Why is colorectal cancer rising in younger adults?

Clinical takeaway: Consider that colorectal cancer diagnosed before age 50 may represent a biologically distinct disease state, characterized by a tumor microenvironment linked to treatment resistance, invasion, and metastasis. However, base colorectal cancer treatment on established clinical and molecular features; these newly identified age-associated differences do not yet justify changing therapy.

Early-onset colorectal cancer (CRC) is now the leading cause of cancer death in adults aged 18 to 49 years, and incidence has been rising despite declining rates in older adults. Younger patients are also more likely to present with advanced disease, but the biological drivers have remained poorly understood.

Researchers created the largest single-nucleus RNA sequencing atlas of colorectal cancer to date, analyzing 189 primary tumors from patients aged 29 to over 90 years, including 54 cases diagnosed before age 50. The dataset included more than 850,000 tumor and microenvironment cells and was supplemented with validation cohorts totaling more than 1,200 additional tumors.

Rather than comparing younger and older patients as two separate groups, investigators examined biological changes across the age continuum. Among microsatellite-stable tumors, cancers from younger patients consistently showed a higher proportion of stromal and connective-tissue cells and fewer epithelial tumor cells. This stromal enrichment was validated in independent cohorts of 564 tumors and 712 pathology specimens and has previously been associated with chemotherapy resistance in solid tumors.

Tumors from younger adults also showed increased expression of long noncoding RNAs, including many poorly characterized “dark” RNAs, as well as genes linked to epithelial-to-mesenchymal transition (EMT). Cell-to-cell communication analyses found roughly 6% more interactions in early-onset than average-onset tumors and identified stronger signaling pathways involved in EMT, angiogenesis, and tumor invasion.

In left-sided, microsatellite-stable tumors, computational analyses also suggested stronger communication through pathways associated with cell migration, invasion, and blood-vessel growth in younger patients.

The findings do not prove causation, but they suggest that early-onset CRC may harbor a distinct, stroma-rich microenvironment that could contribute to advanced-stage presentation and poorer outcomes despite aggressive treatment.

“Our ultimate goal is to discover novel strategies for prevention, diagnosis, and treatment for our young patients,” co-senior author Kimmie Ng, MD, MPH, said in a press release.

Source: Porter CBM, et al. (2026 Oct 29) Nat Med. Insights into early-onset colorectal cancer from a single-nucleus RNA-seq atlas of colorectal cancer across the age continuum