The Causes of the Global Increase in Early Onset Colorectal Cancer

Colorectal cancer diagnosed under 50 years of age has been rapidly increasing over recent decades such that early onset colorectal cancer is soon expected to become the leading cause of cancer-related death in young adults. The cause of the increased incidence is not known. We have developed extensive pilot data supporting the hypothesis that, over recent decades, a global increase in the prevalence of mutagen-producing microbes in the colonic microbiome of infants has caused increased mutation burdens in colorectal cells early in life and, consequently, an increase in early onset colorectal cancer. We will exploit the synergy between international cancer epidemiology, microbiome research and large-scale cancer genomics to comprehensively test this hypothesis. We will collect samples of normal blood, stools, normal colorectal tissue, and colorectal cancer, together with extensive exposure data, from over 3,000 individuals across 10 countries, including individuals with early and late onset colorectal cancer, as well as children and adults without cancer. We will generate over 12,000 whole genome sequences from both tumour and normal colonic tissue, and analyse mutational signatures linked to potential genotoxin producing bacteria. In parallel, we will undertake experiments to link specific bacteria to mutational signatures. This will be achieved by screening bacteria for genotoxic activity in vitro and then by sequencing genomes from gut organoids that had been exposed to genotoxic strains to identify mutational signatures. This unparalleled dataset will be analysed using state-of-the-art computational methods and provide the evidence base for a comprehensive evaluation of mutagen-producing bacteria as causes of early onset colorectal cancer, potentially leading to new prevention strategies. Finally, we will demonstrate the power of the synergy between global cancer epidemiology, microbiome research and large-scale cancer genomics to reveal new causes of cancer.