A study published in Nature Medicine has characterized molecular and cellular features that distinguish early-onset (EO) colorectal cancer (CRC), defined as CRC diagnosed before age 50, from average-onset CRC (AO-CRC), diagnosed at age 50 or older. Researchers constructed a single-nucleus RNA sequencing (snRNA-seq) atlas from 189 primary CRC tumors spanning eight decades of life, making it one of the largest high-resolution transcriptomic datasets assembled for this disease.
Among microsatellite-stable (MSS) tumors, the analysis identified a distinct tumor microenvironment in younger patients, characterized by increased stromal cell proportions and decreased epithelial cell proportions, alongside elevated expression of long noncoding RNAs and FN1, and heightened cell–cell signaling activity linked to epithelial-to-mesenchymal transition (EMT). The findings were generated from banked surgical specimens, and their prognostic or therapeutic implications were not directly tested in the study.
Key finding
In the largest snRNA-seq atlas of CRC to date, MSS tumors from younger patients displayed higher stromal-to-epithelial ratios and increased EMT-related cell–cell signaling compared with tumors from older patients, though the clinical impact of these differences on treatment response or survival was not assessed in this study.
Study Design
| Study | Single-nucleus RNA sequencing atlas of primary CRC tumors across the age continuum |
|---|---|
| Population | 189 patients with primary CRC: 54 with EO-CRC (diagnosed before age 50 years) and 135 with AO-CRC (diagnosed at age ≥50 years), with tumors spanning eight decades of life and at least 20 samples in most age decades |
| Methods | 3′ snRNA-seq of banked frozen resection specimens; analyses stratified by microsatellite status, tumor sidedness, stage, sex, and neoadjuvant treatment history; external validation using multispectral immunofluorescence and machine learning in 712 MSS CRC tumors |
| Primary objective | Characterize age-associated transcriptional and cellular features distinguishing EO-CRC from AO-CRC at single-cell resolution |
Tumors were annotated for microsatellite status, sidedness, stage, sex, Lynch syndrome status, and neoadjuvant treatment history. Age was modeled both continuously and categorically (EO-CRC versus AO-CRC). Consistent with prior reports, the cohort showed significantly more left-sided and stage IV tumors in EO-CRC patients compared with AO-CRC patients, associations that were accounted for in the analyses.
Results and Safety
Among MSS tumors, snRNA-seq analysis revealed that those from younger patients had a higher proportion of stromal cells and a lower proportion of epithelial cells relative to tumors from older patients. This finding was independently confirmed in an external cohort of 712 MSS CRC tumors using multispectral immunofluorescence combined with machine learning, lending cross-cohort support to the observation.
At the cellular level, epithelial cells from younger patients showed increased expression of long noncoding RNAs and FN1, a gene encoding fibronectin that has been implicated in tumor invasiveness and EMT. There was also a trend toward greater heterogeneity in copy number alterations among EO-CRC epithelial cells, though the study did not characterize this finding as statistically definitive. In MSS left-sided EO-CRC tumors specifically, researchers identified more cell–cell interactions overall, with signaling pathways associated with EMT, including FN1, GDF, and ACTIVIN pathways, showing increased, cell type-specific activity compared with AO-CRC tumors.
This was a molecular characterization study and did not consider safety. The study did not report clinical outcome data such as survival, response rates, or recurrence, and it did not evaluate therapeutic interventions.
Clinical Context
The incidence of EO-CRC has increased by 1–3% per year since the mid-1990s and is now the leading cause of cancer death in adults aged 18–49 years in the United States. As such, it has intensified interest in whether this disease represents a biologically distinct entity. Younger patients are approximately 58% more likely than older patients to be diagnosed with advanced-stage disease, and despite often receiving aggressive treatment, their survival rates have not been significantly better than those of older patients. These patterns have raised the hypothesis that EO-CRC may harbor distinct biology that limits treatment responsiveness, though this remains unproven.
The snRNA-seq atlas described in this study provides a high-resolution transcriptomic resource that researchers can use to further investigate EO-CRC biology. However, key questions remain unanswered: whether the stromal enrichment and EMT-associated signaling patterns identified here contribute causally to inferior outcomes, whether they predict differential responses to existing therapies such as immunotherapy or targeted agents, and how environmental and lifestyle factors that differ across age groups might drive these molecular patterns. Prospective studies linking these molecular features to clinical endpoints will be necessary to translate these findings into practice.
Sources
- Porter CBM, et al. Insights into early-onset colorectal cancer from a single-nucleus RNA-seq atlas of colorectal cancer across the age continuum. Nature Medicine (2026). View source
