Intercepting colorectal cancer at the extremes of age

By 2050, the "war on cancer" will have undergone a fundamental shift—moving beyond reactionary interventions to prevent cancer before it begins. Cancer preventive care today still relies on detecting a clinically established yet asymptomatic cancer—a brief window that, once missed, results in symptomatic, advanced disease resistant to cure. An alarming example demanding a paradigm shift is the rising tide of early-onset colorectal cancer (eoCRC)—diagnosed in adults aged under 50 (1)—posing a public health crisis projected to intensify through mid-century (2). Yet, because CRC still primarily manifests in later life, preventing it before it begins requires research to expand across the entire developmental arc. We must model disease at the extremes of age—neonatal and juvenile growth, as well as ageing—and feed this knowledge into innovative preventive measures.

The gastrointestinal (GI) tract is our primary interface with nutrients and microbiota, but also with environmental carcinogens. Its functional unit, the crypt, is uniquely vulnerable during early life ontogeny. Unlike the adult gut, the neonatal GI tract undergoes rapid expansion through crypt fission, whereby acquired mutations become "fixed," propagating through the developing gut architecture (3).

Genotoxins like colibactin, produced by pks+ Escherichia coli, are linked to eoCRC (4, 5). The colibactin mutational signature traces back to exposures as early as age two (6). When mutagens strike during peak crypt fission, they create a legacy of risk. Shoemaker et al. showed this presciently: neonatal exposure to the mutagen N-ethyl-N-nitrosourea dramatically increased intestinal tumorigenesis in Apc^Min mice (7).

By 2050, we will have introduced appropriately aged preclinical models capturing stem cell dynamics in the neonatal colon, where DNA repair and epigenetic programming are in flux—fixing mutations irreversibly into the genome. Equally, we will have modelled the geriatric population better; old age is CRC’s greatest predisposing factor, and the aged microbiome and "inflammaging" remain under-researched contributors (8).

Having moved away from reactionary screenings in old age, we will have established proactive surveillance spanning the entire life-course. Through longitudinal multi-omics profiling of accessible samples such as liquid biopsies and stool, combined with AI-driven stratification, we will have constructed "molecular ledgers" to trace an individual’s cancer risk back to its origins, including genomic hits acquired as early as the first 1,000 days of life.

Prevention will be multimodal; it will involve immunological and microbial priming in neonates, potentially "vaccinating" the gut against genotoxic agents like pks+ E. coli—alongside regenerative therapies designed to maintain a youthful tissue environment. Rejuvenating the microbiome and the stem cell niche may prevent the activation of dormant oncogenic cells. Metabolic interventions will be tailored to the kinetics of developing or ageing crypts alike.

This paradigm could address the projected 40% of GI cancer burden arising in younger populations. However, realising this vision demands equitable global implementation—ensuring resource-limited setting have access to preventive interventions from birth. By expanding our focus to include the extremes of age, we reframe cancer—not as an inevitable consequence of time, but as a preventable error in biological growth and decay. By 2050, we will not just treat the tumour; we will safeguard human health during its most vulnerable stages of development and decline.

References

1. Jayakrishnan T, Ng K. Early-Onset Gastrointestinal Cancers: A Review. JAMA. 2025;334(15):1373-85.
2. Li X, Xiao X, Wu Z, Li A, Wang W, Lin R. Global, regional, and national burden of early-onset colorectal cancer and projection to 2050: An analysis based on the Global Burden of Disease Study 2021. Public Health. 2025;238:245-53.
3. Winton DJ, Blount MA, Ponder BA. A clonal marker induced by mutation in mouse intestinal epithelium. Nature. 1988;333(6172):463-6.
4. Diaz-Gay M, Dos Santos W, Moody S, Kazachkova M, Abbasi A, Steele CD, et al. Geographic and age variations in mutational processes in colorectal cancer. Nature. 2025;643(8070):230-40.
5. Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, van Hoeck A, Wood HM, Nomburg J, et al. Mutational signature in colorectal cancer caused by genotoxic pks(+) E. coli. Nature. 2020;580(7802):269-73.
6. Wang Y, Robinson PS, Coorens THH, Moore L, Lee-Six H, Noorani A, et al. APOBEC mutagenesis is a common process in normal human small intestine. Nat Genet. 2023;55(2):246-54.
7. Shoemaker AR, Moser AR, Dove WF. N-ethyl-N-nitrosourea treatment of multiple intestinal neoplasia (Min) mice: age-related effects on the formation of intestinal adenomas, cystic crypts, and epidermoid cysts. Cancer Res. 1995;55(19):4479-85.
8. Biragyn A, Ferrucci L. Gut dysbiosis: a potential link between increased cancer risk in ageing and inflammaging. Lancet Oncol. 2018;19(6):e295-e304.

Image note: The header image accompanying this article was generated by the FEBS Communications team using artificial intelligence for illustrative purposes only. It does not depict real experimental data, clinical material or microscopy, and should not be interpreted as a scientific image.