Insights into early-onset colorectal cancer from a single-nucleus RNA-seq atlas of colorectal cancer across the age continuum

The incidence of early-onset colorectal cancer (EO-CRC; diagnosed before age 50 years) is increasing worldwide. Although current data indicate that EO-CRC may be biologically distinct from average-onset CRC (AO-CRC; diagnosed at age ≥50 years), molecular differences remain poorly defined. To address this knowledge gap, we generated a single-nucleus RNA sequencing (snRNA-seq) atlas from 189 primary CRC tumors (54 EO-CRC, 135 AO-CRC) spanning eight decades of life, with at least 20 tumors in most age decades. Our analyses stratified tumors by microsatellite status and accounted for tumor sidedness, stage, patient sex and neoadjuvant treatment history, modeling age continuously or categorically (EO-CRC versus AO-CRC). Among microsatellite-stable (MSS) tumors, those from younger patients were characterized by increased stromal and decreased epithelial proportions, which we confirmed using multispectral immunofluorescence and machine learning in an external cohort of 712 MSS CRC tumors (18 EO-CRC, 694 AO-CRC). Tumor epithelial cells from young patients exhibited increased expression of long noncoding RNAs and FN1, with a trend toward increased heterogeneity in copy number alterations. MSS left-sided EO-CRC tumors had more cell-cell interactions, with epithelial-to-mesenchymal transition-related signaling pathways (FN1/GDF/ACTIVIN) showing increased, cell type-specific interactions. Our large high-resolution snRNA-seq atlas uncovers age-associated features of CRC and provides a resource for the community to understand EO-CRC biology.

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Publication Details

Journal
Nature Medicine
Published
2026-10-29
DOI
https://doi.org/10.1038/s41591-026-04721-y
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
0.00

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article

Insights into early-onset colorectal cancer from a single-nucleus RNA-seq atlas of colorectal cancer across the age continuum

Liubou Klindziuk, Atsushi Kondo, Tomotaka Ugai, Caroline B. M. Porter et al.
5 links
Nature Medicine
Single-cell and spatial transcriptomics
article

Insights into early-onset colorectal cancer from a single-nucleus RNA-seq atlas of colorectal cancer across the age continuum

Liubou Klindziuk, Atsushi Kondo, Tomotaka Ugai, Caroline B. M. Porter, Orr Ashenberg, Lauren K. Brais, Satoko Ugai, Jennifer S. Thalappillil, Marios Giannakis, Ramnik J. Xavier, Elizabeth Andrews, Liat Amir-Zilberstein, Shuji Ogino, Kimmie Ng, Toni Marie Delorey, Jacques Deguine, Ana Carrizosa Anderson, Ewa T. Sicinska, Jules Cazaubiel, William Tan, Emily P. Finan, Shane P. Murphy, Kosuke Matsuda
article en

Abstract

The incidence of early-onset colorectal cancer (EO-CRC; diagnosed before age 50 years) is increasing worldwide. Although current data indicate that EO-CRC may be biologically distinct from average-onset CRC (AO-CRC; diagnosed at age ≥50 years), molecular differences remain poorly defined. To address this knowledge gap, we generated a single-nucleus RNA sequencing (snRNA-seq) atlas from 189 primary CRC tumors (54 EO-CRC, 135 AO-CRC) spanning eight decades of life, with at least 20 tumors in most age decades. Our analyses stratified tumors by microsatellite status and accounted for tumor sidedness, stage, patient sex and neoadjuvant treatment history, modeling age continuously or categorically (EO-CRC versus AO-CRC). Among microsatellite-stable (MSS) tumors, those from younger patients were characterized by increased stromal and decreased epithelial proportions, which we confirmed using multispectral immunofluorescence and machine learning in an external cohort of 712 MSS CRC tumors (18 EO-CRC, 694 AO-CRC). Tumor epithelial cells from young patients exhibited increased expression of long noncoding RNAs and FN1, with a trend toward increased heterogeneity in copy number alterations. MSS left-sided EO-CRC tumors had more cell-cell interactions, with epithelial-to-mesenchymal transition-related signaling pathways (FN1/GDF/ACTIVIN) showing increased, cell type-specific interactions. Our large high-resolution snRNA-seq atlas uncovers age-associated features of CRC and provides a resource for the community to understand EO-CRC biology.

Nature Medicine
Broad Institute (US), Brigham and Women's Hospital (US), Harvard University (US), Keio University (JP), Massachusetts General Hospital (US), Dana-Farber Cancer Institute (US), Dana-Farber/Harvard Cancer Center (US), Institute of Science Tokyo (JP), Klarman Cell Observatory (US), Center for Computational and Integrative Biology, Massachusetts General Hospital (US), National Cancer Center Research Institute (JP), National Cancer Research Institute (GB)
Broad Institute, National Institutes of Health, Klarman Cell Observatory, Broad Institute, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 22%
Single-cell and spatial transcriptomics
DOIOpen Access PDFOpenAlex
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