Early-Onset Colorectal Cancer Risk Factors Identified in Two Studies

 Two new studies have identified risk factors that may be associated with the increasing incidence of colorectal cancer (CRC) among younger Americans.

“The majority of cases are sporadic, suggesting modifiable, nongenetic factors may play an important role,” said Mohamed Eldesouki, MD, internal medicine resident at New York Medical College at Saint Michael’s Medical Center in Newark, New Jersey, at Digestive Disease Week (DDW) 2026.

In the first study, Eldesouki and colleagues identified a distinct phenotype, based on multiple factors, associated with an elevated risk in people aged 18-49 years. In addition, they found that inflammatory bowel disease, family history of CRC, severe obesity, and obesity were independent predictors that increased the risk for early-onset vs late-onset CRC more than twofold.

In the second study, a history of oral antibiotic exposure was associated with an increased risk for colorectal adenomas, especially among people with a greater or longer history of using these agents.

Metabolic, Inflammatory Disease Drivers

“Growing evidence links early-onset CRC with obesity, metabolic syndrome, and diabetes,” but the predictors of the disease “remain poorly defined,” Eldesouki told Medscape Medical News.To find out more, he and his colleagues evaluated 46,099 people with CRC and matched control individuals from the TriNetX US Collaborative Network database from 2010 to 2023. The researchers compared three groups: 2584 people with early-onset CRC vs 5168 people with late-onset CRC; 3217 people with early-onset CRC vs 6434 control individuals; and 12,112 people with late-onset vs 24,336 control individuals.

They identified a number of factors predicting early-onset CRC, including inflammatory bowel disease (adjusted odds ratio [aOR], 2.52), family history (aOR, 2.44), obesity (aOR, 2.14), severe obesity (aOR, 2.61), metabolic syndrome, diabetes, and hepatic steatosis within 24 months before diagnosis.

Also, microcytosis (aOR, 2.29), low ferritin (aOR, 2.11), elevated C-reactive protein (aOR, 1.87), increased red cell distribution width (aOR, 1.72), low high-density lipoprotein, hypertriglyceridemia, diabetes-range glycated hemoglobin, and thrombocytosis were laboratory predictors of early-onset CRC. The discrimination in this model was high (area under the curve [AUC], 0.86).

In contrast, similar risk factors emerged for late-onset CRC, but with 25%-40% weaker associations and lower discrimination (AUC, 0.77).

African Americans, Hispanics, and those without prior screening had the strongest associations with risk in the study.

Rectal tumors were more common in patients with early-onset CRC than in those with late-onset CRC (37% vs 27%). At the same time, proximal colon tumors were more common in patients with late-onset CRC than in those with early-onset CRC (34% vs 23%).

In a multivariate analysis, severe obesity, microcytosis, and low ferritin levels were the strongest independent signals in the early-onset group. Metabolic dysfunction-associated steatotic liver disease remained a significant risk factor among younger patients but became nonsignificant in the late-onset group.

“Early colorectal cancer may present a distinct metabolic, inflammatory, and hematologic phenotype,” Eldesouki said. Abdominal pain, rectal bleeding, weight loss, iron-deficiency anemia, tenesmus, and diarrhea were more common in patients with early-onset CRC, whereas constipation was more common among patients with late-onset CRC.

Future studies should validate these risk factors for early-onset CRC and help develop risk-stratified models by age, he added.

Tailoring Screening Strategies to Age

The study was “really interesting. I think it’s really important for us to start to understand risk factors for individuals developing early age-onset cancer and how they might be different from older adults,” Swati Patel, MD, session co-moderator and director of the Hereditary Gastrointestinal Cancer Center and associate professor of medicine-gastroenterology at the University of Colorado Anschutz in Aurora, Colorado, told Medscape Medical News when asked to comment.

“We understand established risk factors in older adults like metabolic syndrome, diabetes, fatty liver disease, and obesity. We’re also actually seeing similar trends in younger individuals, and this moves the needle towards personalizing screening a little bit more,” she added.

“Understanding these risk factors for early-onset disease helps us think about tailoring the strategies to improve screening. But I think it’s not enough data at this point to lower the screening age [below 45 years],” Patel said.

Oral Antibiotic Risk

In the second study presented at DDW 2026, researchers examined whether a history of oral antibiotic exposure elevated the risk for colorectal adenomas among people aged 50 years or younger.

“Studies have shown that patients with CRC have an altered colonic microbial profile compared to controls, including reduced microbial diversity and enrichment of potentially pathogenic microbes,” said Amanat Bal, MD, an internal medicine resident at Kaiser Permanente San Francisco Medical Center in San Francisco.

“Interestingly, recent studies have also shown that precancerous adenomas with high-grade dysplasia also show enrichment of fusobacteria, so that’s suggesting that perhaps gut bacteria are playing a role in early tumorigenesis,” she added.

The investigators compared 6936 people with early-onset colorectal adenomas to 16,900 matched control individuals identified from January 1, 2006, to December 31, 2023, using electronic health records. The study population for this nested, case-control study included members of the Kaiser Permanente Northern California healthcare system.

Bal and colleagues noted oral antibiotic use 2 years or more before the detection of adenoma. They evaluated antibiotic exposure as a binary yes or no, as cumulative use over time, and based on specific time intervals (2 years to less than 5 years; 5 years to less than 8 years; or more than 8 years) prior to early onset of colorectal adenomas.

All participants had at least 10 years of follow-up. Control individuals had normal colonoscopies.

Risk Increases With Increased Exposure

Overall, Bal and colleagues linked oral antibiotic use to an increased risk for early-onset colorectal adenomas in both unadjusted (OR, 1.59) and adjusted calculations (aOR, 1.45) vs control individuals. The findings included an increased risk regardless of antibiotic class, such as broad- or narrow-spectrum agents.

“As the number of dispensings increase, you see a modest increase in the significance of the association as well,” Bal said. Risk grew steadily with an increasing history of oral antibiotic use, peaking at seven to nine courses (aOR, 1.60).

The risk for colorectal adenoma increased with time since antibiotic exposure, peaking from 5 years to less than 8 years (aOR, 1.71).

People who developed colorectal adenomas were more likely to have obesity than control individuals and had higher family history rates of CRC (29%) than control individuals (18%).

Strengths of the study included a large number of early-onset cases and control individuals in a diverse and socioeconomically representative population, Bal said. In addition, all controls had negative colonoscopies, and Kaiser Permanente electronic pharmacy records allowed for including oral antibiotic use 8 years or longer.

Limitations of the observational study include an inability to account for any childhood or adolescent antibiotic use, “which might represent an important window of exposure,” she said. Also, 98% of members obtain their medications through Kaiser, so some participants might have picked up antibiotics outside the system as well.

Additional studies looking at earlier-life exposures to antimicrobials are warranted, Bal said, “and further elucidation of the mechanisms of which specific antibiotics and antibiotic classes alter the microbiome is needed in order to inform antibiotic prescription choices.”

Hypothesis-Generating

Patel also offered perspective on this study. “It’s really, really interesting data. There’s a lot of emerging data on modulation with gut microbiome as a potential longitudinal risk factor.”

However, she added, “It’s hard to interpret it without adjusting for all the other factors that influence cancer.”

“The study found associations that I think are hypothesis-generating. But I don’t walk away with a clinically actionable conclusion,” Patel said, noting that she is already very conservative in her use of antibiotics in her practice.

The studies were independently supported. Eldesouki, Bal, and Patel reported having no relevant financial disclosures. 

https://www.medscape.com/viewarticle/early-onset-colorectal-cancer-risk-factors-identified-two-2026a1000ffn