Nature Medicine Study of 189 Colorectal Tumors Finds Younger Patients Have More Stromal Cells, Different Gene Activity

Why are young people getting colorectal cancer? A first set of biological answers about the tumors themselves was published today, Oct. 29, in Nature Medicine.

Researchers from Dana-Farber Cancer Institute, Mass General Brigham's Gene Lay Institute of Immunology and Inflammation, and the Broad Institute analyzed 189 tumors. Patients ranged from 29 to over 90 years old. Fifty-four were diagnosed before age 50. The other 135 were diagnosed at 50 or older.

The team measured gene activity in more than 850,000 cells using single-nucleus RNA sequencing. The technique works on frozen tissue, so the researchers could use archived samples from surgeries at Brigham and Women's Hospital stored in Dana-Farber's Gastrointestinal Biobank. The first author is Caroline Porter of the Broad's Klarman Cell Observatory.

The authors and Dana-Farber describe it as the largest dataset of its kind. Dr. Kimmie Ng, who directs Dana-Farber's Young-Onset Colorectal Cancer Center, said it includes the highest number of young patients of any colorectal cancer dataset to date.

What the tumors showed

Tumors in younger patients had a higher proportion of stromal cells, the connective and supporting cells that include fibroblasts. Older patients showed the reverse pattern: fewer stromal cells and proportionally more malignant cells.

The researchers did not just compare two age groups. With 189 samples, they tracked gradual shifts across the age spectrum. Stromal presence generally declined from the youngest patients to the oldest.

Ana Anderson, a co-senior author who leads the cancer immunology program at the Gene Lay Institute, said stromal cells can suppress the immune response. "They essentially can form a shield that protects the tumor from infiltration," she said. She also said the cells can physically block chemotherapy drugs from reaching cancer cells.

The Boston Globe noted that studies of other solid cancers have linked stromal cells to chemotherapy resistance. The Broad Institute release says the findings do not yet provide proof that these differences cause more aggressive disease.

Younger patients also showed higher activity of long non-coding RNAs, which are tied to cellular signaling in cancer. Many are "dark" RNAs whose functions remain largely unknown. Their tumors showed gene activity suggesting stronger signaling between cells, which could help cancer cells move and invade nearby tissue.

The limits the authors state

The researchers did not claim early-onset colon cancer is always more aggressive. Anderson told Business Insider that would take more study. She said clinical data suggest younger patients "generally have more aggressive disease and they are generally more resistant to the standard of care therapies, which is mostly chemotherapy."

The study also does not explain why the disease is rising. "There's a lot of interest in lifestyle factors and environmental exposures as potential contributors; however, nothing specific has been pinned down," Anderson said. A growing body of research has linked risk to diet and ultra-processed foods, among other factors, but this paper does not test those links.

The researchers' methods also captured relatively few immune cells, leaving open whether immune responses in these tumors differ across ages.

Anderson's own framing is cautious in the institutional release: "While we're still at the beginning of understanding what these differences mean, our work gives researchers a new direction to pursue." She was more expansive in an interview with Live Science, calling the study "essentially a turning point now in the field," because "up until now, we've had more questions than answers."

The numbers behind the urgency

According to the American Cancer Society, U.S. colorectal cancer diagnosis rates among people younger than 50 rose 2.9% per year from 2013 through 2022. The society's 2026 report identifies colorectal cancer as the leading cause of cancer death in that age group. Younger patients are also more likely to be diagnosed at advanced stages.

Ng said her clinic sees the toll directly. "We see how profoundly this disease can affect younger patients and their families, often during the busiest and most formative years of life," she said.

Anderson told the Boston Globe the field has been "a bit of a black box." She said the data now provides "a path to follow" toward therapies tailored to young-onset disease. Ng called the dataset "a guidepost to where we should direct" future work.

What comes next

This is a descriptive map. Anderson told Business Insider the study does not present any immediate new takeaways for young people concerned about colon cancer, and she suggested following existing guidance: the recommended screening age for most people was lowered from 50 to 45, and it is wise to see a doctor sooner for symptoms like rectal bleeding, abdominal pain, bloating, or changes in bowel movements.

The next step is follow-up research. According to the Broad Institute release, future studies will explore how these changes may affect cancer growth and spread, and whether they offer opportunities for prevention or treatment. Anderson also hopes to explore immune cells in younger colon cancer cases, and her team is already working on manipulating the long non-coding RNA they found inside cancer cells in petri dishes. Whether any of this explains why the disease is rising in the first place remains unanswered.