Molecular genetics of early-onset colorectal cancer

Abstract

Early-onset colorectal cancer (EOCRC) has been rising in global prevalence and incidence over the past several decades. Environmental influences, including generational lifestyle changes and rising obesity, contribute to these increased rates. While the rise in EOCRC is best documented in western countries, it is seen throughout the world, although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds. Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer (LOCRC). Recent studies have identified DNA, RNA, and protein-level alterations unique to EOCRC, revealing much-needed biomarkers and potential novel therapeutic targets. Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts, however, studies of other ethnic backgrounds are limited. In addition, certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC, including high-throughput analyses of histone modifications, mRNA splicing, and proteomics on large cohorts. We propose that the complex relationship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC. In this review, we summarize current EOCRC literature, focusing on sporadic molecular alterations in tumors, and their clinical implications. We conclude by discussing current challenges and future directions of EOCRC research efforts.

Keywords: Early-onset colorectal cancer; Later-onset colorectal cancer; Mutations; oncogenes; Molecular characteristics; Transcriptomics

Core Tip: Early-onset colorectal cancer (EOCRC) has a considerably different clinical presentation and genetic profile compared with later-onset colorectal cancer. Furthermore, molecular alterations in EOCRC tumors differ in patients from separate geographical locations and distinct ethnic groups. Small human cohorts and the lack of a suitable mouse model system limit EOCRC studies, however, several actionable clinical targets and biomarkers specific to EOCRC have been identified. In this review, we discuss molecular alterations in EOCRC tumors at the DNA, RNA, and protein levels, and suggest future work to examine how these changes contribute to EOCRC pathogenesis.