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; Molecular characteristics; Mutations; Transcriptomics; oncogenes.

Figure 1

Progression of normal mucosa to colorectal cancer subtypes. Shown are the major mutations in genes or pathways that have been implicated in the change from a normal colonic mucosa to cancer. In blue are the consensus molecular subtypes of cancers that arise from the preceding mutations based on transcriptomic analyses of colorectal cancer. This flow chart was assembled and modified from figures and information published in Langner et al[29] and Nguyen et al[31]. CMS: Consensus molecular subtype; MMR: Mismatch repair; CIMP: CpG island methylator phenotype-high.

Figure 2

Summary of key DNA, RNA, and protein alterations identified in early-onset colorectal cancer. Shown are DNA mutations and modifications, mRNA expression changes, and protein expression changes that have been reported to contribute to early-onset colorectal cancer and that may serve as biomarkers. miRNA: microRNAs.