In a large, two-cohort prospective study, researchers identified 27 oral microorganisms—bacteria and fungi—that, when combined into a microbial risk score, were linked to more than a threefold increase in pancreatic cancer risk per one–standard-deviation increase in the score, suggesting a potential avenue for earlier detection of one of medicine’s most lethal malignancies.
The nested case–control analysis drew on oral samples from 122,000 participants across two major US cohorts with a median follow-up of 9 years. Among these patients, 445 developed pancreatic cancer and were matched to 445 controls. Using whole-genome shotgun sequencing (bacteria) and internal transcribed spacer (ITS) sequencing (fungi), investigators detected microbial signatures that preceded cancer diagnosis by years.
“In this cohort study, oral bacteria and fungi were significant risk factors for pancreatic cancer development,” reported lead author Yixuan Meng, PhD, NYU Grossman School of Medicine, and colleagues.
Periodontal Pathogens and Bacteriome-Wide Signals
Three periodontal pathogens showed statistically significant associations with increased pancreatic cancer risk: Porphyromonas gingivalis (odds ratio [OR], 1.27), Eubacterium nodatum (OR, 1.42), and Parvimonas micra (OR, 1.36).
A bacteriome-wide scan using Analysis of Compositions of Microbiomes with Bias Correction 2 (ANCOM-BC2) identified 21 additional bacterial species associated with risk after multiple-comparison correction. Eight species were associated with decreased risk, while 13 were linked to increased risk. Protective taxa included members of Proteobacteria, Bacteroidetes, and Actinobacteria; higher-risk taxa included species within Bacteroidetes, Actinobacteria, Fusobacterium, and selected Firmicutes.
Fungal Microbiome Showed a Strong Signal
Among oral fungi, Candida was the most abundant genus (47.6% abundance) and was associated with increased pancreatic cancer risk. Within this genus, Candida tropicalis and Candida spp correlated with elevated risk, whereas C. albicans was associated with decreased risk. Malassezia was the second most common genus; the species M. globosa was associated with decreased risk.
In an exploratory analysis comparing oral and pancreatic tissue samples from New York University Langone patients, Candida species present in the oral cavity were also preferentially observed in pancreatic tumor tissue, suggesting potential translocation pathways.
Microbial Risk Score Demonstrated Clinical Utility
The study’s most consequential finding was a microbial risk score that incorporated all 27 risk-associated species. The composite score yielded a multivariate OR of 3.44 per per one–standard-deviation increase in microbial risk score with strong reproducibility demonstrated through Monte Carlo cross-validation.
Community clustering revealed three distinct microbial patterns among the 27 taxa. Cluster 1 was enriched for higher-risk bacteria linked to carbohydrate and lipid metabolism pathways. Cluster 2 was characterized by Candida and other fungi associated with environmental processing and pathogenicity pathways. Cluster 3 contained Prevotella and Propionibacterium species potentially involved in nucleotide and amino acid metabolism.
Methodological Rigor and Validation
Investigators analyzed samples from the American Cancer Society Cancer Prevention Study-II Nutrition Cohort (CPS-II) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Patients provided oral wash samples via standardized protocols, with DNA extraction performed centrally using harmonized procedures.
Quality control supported excellent reproducibility (intraclass correlation coefficients: 0.96 for whole-genome shotgun sequencing and 0.80 for ITS). To minimize reverse-causation bias, the first 3 years of follow-up were excluded. Associations remained robust across strata defined by body mass index, diabetes, smoking status, and alcohol consumption.
Statistical analysis used ANCOM-BC2 with adjustments for matched pairs, age, body mass index, diabetes, and smoking status; covariates were retained if they changed effect estimates by more than 10%. Bacterial species were considered noteworthy if the false-discovery-rate–adjusted q-value was < .05 and between-cohort heterogeneity was not significant.
Clinical and Research Implications
Established risk factors—smoking, obesity, pancreatitis, and genetic susceptibility—explain < 30% of pancreatic cancers, and the 5-year survival rate remains 13%. These findings support the oral microbiota as a promising biomarker to flag patients at higher risk, potentially enabling targeted surveillance and earlier intervention.
The work builds on prior, smaller studies linking periodontal disease and oral bacterial dysbiosis to pancreatic cancer. Notably, this investigation prospectively examined both the bacterial and fungal components of the oral microbiome using advanced sequencing, including the first prospective use of ITS sequencing to evaluate the oral mycobiome in relation to pancreatic cancer risk.
The authors acknowledged limitations: the observational design precludes causal inference; dental history data were unavailable; the 92% White study population may limit generalizability; and current fungal reference databases remain incomplete, which may constrain species-level fungal identification.
“The oral microbiota holds promise as a biomarker to identify individuals at high risk of pancreatic cancer, potentially enabling personalized pancreatic cancer prevention,” concluded the study authors.
Disclosures: None reported.
Source: JAMA Oncology
