Researchers Identify Tumor Microbiome Differences in Early- vs. Average-Onset Pancreatic Adenocarcinoma

Early-onset gastrointestinal cancers, including pancreatic adenocarcinoma (PDAC), are on the rise; however, our understanding of the underlying pathogenesis remains unclear. Recognizing the need for further study, a team of Cleveland Clinic researchers examined the microbiome profiles of patients with early- and average-onset PDAC.

Their findings, which were recently highlighted during the American Society of Clinical Oncology (ASCO) annual meeting, demonstrated a distinct microbiome profile in patients with early-onset PDAC when compared to their average-onset counterparts. This data supports ongoing efforts to develop microbiome-based biomarkers for screening and treatment.

“As a field, we have been investigating early-onset cancers and trying to better understand the growing increase of different cancer types in younger people. Most of the research in the past has focused on colorectal cancer because it is the most widely known,” notes senior study author Alok Khorana, MD, Department of Hematology and Medical Oncology, Cleveland Clinic.

“Previously, we have shown that there are differences in the microbiome of younger people who get colorectal cancers versus older individuals,” he continues. “In more recent years, we have taken a closer look at non-colorectal cancers, including pancreatic and biliary cancers, and have confirmed there is an increase in incidence of these malignancies as well. And so, we wanted to investigate whether the pancreatic cancer microbiome is also different among patients who have younger-onset cancer versus older-onset.”

Methodology and results

The research team consecutively selected PDAC specimens from biorepositories at Cleveland Clinic and Roswell Park Cancer Institute. These specimens were then categorized based on age at diagnosis—early-onset PDAC (< 50 years) and average-onset PDAC (> 50 years).

Co-first author Thejus Jayakrishnan, MD, hematology-oncology fellow at Cleveland Clinic, and colleagues used shotgun metagenomic sequencing to characterize the tissue microbiome. “Alpha diversity—denoting the richness and evenness of microbial species within a specific sample—was compared using the Wilcoxon rank-sum test,” the researchers explain.

“The differential test of Beta-diversity distances (Bray Curtis distance) representing microbial taxonomic differences between the specimens was performed using Permutational MANOVA,” they note. “All p-values were adjusted for multiple testing."

This study included 44 patients with resected PDAC. Of those, 24 had early-onset disease and 20 had average-onset. The distribution of individual characteristics such as sex, race, ethnicity and tumor stage was similar across the two groups.

The researchers successfully identified several bacteria and fungi with variable abundances in the two groups. Data showed a higher alpha diversity for bacteria in early-onset PDAC compared to average onset PDAC (P=0.04). The fungal alpha diversity was higher for average-onset PDAC compared to early-onset PDAC (P = 0.02). The beta diversity analysis also showed significantly different diversity of genera between all groups, which were more pronounced for bacteria compared to fungi. The researchers observed no overlap in the majority of the species in early-onset versus average-onset PDAC and early-onset PDAC versus normal comparisons.

When conducting differential abundance analysis, Dr. Jayakrishnan and his colleagues found a significant variation of tumor microbiome in early-onset PDAC when compared to average-onset disease. Differentially abundant organisms included bacteria such as Klebsiella, Escherichia, Neisseria and fungi such as Malassezia and Candida.

The study authors also examined survival among these patients and found a clear correlation between the diversity of the organisms and survival, especially among young people. “The more diversity of bacteria there was, the better survival,” says Dr. Jayakrishnan. “There was a similar trend in older patients, but it was not significant.”

Significance and next steps

“Our study offers further insight into the role of the microbiome in cancer as well as how there might be distinct microbiome signatures associated with early-onset PDAC,” notes Dr. Jayakrishnan, while emphasizing the need for further exploration of the microbiome as a biomarker in PDAC.

“Microbiome associations with survival was observed in early-onset PDAC, indicating unique potential as a prognostic biomarker,” he concludes. “These findings need to be validated, and our team plans to continue research efforts in the area of early-onset disease as well as the microbiome.”