CCE Lecture: Exposomic epigenetic fingerprints of early-onset colorectal cancer (Jose A. Seoane)

Colorectal cancer incidence is rising dramatically among individuals under 50 years of age. Epidemiological studies have identified exposome-related risk factors, including dietary patterns, smoking or alcohol consumption, as contributors to this trend. However, many environmental exposures remain unknow, largely due to the challenge of obtaining reliable historical exposure data. Recently, colibactin, a genotoxin produced by specific pks+ E. coli strains, has been implicated in early-onset colorectal cancer through its distinctive mutational signature in tumor DNA. Yet, mutational signatures can only detect mutagenic exposures, limiting their utility for investigating the full spectrum of carcinogens.

Here, we present a novel methodology that leverages tumor DNA methylation patterns to reconstruct patients’ historical exposome, enabling identification of non-mutagenic
environmental exposures. Applied to early-onset colorectal cancer cohorts, this approach uncovers both known and novel exposure signatures associated with early-onset colorectal cancer and identifies a specific pesticide as a potential risk factor for colorectal cancer development.

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