Table 1.
Reviews and studies suggesting associations between microbial and oncogenomic changes in PC.
| Reference | Study Population | Specimen | Analytical Methods | Main Findings | Microbial Changes | Oncogenomic Changes | Possible Associations between the Microbiota and Oncogenetics in PC |
|---|---|---|---|---|---|---|---|
| Mitsuhashi 2015 [42] | Human PDAC vs. HC | Pancreatic | TaqMan Gene Expression Assay | Fusobacterium spp. is present in 8.8% of PC tissue and independently associated with a worse prognosis; F. spp. could be used as a prognostic biomarker of PC. | ↑ F. spp. detected in 8.8% of PC tissue specimens. | Mutations in KRAS, NRAS, BRAF or PIK3CA, epigenetic changes or mi-R21, mi-R31 or mi-R143 expression levels. | No significant association was found between the Fusobacterium species status and molecular alterations of pancreatic cancers. |
| Michaud 2013 [44] | NA | NA | Review on bacterial infections linked to PC and their possible pathways | Bacteria may cause an inflammatory response of the host immune defense, promoting carcinogenesis. | H. pylori and P. gingivalis are positively associated with PC. | Aberrant miRNA expression | Microbes like P. gingivalis may regulate miRNA expression (even in a far-distance manner), which may influence important immunologic and cancer-related signaling pathways. |
| Shirazi et al. 2020 [94] | NA | NA | Review aiming to evaluate bacterial agents as cancer biomarkers | Bacteria can influence the cell cycle through inflammation, aberrant cell signaling, immune evasion, DNA damage and mutations, aberrant miRNA expression and epigenetic changes. | H. pylori and P. gingivalis are associated with PC. | DNA damage, mutations, expression of certain microRNAs, and epigenetic effects | Bacteria involved in carcinogenesis cause alterations in the cell cycle by the induction of DNA damage, mutations, expression of microRNA and epigenetic effects, amongst others. H. pylori and P. gingivalis cause inflammation and P.gingivalis may regulate miRNAs. |
| Ögrendik 2017 [95] | Human PC | Oral | Hypothesis based on earlier findings | P. gingivalis, Tannerella forsythia and Treponema denticola secrete peptidylarginine deaminase, which might cause p53 and KRAS point mutations. |
P. gingivalis, T. forsythia and T. denticola are major pathogens of CPO. |
Mutations in p53, KRAS | Bacterial peptidylarginine deaminases originating from P. gingivalis, T. forsythia and T. denticola might cause p53 and KRAS point mutations by the degradation of arginine. CPO has been associated with orodigestive cancer. |
| Gnanasekaran et al. 2020 [96] | Human (PC cell lines, xenograft model) | Pancreatic | Gene expression analysis by qRT-PCR, detection of P. gingivalis by RT PCR | Exposure to P. gingivalis increases tumorigenic behavior in PC cell lines. | P. gingivalis influences PC progression. | Mutant KRAS | P.gingivalis may synergize with mutant KRAS to promote tumorigenesis. |
| Pushalkar et al. 2018 [17] | Human PDAC, mouse (KPC or KRASG12D Trp53R172H PdxCre) | Pancreatic (mouse); pancreatic and fecal (human) | 16S rRNA gene sequencing | The PDAC microbiome promotes oncogenesis by immune suppression via TLR; this could be used as a therapeutic target. | ↑ Probacteria (Pseudomonas, Elizabethkingia) in human PC tissue, is associated with advanced disease; ↑↑ Proteobacteria, Synergistetes, Euryarchaeotain the feces of PC patients. |
Mutated Kras(G12D) | The composition and diversity of the gut and pancreatic microbiota may be influenced by oncogenic Kras expression. |
| Thomas et al. 2018 [35] | Human PDAC vs. CP and HC; mouse (Kras(G12D)/PTENlox/+) | Pancreatic | 16S rRNA gene sequencing, RNAseq of human PDAC xenografts in mice | The pancreatic microbiota in PC accelerates carcinogenesis. No distinct microbiota profile is significantly associated with PC. Gut bacteria exert a long-distance effect on PC carcinogenesis. Bacterial colonization of the pancreas is not a physiological process. | 50% of PC mice harbored intrapancreatic bacteria. ↑ Acinetobacter, Afipia, Enterobacter, Pseudomonas in human PC tissue. | Mutated Kras (Kras(G12D)/ PTENlox/+ mouse model) | The gut microbiota accelerates pancreatic carcinogenesis in a mouse model of PC. Many genes involved in carcinogenesis are differently expressed depending on the gut microbiota state. The microbial effect seems to be independent of the Kras mutational status. The pancreatic microbiota is not correlated with carcinogenesis. |
| Riquelme et al. 2019 [53] | Human PDAC STS vs. PDAC LTS | Pancreatic | 16S rRNA gene sequencing | Higher α-diversity in the LTS tumor microbiome; predominant taxa could be used as biomarkers for the prediction of LTS; PDAC microbiome composition influences host immune response. | Enrichment of proteobacteria (Pseudoxanthomanas), Actinobacteria (Streptomyces, Saccharopolyspora), Bacillus clausii in LTS compared to STS. | No genomic differences in PDAC LTS vs. STS. | No genomic differences in stage matched PDAC LTS compared to STS. |
| Chakladar et al. 2020 [54] | Human PDAC | Pancreatic | Next generation RNA sequencing | The PC tumor microbiota is associated with gene expression dysregulation, metastasis and immune suppression. A worse prognosis in males and smokers is linked to the presence of cancer-promoting microbiota profiles. | A. ebreus (Betaproteobacteria) correlated with immune dysregulation and poor prognosis, Gammaproteobacteria correlated with increased metastasis. A. baumannii and M. hypneumoniae associated with smokers. | Oncogenic gene expression signatures, CNA; Deletions at the 9q13 locus. |
An increased abundance of A. baumannii and M. hypneumoniae is associated with an increase of oncogenic and decrease of tumor suppressive and immune signatures in smokers; E. coli abundance is correlated with CNA; M. hyopneumoniae is significantly correlated with deletions at 9q13 (potential tumor suppressor) in smokers. |
| Guo et al. 2021 [97] | Human (different PDAC subtypes) | Pancreatic | Metagenomic sequencing, RNA-seq | Analysis of the tumor microbiome in different subtypes of PDAC: the microbial profile in basal-like PDAC was highly associated with carcinogenesis, possibly through the induction of pathogen-related inflammation. Host genetics influence the composition of the tumor microbiome. | ↑ Acinetobacter, Pseudomonas and Sphingopyxis in basal-like tumors | KRAS signaling | Acinetobacter, Pseudomonas and Sphingopyxis are associated with carcinogenic gene-expression, KRAS signalling, DNA replication and other PC-related pathways. Bacterial LPS can hyperstimulate KRAS and initiate carcinogenesis. A microbial procarcinogenic effect is caused by continuous inflammation rather than direct mutagenesis. Host genetics participate in shaping the tumor microbiome. |
↑ = increased abundance of bacteria in PC compared to HC, ↑↑ = significantly increased abundance of bacteria in PC compared to HC, CNA = copy number alteration, CP = chronic pancreatitis, CPO = chronic periodontitis, HC = healthy controls, LTS = long-term survivors, NA = not applicable, PDAC = pancreatic ductal adenocarcinoma, PC = pancreatic cancer, STS = short-term survivors.