Dr David Church has recently been awarded a CRUK Advanced Clinician Scientist Fellowship, which supports excellent clinician scientists to develop independence and leadership in their field of academic research.
David’s project aims to define the functional genomic landscape of mismatch repair deficiency (dMMR) and POLE exonuclease domain mutations (POLE-exo*) in colorectal cancer and endometrial cancer, and to determine how variation in these molecular features correlate with patient outcome. By addressing the critical gaps in our understanding of how these factors interact, David hopes to improve care for the large number of patients diagnosed with these cancers, by refining their treatment, and identifying new therapeutic targets.
More than 800,000 people are diagnosed yearly with colorectal (CRC) or endometrial (EC) cancer in Europe and the US. Over 100,000 of these tumours carry a substantially elevated mutational load, usually owing to defective DNA mismatch repair (dMMR), POLE exonuclease domain mutations (POLE-exo*), or in 3–7% cases, unknown causes. These cancers typically display an enhanced T-cell response, and in some contexts, a good prognosis, although the reasons why this association varies are unknown. They are also sensitive to immune checkpoint inhibition; however the determinants of this and the optimum use of these agents is unclear.
David and his team will pool multiple series to generate the largest cohort of hyper/ultramutated CRCs and ECs analysed by genome/exome sequencing to date, and extend their existing preclinical models to provide a detailed assessment of intestinal and endometrial dMMR and POLE-exo* tumorigenesis. The researchers will analyse these in parallel to identify novel drivers and therapeutic targets, and use multispectral immunoprofiling to determine the impact of these variants on the antitumour immune response. They aim to integrate these datasets to understand the basis of the tissue dependency of the association between hyper/ultramutation and prognosis, and identify key prognostic/predictive markers which they will validate in large clinical trial cohorts. They will identify non-dMMR/POLE-exo* hyper/ultramutated cases among the sequenced tumours and investigate their cause using these data and preclinical models, and their consequences using the trial cohorts.