title: Potential contribution of the uterine microbiome in the development of endometrial cancer.
abstract: Endometrial cancer studies have led to a number of well-defined but mechanistically unconnected genetic and environmental risk factors. One of the emerging modulators between environmental triggers and genetic expression is the microbiome. We set out to inquire about the composition of the uterine microbiome and its putative role in endometrial cancer.
  
  
  
  We undertook a study of the microbiome in samples taken from different locations along the female reproductive tract in patients with endometrial cancer (n = 17), patients with endometrial hyperplasia (endometrial cancer precursor, n = 4), and patients afflicted with benign uterine conditions (n = 10). Vaginal, cervical, Fallopian, ovarian, peritoneal, and urine samples were collected aseptically both in the operating room and the pathology laboratory. DNA extraction was followed by amplification and high-throughput next generation sequencing (MiSeq) of the 16S rDNA V3-V5 region to identify the microbiota present. Microbiota data were summarized using both α-diversity to reflect species richness and evenness within bacterial populations and β-diversity to reflect the shared diversity between bacterial populations. Statistical significance was determined through the use of multiple testing, including the generalized mixed-effects model.
  
  
  
  The microbiome sequencing (16S rDNA V3-V5 region) revealed that the microbiomes of all organs (vagina, cervix, Fallopian tubes, and ovaries) are significantly correlated (p < 0.001) and that there is a structural microbiome shift in the cancer and hyperplasia cases, distinguishable from the benign cases (p = 0.01). Several taxa were found to be significantly enriched in samples belonging to the endometrial cancer cohort: Firmicutes (Anaerostipes, ph2, Dialister, Peptoniphilus, 1-68, Ruminococcus, and Anaerotruncus), Spirochaetes (Treponema), Actinobacteria (Atopobium), Bacteroidetes (Bacteroides and Porphyromonas), and Proteobacteria (Arthrospira). Of particular relevance, the simultaneous presence of Atopobium vaginae and an uncultured representative of the Porphyromonas sp. (99 % match to P. somerae) were found to be associated with disease status, especially if combined with a high vaginal pH (>4.5).
  
  
  
  Our results suggest that the detection of A. vaginae and the identified Porphyromonas sp. in the gynecologic tract combined with a high vaginal pH is statistically associated with the presence of endometrial cancer. Given the documented association of the identified microorganisms with other pathologies, these findings raise the possibility of a microbiome role in the manifestation, etiology, or progression of endometrial cancer that should be further investigated.
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Marina R S
authors.initials: MR
authors.lastname: Walther-António
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Multinu
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Hokenstad
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Tammy J
authors.initials: TJ
authors.lastname: Distad
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: E Heidi
authors.initials: EH
authors.lastname: Cheek
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Keeney
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, 55905, USA.|Present Address: North Memorial Medical Center, Robbinsdale, MN, 55442, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Creedon
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, MN, 55905, USA.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Nelson
authors.affiliation: Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, 55905, USA. Mariani.Andrea@mayo.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mariani
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, MN, 55905, USA. Chia.Nicholas@mayo.edu.|Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. Chia.Nicholas@mayo.edu.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA. Chia.Nicholas@mayo.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chia
mesh_terms: D000328:Adult; D000368:Aged; D001419:Bacteria / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D004269:DNA, Bacterial / Q000032:analysis; D004275:DNA, Ribosomal / Q000032:analysis; D004714:Endometrial Hyperplasia / Q000382:microbiology*; D016889:Endometrial Neoplasms / Q000382:microbiology*; D005187:Fallopian Tubes / Q000382:microbiology; D005260:Female; D006801:Humans; D008875:Middle Aged; D010053:Ovary / Q000382:microbiology; D010802:Phylogeny; D012336:RNA, Ribosomal, 16S / Q000032:analysis; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods*; D014556:Urine / Q000382:microbiology; D014599:Uterus / Q000382:microbiology*; D014621:Vagina / Q000382:microbiology
chemical_list: D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D012336:RNA, Ribosomal, 16S
keywords: 16S rDNA; Atopobium; Endometrial cancer; Microbiome; Porphyromonas; Uterus