Breakthrough Perspective from Singapore's Leading Institutions
The field of oncology is witnessing a paradigm shift with the growing recognition that the human microbiome—the diverse community of bacteria, fungi, viruses, and other microorganisms living within and on our bodies—plays a crucial role in cancer development, progression, and treatment response. A landmark perspective article published in Nature Cancer on February 19, 2026, led by researchers from the National University of Singapore's Yong Loo Lin School of Medicine (NUS Medicine) and the Agency for Science, Technology and Research's Genome Institute of Singapore (A*STAR GIS), addresses critical challenges in cancer microbiome research. Titled "Setting higher standards for reports of microbial species in human cancers," this collaborative effort underscores the need for rigorous quality controls to distinguish genuine tumor-resident microbes from contaminants, preventing false discoveries that could mislead clinical applications.
Lead investigator Associate Professor Niranjan Nagarajan, who holds positions at both NUS Medicine's Department of Biochemistry and Infectious Diseases Translational Research Programme and A*STAR GIS as Senior Group Leader of the Laboratory of Metagenomic Technologies and Microbial Systems, explained the core issue: "Finding microbial DNA in tumours is like finding a needle in a haystack. If appropriate checks and additional validation are not built into the analysis, it becomes very difficult to distinguish genuine microbial signals from background noise." Co-author Dr. Minghao Chia, GIS Fellow at A*STAR, added a vivid analogy: "Imagine investigating a crime scene with contaminated evidence. You might end up accusing the wrong suspect."
The Rise and Challenges of Tumor Microbiome Research
Since the early 2010s, high-throughput DNA sequencing has revolutionized our understanding of the microbiome's influence on health. In cancer, studies have reported microbial communities within tumors across various types, from colorectal to brain cancers, suggesting roles in modulating immune responses, therapy efficacy, and metastasis. For instance, Fusobacterium nucleatum is enriched in colorectal tumors and linked to poor prognosis, while certain bacteria may enhance immunotherapy outcomes by altering the tumor microenvironment.
However, excitement has been tempered by reproducibility crises. Many findings, especially in low-biomass environments like pancreatic or breast tumors, stem from bioinformatics analyses prone to errors. Contamination—ubiquitous bacterial DNA in lab reagents, surgical tools, or even air—introduces false positives. Outdated microbial reference databases misclassify human reads as microbial, and inadequate negative controls exacerbate issues. Recent re-analyses have invalidated claims, such as a retracted landmark study due to computational flaws and contamination. A 2025 Johns Hopkins study sequencing thousands of tumors found microbial signals primarily in gastrointestinal cancers, urging caution elsewhere.
Singapore's Pioneering Role in Genomics and Oncology
Singapore, with one of Asia's highest cancer incidences—over 20,000 new cases annually—has invested heavily in precision medicine. NUS Medicine and A*STAR GIS exemplify this through initiatives like the Singapore Gut Microbiome Project and population genomics efforts. The GIS, established to harness genomics for health, integrates AI and computational biology, positioning Singapore as a hub for microbiome research. Collaborations with global leaders like Johns Hopkins amplify impact.
In cancer, local studies have linked oral bacteria to gastric cancer risk when combined with age, smoking, and mutations—a February 2026 finding from Singapore researchers. Engineered gut bacteria improving colorectal cancer survival highlight therapeutic potential. This Nature Cancer paper builds on such work, advocating standards to ensure Singapore-led discoveries translate reliably to clinics.
Identifying Key Pitfalls in Current Practices
The perspective dissects contamination pathways:
- Sample Collection: Surgical aerosols or skin flora infiltrate tissues.
- Handling/Storage: Formalin-fixed paraffin-embedded (FFPE) blocks absorb ambient microbes; freezing-thawing cycles introduce artefacts.
- Lab/Sequencing: Reagent kits harbor bacterial DNA (e.g., Bradyrhizobium from soil); multiplexing causes index-switching.
- Bioinformatics: Incomplete human genome assemblies misalign reads to microbes; low-quality databases propagate errors.
Low tumor biomass amplifies noise—e.g., brain tumors yield <0.01% microbial reads. Without blanks (extraction/PCR controls), signals can't be deconvoluted.
The Proposed 26-Item Best Practices Checklist
Drawing from ancient DNA standards, the authors outline a 26-item checklist across seven categories, detailed in the paper and press annexes.
| Category | Key Recommendations |
|---|---|
| 1. Collection | Aseptic techniques; environmental swabs; match normal tissues. |
| 2. Handling/Storage | Separate pre-PCR areas; blank paraffin blocks for FFPE. |
| 3. Controls | Blanks in every step; mock communities; replicate labs. |
| 4. Sequencing | Pre-seq library QC; dual indexing; metadata reporting. |
| 5. Analysis | High-quality refs (e.g., CheckM); contaminant removal (svaseq). |
| 6. Validation | PCR/FISH/IHC; spatial imaging; viability (RNA/culture). |
| 7. Reporting | Limitations; multi-evidence claims. |
Adoption promises reproducibility, as seen in matured fields like low-biomass blood microbiomes.
Validation Strategies: From Bioinformatics to Microscopy
Beyond controls, orthogonal validation is pivotal. Quantitative PCR confirms abundance; fluorescence in situ hybridization (FISH) localizes microbes to tumor cells; culturomics proves viability. Spatial transcriptomics maps interactions. The paper stresses multi-line evidence, e.g., correlating microbial genes with host immune markers. For Singapore researchers, tools at GIS's metagenomics lab enable this pipeline.
Implications for Precision Oncology in Singapore
Rigorous standards will refine biomarkers—e.g., validating Fusobacterium for colorectal screening—and guide microbiome-modulating therapies like fecal transplants or antibiotics enhancing PD-1 inhibitors. In Singapore, where colorectal cancer is prevalent (2,900 cases/year), this accelerates translation via A*STAR's Precision Health initiatives. Read the full paper for detailed guidelines: Nature Cancer Perspective.
NUS Medicine's Infectious Diseases TRP integrates this with immunotherapy trials, positioning graduates for impactful roles.
Spotlight on Key Researchers and Collaborators
Assoc Prof Nagarajan's dual affiliation bridges clinical and computational frontiers. Dr. Chia, with GIS/BII, excels in microbiome systems. Steven Salzberg (Johns Hopkins) brings bioinformatics expertise. International co-authors from Netherlands' Hubrecht Institute, Denmark's Novo Nordisk Foundation Center, Australia's Peter MacCallum Cancer Centre enrich perspectives. NUS/A*STAR foster such global ties via scholarships and joint PhDs.
Broader Context: Singapore's Cancer Research Ecosystem
Singapore's National Precision Medicine (NPM) program sequences 100,000 genomes, including tumor microbiomes. Cancer Science Institute Singapore (CSI@NUS) pioneers multi-omics. A*STAR's Bioinformatics Institute advances AI for metagenomics. With SGD 25 billion RIE2025 investment, these standards align with goals for AI-driven oncology. Recent NUS studies on gut bacteria in colorectal cancer survival underscore momentum. Press releases detail impacts: NUS Release, A*STAR Release.
Future Outlook and Opportunities for Researchers
Standardization will unlock microbiome-based diagnostics (e.g., liquid biopsies) and therapies, potentially reducing Singapore's 10,000 annual cancer deaths. Ongoing GIS projects profile Asian microbiomes for ethnicity-specific insights. For aspiring researchers, NUS offers PhDs in metagenomics; A*STAR fellowships target postdocs. Explore research positions or postdoc opportunities in Singapore's vibrant ecosystem. This paper not only elevates global standards but cements Singapore's leadership in transformative cancer research.
