Mass General Brigham researchers from the Gene Lay Institute of Immunology and Inflammation, along with researchers at Dana-Farber Cancer Institute and the Broad Institute, have identified biological differences in colorectal tumors that may help explain why the disease can behave more aggressively in younger patients. Published by Porter et al in Nature Medicine, the study’s findings lay a foundation for understanding age-associated differences in colorectal cancer and exploring future treatments.
In the United States, colorectal cancer diagnosis rates among people younger than age 50 (early-onset colorectal cancer) rose 2.9% per year from 2013 through 2022, according to the American Cancer Society. Its 2026 report identifies colorectal cancer as the leading cause of cancer death in this age group. Younger patients are also more likely to be diagnosed at advanced stages, underscoring the need to better understand the biology of early-onset disease.
The research team, including first author Caroline Porter, PhD, of the Klarman Cell Observatory at the Broad Institute, studied specimens from surgeries at Brigham and Women’s Hospital and stored in Dana-Farber’s Gastrointestinal Biobank. Co-senior authors include Ana C. Anderson, PhD, a core faculty member of the Gene Lay Institute of Immunology and Inflammation at Brigham and Women’s Hospital, Massachusetts General Hospital, and Harvard Medical School; Kimmie Ng, MD, MPH, of Dana-Farber Cancer Institute; and Ramnik J. Xavier, MD, PhD, a core institute member at the Broad Institute, Kurt Isselbacher Professor at Massachusetts General Hospital and Harvard Medical School, and Vice Director of the Gene Lay Institute. Dr. Xavier is also a gastroenterologist at Mass General Brigham. Drs. Anderson, Ng, and Xavier jointly supervised this work.
“The need to understand why colorectal cancer is affecting younger adults at increasing rates is urgent,” said Dr. Anderson. “And that starts with understanding the biology of the disease across the entire lifespan. By looking beyond conventional age cutoffs, we’ve uncovered biological patterns that earlier studies may have missed and created a foundation for the field to investigate them further. While we’re still at the beginning of understanding what these differences mean, our work gives researchers a new direction to pursue in tackling this urgent problem in human disease.”
Research Details
The research team analyzed 189 tumors from patients aged 29 to 90+ years, including 54 patients diagnosed before age 50 and 135 diagnosed at age 50 or older. Using single-nucleus RNA sequencing, the researchers analyzed gene activity in more than 850,000 nuclei from cancer cells and other cells within the tumors. The technique, which works with frozen tissue, enabled the team to build a detailed map of tumor cells by studying archived samples with extensive clinical record data.
Rather than relying solely on comparisons between younger and older patients, the researchers also examined biological changes across the age continuum, accounting for tumor location (right vs left side), stage, sex, and prior treatment where appropriate. This approach revealed subtle differences that likely would have been obscured by a simple two-data set comparison.
Key Findings
Among patients with microsatellite-stable colorectal cancer, tumors from younger patients had a significantly higher proportion of stromal cells relative to malignant epithelial cells. Increased stromal composition has been associated with chemotherapy resistance in several types of solid tumors, although this study did not establish such a relationship in early-onset colorectal cancer. The team confirmed this pattern using gene-activity data from 564 other tumors and computer analysis of stained tissue images from another 712 tumors.
Younger patients also had higher activity of long noncoding RNAs. Some appeared repeatedly across different types of cancer cells, the team reported, adding that many are “dark” RNAs, whose functions remain largely unknown. The researchers also identified increased activity in cell-signaling pathways associated with epithelial-to-mesenchymal transition, a biological process involved in cancer cell migration and invasion, particularly in left-sided MSS tumors from younger patients.
“Our study is an advance from previous work in that we analyzed tumors from a large number of patients and used single-cell approaches to find novel features unique to tumors from young patients,” said Dr. Xavier. He added that “This work sets the stage for future mechanistic studies on how these cell programs interact with chemicals from the diet and from gut microbes to cause early-onset colorectal cancer.”
Although the findings provide key insight into colorectal cancer in young individuals, they do not yet provide proof that these differences cause more aggressive disease. The investigators also noted that some analyses were conducted in smaller subsets of tumors and could not account for all potentially confounding clinical factors. One remaining question is whether there are differences in immune responses in these tumors across ages, as the researchers’ methods captured relatively few immune cells. Future studies will explore how these changes may affect cancer growth and spread and whether they offer opportunities for prevention or treatment.
“Through Dana-Farber’s Young-Onset Colorectal Cancer Center, we see how profoundly this disease can affect younger patients and their families, often during the busiest and most formative years of life,” said Dr. Ng. “This collaborative work with Mass General Brigham researchers from the Gene Lay Institute and researchers from the Broad Institute gives us important new insight into the biology of these tumors. The findings provide a valuable roadmap for further investigating the distinct features of young-onset colorectal cancer. Our ultimate goal is to discover novel strategies for prevention, diagnosis, and treatment for our young patients.”
DISCLOSURE: For full disclosures of the study authors, visit nature.com.
