The Metabolic Roots of Early-Onset Colorectal Cancer

Once considered a rarity, the rise in colorectal cancer diagnoses among individuals under 50 is now a well-documented and pressing public health trend. Recent investigations show that metabolic dysregulation, specifically obesity and type 2 diabetes mellitus (T2DM), is more than just a comorbidity—it could potentially be a driver of early-onset colorectal cancer (EOCRC).

Over the past three decades, EOCRC incidence has increased by over 60% in the U.S., mirroring sharp rises in obesity and T2DM rates among individuals aged 20–49. Cohort and case-control studies consistently associate higher BMI and poor glycemic control with elevated EOCRC risk, even after adjusting for other risk factors.

What distinguishes EOCRC is its clinical, molecular, and anatomical profile. EOCRC tumors tend to occur in the distal colon and rectum, often presenting at more advanced stages. Additionally, atypical mutational landscapes, such as higher prevalence of TP53,CTNNB1, and PTEN mutations and lower rates of KRAS, APC, and BRAF, are more common in EOCRC compared to traditional, late-onset CRC.

Pathways Linking Metabolic Disease and EOCRC

The review outlines three key mechanistic pathways through which metabolic dysfunction likely contributes to colorectal carcinogenesis in young adults:

1. Insulin resistance and hyperinsulinemia: Chronic metabolic overload in obesity and T2DM promotes excess insulin and IGF-1 signaling—factors that drive cellular proliferation and inhibit apoptosis via PI3K–AKT–mTOR and RAS–MAPK pathways.
2. Chronic low-grade inflammation: Visceral adiposity and insulin resistance promote pro-inflammatory cytokines (IL-6, TNF), ROS generation, and impaired intestinal barrier integrity, facilitating mutagenesis and tumor growth.
3. Altered gut microbiota: Obesity and T2DM induce dysbiosis, reducing protective butyrate-producing bacteria while increasing pro-tumorigenic species like Fusobacterium nucleatum. These changes disrupt mucosal immunity and can amplify oncogenic signaling.

Diet, Lifestyle, and Early Exposure

Western dietary patterns, defined by ultra-processed foods, sugar-sweetened beverages, and red/processed meats, are potent upstream contributors to both metabolic dysfunction and EOCRC risk. One study revealed that women consuming two or more servings of sugary drinks per day had over twice the risk of EOCRC.

Physical inactivity, antibiotic exposure, and early-life obesity further compound this risk, suggesting that early-life metabolic trajectory may be a critical determinant in EOCRC pathogenesis.

Screening, Risk Stratification, and Interventions

Current colorectal cancer screening guidelines typically begin at age 45, potentially missing up to half of EOCRC cases. This has prompted calls for a metabolic risk-based screening strategy, especially for individuals with obesity, T2DM, or adverse lifestyle factors.

Promising approaches include lifestyle interventions, pharmacologic tools, and policy levers. Community and tech-based weight loss and glycemic control programs modeled on the Diabetes Prevention Program show early promise. Additionally, agents like GLP-1 receptor agonists, metformin, and possibly aspirin may offer dual benefit in managing metabolic disease and lowering EOCRC risk, although targeted trials are still needed.

Implications for Practice and Research

The authors call for longitudinal, multi-omics-driven studies to decode the interplay of metabolism, microbiome, and genetics in EOCRC. The Cancer Grand Challenges Team PROSPECT, launched in 2024, is one such effort aiming to fill these gaps.

EOCRC is biologically and epidemiologically distinct, and recognizing obesity and T2DM as upstream contributors offers an opportunity to shift from reactive treatment to precision prevention.

Reference
Du M, Drew DA, Goncalves MD, Cao Y, Chan AT. Early-onset colorectal cancer as an emerging disease of metabolic dysregulation. Nat Rev Endocrinol. 2025;21(11):686–702. doi:10.1038/s41574-025-01159-z