Unraveling the genomic landscape of colorectal cancer through mutational signatures

Abstract

Colorectal cancer, along with most other cancer types, is driven by somatic mutations. Characteristic patterns of somatic mutations, known as mutational signatures, arise as a result of the activities of different mutational processes. Mutational signatures have diverse origins, including exogenous and endogenous sources. In the case of colorectal cancer, the analysis of mutational signatures has elucidated specific signatures for classically associated DNA repair deficiencies, namely mismatch repair (leading to microsatellite instability), base excision repair (due to MUTYH or NTHL1 mutations), and polymerase proofreading (due to POLE and POLD1 exonuclease domain mutations). Additional signatures also play a role in colorectal cancer, including those related to normal aging and those associated with gut microbiota, as well as a number of signatures with unknown etiologies. This chapter provides an overview of the current knowledge of mutational signatures, with a focus on colorectal cancer and on the recently reported signatures in physiologically normal and inflammatory bowel disease-affected somatic colon tissues.

Keywords: Cancer genomics; Colorectal cancer; DNA repair; Microbiota; Mutational signatures; Somatic mutations.