Microbial and Molecular Drivers of early-Onset Colorectal Cancer

Abstract

Global incidence of early-onset colorectal cancer (EO-CRC) has increased by approximately 2% annually over the past three decades, representing a fundamental shift in the epidemiology of colorectal cancer (CRC). EO-CRC, defined as a diagnosis before the age of 50, now accounts for approximately 10-12% of all new CRC cases, while incidence rates in older populations have stabilized or declined. This narrative review compares the molecular, genetic, epigenetic, and microbial landscapes of EO-CRC and late onset colorectal cancer (LO-CRC) through synthesis of the available evidence. We highlight growing evidence that EO-CRC may not be just an early manifestation of sporadic disease but rather a heterogeneous malignancy with distinct molecular signatures by combining data from recent multi-omics studies and large-scale genomic consortia such as TCGA and GECCO. Notably, emerging multi-omics evidence highlights a distinct microbiome signature in EO-CRC, with enrichment of Flavonifractor plautii and genotoxic pks+ (polyketide synthase-positive) Escherichia coli, which may contribute to early carcinogenesis through flavonoid depletion, immune modulation, and colibactin-mediated DNA damage. These molecular and microbial features correlate clinically with a left-sided anatomical predominance, advanced stage at diagnosis, and aggressive histopathological characteristics, including mucinous and signet ring cell differentiation, particularly in patients under 35 years. These findings have important clinical implications for age-stratified screening, biomarker-guided risk assessment, and the development of targeted therapeutic strategies tailored to younger CRC patients. This review highlights critical gaps related to missing heritability and proposes a precision oncology framework for age-stratified screening and biomarker directed therapy. Addressing the unmet clinical need for earlier detection strategies tailored to younger populations remains a central priority for reducing the growing public health burden of this disease. Although hereditary syndromes such as Lynch syndrome are enriched among younger patients (16-25%), the majority of EO-CRC cases are sporadic and exhibit a predominantly microsatellite stable (MSS), low tumour mutational burden (TMB) phenotype, suggesting distinct non-hereditary molecular and environmental drivers. Transcriptomic analyses demonstrate a marked enrichment of the CMS2 subtype in EO-CRC (~75%) compared to LO-CRC (~40%), reflecting dominant activation of canonical Wnt/MYC signalling pathways. Somatically, the mutational landscape of EO-CRC may exhibit a distinct hierarchy of driver mutations, with an increased frequency of TP53 and CTNNB1 mutations and a reduced frequency of BRAF V600E and APC mutations compared with older patients. Epigenetically, young tumours have been reported to present with more extensive global hypomethylation, especially of LINE-1 elements, and more pronounced methylation canyon erosion, compared with the CpG Island Methylator Phenotype (CIMP-High) commonly observed in right-sided tumours of older patients.