genome wide association studies and meta-analyses have discovered >170 prostate cancer risk loci. Utilising a prostate cancer risk score (PRS) could allow screening to be stratified by genetic risk. This thesis aims to investigate the potential role of germline genetic profiles in targeted screening for healthy men, and personalising treatment for affected patients. Utilising a SNP based genetic profile in the community to target prostate cancer screening to men with increased risk was acceptable to men in the community and their primary care teams. Within the BARCODE1 pilot study (N=307), uptake of screening procedures by men with a PRS in the top 10% of the risk distribution was 76%. Of the men screened, 33% were diagnosed with a low grade cancer. Further follow up is required to assess whether these are over-diagnosed indolent cases or early stage cancers that will progress further. The pilot study has moved on to the development of the main BARCODE1 study which is recruiting a further 4700 men. I set up the lab workflow for the phase II BARCODE2 trial which is recruiting men with advanced prostate cancer for germline NGS using a study specific gene panel. I sequenced the first 100 patients recruited to the trial and found that 22% carried a germline protein truncating variant in a DNA repair gene. Carriers had more aggressive disease features compared with non-carriers. I also sequenced somatic DNA for a subset of the BARCODE2 carrier patients (N=8) using FFPE derived DNA. One case displayed evidence of loss of heterozygosity for the germline variant. Low frequency somatic variants in MMR and HR genes were identified in some cases. With the recently reported response rates to targeted agents such as PARPi in prostate cancer patients with DNA repair defects, germline and somatic NGS will be increasingly important in the management of prostate cancer patients.
Prostate Cancer - Genetics
Prostate Cancer - Therapy
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Institute of Cancer Research (University Of London)