Location of Repository

Microbiomic subprofiles and MDR1 promoter methylation in head and neck squamous cell carcinoma

By Gurkan Bebek, Kristi L. Bennett, Pauline Funchain, Rebecca Campbell, Rahul Seth, Joseph Scharpf, Brian Burkey and Charis Eng


Clinical observations and epidemiologic studies suggest that the incidence of head and neck squamous cell carcinoma (HNSCC) correlates with dental hygiene, implying a role for bacteria-induced inflammation in its pathogenesis. Here we begin to explore the pilot hypothesis that specific microbial populations may contribute to HNSCC pathogenesis via epigenetic modifications in inflammatory- and HNSCC-associated genes. Microbiomic profiling by 16S rRNA sequencing of matched tumor and adjacent normal tissue specimens in 42 individuals with HNSCC demonstrate a significant association of specific bacterial subpopulations with HNSCC over normal tissue (P < 0.01). Furthermore, microbial populations can separate tumors by tobacco status (P < 0.008), but not by alcohol status (P = 0.41). If our subhypothesis regarding a mechanistic link from microorganism to carcinogenesis via inflammation and consequent aberrant DNA methylation is correct, then we should see hypermethylation of relevant genes associate with specific microbiomic profiles. Methylation analysis in four genes (MDR1, IL8, RARB, TGFBR2) previously linked to HNSCC or inflammation shows significantly increased methylation in tumor samples compared with normal oral mucosa. Of these, MDR1 promoter methylation associates with specific microbiomic profiles in tumor over normal mucosa. Additionally, we report that MDR1 methylation correlates with regional nodal metastases in the context of two specific bacterial subpopulations, Enterobacteriaceae and Tenericutes (P < 0.001 for each). These associations may lead to a different, and potentially more comprehensive, perspective on the pathogenesis of HNSCC, and support further exploration of mechanistic linkage and, if so, novel therapeutic strategies such as demethylating agents and probiotic adjuncts, particularly for patients with advanced or refractory disease

Topics: Articles
Publisher: Oxford University Press
OAI identifier: oai:pubmedcentral.nih.gov:3298279
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles



    1. (2009). A novel mechanism for inflammation-associated carcinogenesis; an important role of activation-induced cytidine deaminase (AID) in mutation induction.
    2. (2009). Bacterial community variation in human body habitats across space and time.
    3. (2007). Case-control study of human papillomavirus and oropharyngeal
    4. (2006). Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair.
    5. (2007). Cigarette smoke extract affects functional activity of MRP1 in bronchial epithelial cells.
    6. (1997). COBRA: a sensitive and quantitative DNA methylation assay.
    7. (2008). Colorectal carcinogenesis in germ-free and conventionally reared rats: different intestinal environments affect the systemic immunity.
    8. (2001). Commensal host-bacterial relationships in the gut.
    9. (2009). Do probiotics have a role in the management of inflammatory bowel disease?
    10. (2009). Effect of MDR1 gene promoter methylation in patients with ulcerative colitis.
    11. (2001). Expression of multidrug resistance related proteins and proliferative activity is increased in advanced clinical prostate cancer.
    12. (1986). Gastrointestinal microflora in mammalian nutrition.
    13. (2008). Genetic aspects of inflammation and cancer.
    14. (2011). Gut microbiota and probiotics in colon tumorigenesis.
    15. (2005). Gut microorganisms, mammalian metabolism and personalized health care.
    16. (2008). Host-bacterial interactions in Helicobacter pylori infection.
    17. (2010). HPV status-independent association of alcohol and tobacco exposure or prior radiation therapy with promoter methylation of FUSSEL18, EBF3, IRX1, and SEPT9, but not SLC5A8, in head and neck squamous cell carcinomas.
    18. (1990). Hyperplastic gastric polyps associated with persistent Helicobacter pylori infection and active gastritis.
    19. (2009). Inflammation-related aberrant patterns of DNA methylation: detection and role in epigenetic deregulation of cancer cell transcriptome. Methods Mol.
    20. (2004). Inflammatory gene profiles in gastric mucosa during Helicobacter pylori infection in humans.
    21. (2011). Interactive metagenomic visualization in a Web browser.
    22. (2007). Methylation of multiple genes as diagnostic and therapeutic markers in primary head and neck squamous cell carcinoma.
    23. (2010). Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas.
    24. (2007). Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy.
    25. (2003). Radical causes of cancer.
    26. (2007). Reduced inflammatory response in cigarette smoke exposed Mrp1/Mdr1a/ 1b deficient mice.
    27. (2011). The molecular biology of head and neck cancer.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.