Title: Mechanisms and consequences of hyper/ultramutation in colorectal and endometrial cancer
Funder: Cancer Research UK

Abstract: Background 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. This proposal seeks to address these critical gaps in our understanding and improve care for this large patient group. Aims i. To define the functional genomic landscape of dMMR and POLE-exo *CRC and EC and how variation in this correlates with patient outcome ii. To dissect the functional interaction between the dMMR/POLE-exo *tumour (epi)genome and the anti-tumour immune response iii. To confirm the value of novel prognostic or predictive markers identified in (i) and (ii) in trial cohorts iv. To determine the mechanisms and clinical consequences of hyper/ultramutation unexplained by dMMR or POLE-exo* in CRC and EC Methods We will pool multiple series to generate the largest cohort of hyper/ultramutated CRCs and ECs analysed by genome/exome sequencing to date, and extend our existing preclinical models to provide a portfolio of intestinal and endometrial dMMR and POLE-exo* tumorigenesis. We 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. We will 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 we will validate in large clinical trial cohorts available to us. We 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. How the results of this research will be used. This research will improve our understanding of the biology of hyper/ultramutated CRCs and ECs, and provide new molecular stratifiers for prospective validation and clinical implementation. Ultimately it seeks to improve the care of many thousands of patients with hyper/ultramutated CRC and EC each year, by avoiding toxic treatment in those who don’t need it, and targeting better treatments to those who do.

Lay abstract: Background 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. This proposal seeks to address these critical gaps in our understanding and improve care for this large patient group. Aims i. To define the functional genomic landscape of dMMR and POLE-exo *CRC and EC and how variation in this correlates with patient outcome ii. To dissect the functional interaction between the dMMR/POLE-exo *tumour (epi)genome and the anti-tumour immune response iii. To confirm the value of novel prognostic or predictive markers identified in (i) and (ii) in trial cohorts iv. To determine the mechanisms and clinical consequences of hyper/ultramutation unexplained by dMMR or POLE-exo* in CRC and EC Methods We will pool multiple series to generate the largest cohort of hyper/ultramutated CRCs and ECs analysed by genome/exome sequencing to date, and extend our existing preclinical models to provide a portfolio of intestinal and endometrial dMMR and POLE-exo* tumorigenesis. We 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. We will 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 we will validate in large clinical trial cohorts available to us. We 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. How the results of this research will be used. This research will improve our understanding of the biology of hyper/ultramutated CRCs and ECs, and provide new molecular stratifiers for prospective validation and clinical implementation. Ultimately it seeks to improve the care of many thousands of patients with hyper/ultramutated CRC and EC each year, by avoiding toxic treatment in those who don’t need it, and targeting better treatments to those who do.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS