YSPH study provides new insights into colorectal cancer

A surge in colorectal cancer among people under 50 in the United States has both doctors and the cancer research community deeply concerned.

A new study led by researchers at the Yale School of Public Health (YSPH) may provide important insights.

The study, published in Free Radical Biology and Medicine, identified stark biological differences between tumors found in younger and older adults with colorectal cancer—discoveries that may help explain the rise in colorectal cancer among people under 50 and pave the way for more tailored treatment strategies.

The research is the first comprehensive metabolomic comparison of early-onset colorectal cancer and late-onset colorectal cancer using tumor tissue matched to normal adjacent tissue. In the study, the researchers identified key metabolic and genetic patterns that differ significantly by age group—suggesting that tumors in younger adults may develop and grow through distinct biochemical pathways.

“The tumors from early-onset patients seem to have a different biology,” said Dr. Oladimeji Aladelokun, PhD, a post-doctoral assistant at YSPH and contributing author of the study. The researchers caution that more investigation is needed to fully understand the metabolic nuances of tumor tissues in early-onset and late-onset colorectal cancer patients.

Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death among men and women in the U.S. Early-onset colorectal cancer—termed “early” because it occurs in people younger than 50—is particularly deadly, and rates are increasing around the world. Since the mid-1990s, the number of colorectal cancer cases in the U.S. has consistently increased by about 2% per year in people aged 20-39. The American Cancer Society estimates that there will 154,000 new cases of colorectal cancer in the U.S. in 2025, with one in every five people diagnosed under age 55.

Scientists have cited multiple factors as possible reasons for the increased diagnoses. Obesity, alcohol use, lack of exercise, and an increase in consumption of ultra processed foods have all been referenced as possible contributors to the disease. Researchers are also looking into whether genetics and disruptions in gut bacteria may play a role in tumor progression.

The Yale study took a fresh tack—focusing specifically on metabolites and the biology of early onset colorectal cancer tumors. “We wanted to use the metabolomics technologies in our lab to really improve our understanding of the biology of these tumors that are impacting younger people,” said Dr. Caroline Johnson, PhD, an associate professor of epidemiology (environmental health sciences) at YSPH and the study’s senior author.

Dr. Johnson is an expert in metabolomics, which is the study of metabolites, the small molecules that are a key part of human metabolism, and vital for creating energy. Using technologies such as mass spectrometry and nuclear magnetic resonance imaging, metabolomics has identified biomarkers for disease, advanced personalized medicine, and improved food safety.

Dr. Johnson’s team analyzed frozen tumor tissue collected between 1991 and 2001. They examined metabolic differences in normal tissue compared to tumor tissue and also compared tissue from patients with early-onset and late-onset colorectal cancer. The team found that 91 metabolites were significantly altered between normal tissue and colorectal cancer tumor tissue. Of these, only one metabolite—homovanillic acid—a molecule produced during the breakdown of dopamine—was uniquely decreased in early-onset tumors. Dopamine levels are used clinically to screen for several kinds of cancerous tumors.

“Right now, we don’t know if homovanillic acid has any direct effect on the colon or colon cancer, but it could potentially be a marker for disruption to dopamine metabolism,” Dr. Johnson said.

In another key finding, the researchers discovered that levels of a protein called PD-L1, a common target of cancer immunotherapies, were significantly lower in early-onset tumors but unchanged in late-onset cancers. Lower PD-L1 expression could indicate that early-onset colorectal cancer tumors create a more immunosuppressive environment, potentially influencing how well younger patients respond to immunotherapy.

Dr. Johnson’s lab plans to further investigate the dopamine pathway to determine how it may be altered in early-onset colorectal cancer. The lab is collecting samples at Yale New Haven Hospital to test if their findings are consistent across a larger cohort of patients. They also hope to validate their findings, not just in tumor tissue, but in blood samples.

The research is unique, Johnson said, because finding frozen tumor tissues for study is extremely difficult. “Normally in pathology, they’ll take the tumor and put it into paraffin, but in order to look at metabolites, you need to have the tumors frozen,” she said. “It's actually quite hard to find biobanks that have frozen tissue.”