Oral squamous cell carcinoma (OSCC) is a highly aggressive cancer and the fourth leading malignancy among males in Taiwan. Some pathogenic bacteria are associated with periodontitis and oral cancer. However, the comprehensive profile of the oral microbiome during the cancer's progression from the early stage to the late stage is still unclear. We profiled the oral microbiota and identified bacteria biomarkers associated with OSCC. The microbiota of an oral rinse from 51 healthy individuals and 197 OSCC patients at different stages were investigated using 16S rRNA V3V4 amplicon sequencing, followed by bioinformatics and statistical analyses. The oral microbiota communities from stage 4 patients showed significantly higher complexity than those from healthy controls. The populations also dynamically changed with the cancer's progression from stage 1 to stage 4. The predominant phyla in the oral samples showed variation in the relative abundance of Fusobacteria, Bacteroidetes, and Actinobacteria. The abundance of Fusobacteria increased significantly with the progression of oral cancer from the healthy controls (2.98%) to OSCC stage 1 (4.35%) through stage 4 (7.92%). At the genus level, the abundance of Fusobacterium increased, while the number of Streptococcus, Haemophilus, Porphyromonas, and Actinomyces decreased with cancer progression. Fusobacterium periodonticum, Parvimonas micra, Streptococcus constellatus, Haemophilus influenza, and Filifactor alocis were associated with OSCC, and they progressively increased in abundance from stage 1 to stage 4. The abundances of Streptococcus mitis, Haemophilus parainfluenzae, and Porphyromonas pasteri were inversely associated with OSCC progression. We selected a bacterial marker panel of three bacteria (upregulated F. periodonticum, down-regulated S. mitis, and P. pasteri), which had an AUC of 0.956 (95% CI = 0.925–0.986) in discriminating OSCC stage 4 from the healthy controls. Furthermore, the functional prediction of oral bacterial communities showed that genes involved in carbohydrate-related metabolism, such as methane metabolism, and energy-metabolism-related parameters, such as oxidative phosphorylation and carbon fixation in photosynthetic organisms, were enriched in late-stage OSCC, while those responsible for amino acid metabolism, such as folate biosynthesis and valine, leucine, and isoleucine biosynthesis, were significantly associated with the healthy controls. In conclusion, our results provided evidence of oral bacteria community changes during oral cancer progression and suggested the possibility of using bacteria as OSCC diagnostic markers.
Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n = 188; p = 0.004). The frequency of APOBEC3B-deletion alleles is ~50% in 143 genotyped oral squamous cell carcinoma -Taiwan samples (27A3B −/−:89A3B +/−:27A3B +/+), compared to the 5.8% found in 314 OSCC-TCGA samples. We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance. Our finding might be recapitulated by genomic studies in other cancer types.
Gene duplication is an important evolutionary mechanism and no eukaryote has more duplicated gene families than the parasitic protist Trichomonas vaginalis. Iron is an essential nutrient for Trichomonas and plays a pivotal role in the establishment of infection, proliferation, and virulence. To gain insight into the role of iron in T. vaginalis gene expression and genome evolution, we screened iron-regulated genes using an oligonucleotide microarray for T. vaginalis and by comparative EST (expressed sequence tag) sequencing of cDNA libraries derived from trichomonads cultivated under iron-rich (+Fe) and iron-restricted (−Fe) conditions. Among 19,000 ESTs from both libraries, we identified 336 iron-regulated genes, of which 165 were upregulated under +Fe conditions and 171 under −Fe conditions. The microarray analysis revealed that 195 of 4,950 unique genes were differentially expressed. Of these, 117 genes were upregulated under +Fe conditions and 78 were upregulated under −Fe conditions. The results of both methods were congruent concerning the regulatory trends and the representation of gene categories. Under +Fe conditions, the expression of proteins involved in carbohydrate metabolism, particularly in the energy metabolism of hydrogenosomes, and in methionine catabolism was increased. The iron–sulfur cluster assembly machinery and certain cysteine proteases are of particular importance among the proteins upregulated under −Fe conditions. A unique feature of the T. vaginalis genome is the retention during evolution of multiple paralogous copies for a majority of all genes. Although the origins and reasons for this gene expansion remain unclear, the retention of multiple gene copies could provide an opportunity to evolve differential expression during growth in variable environmental conditions. For genes whose expression was affected by iron, we found that iron influenced the expression of only some of the paralogous copies, whereas the expression of the other paralogs was iron independent. This finding indicates a very stringent regulation of the differentially expressed paralogous genes in response to changes in the availability of exogenous nutrients and provides insight into the evolutionary rationale underlying massive paralog retention in the Trichomonas genome.
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