Potential contribution of the uterine microbiome in the development of endometrial cancer

Abstract

BackgroundEndometrial 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.MethodsWe 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.ResultsThe 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).ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0368-y) contains supplementary material, which is available to authorized users.

Case for a role of the microbiome in gynecologic cancers: Clinician's perspective

“…116,[119][120][121] In another study, when the magnitude of EOC risk reduction conveyed by tubal ligation was compared with bilateral salpingectomy, the latter had a higher risk reduction (42-78%), but tubal ligation was still found to decrease the risk by 13-41%. 122 In our study, 53 the bacterial burden was different in different body parts, and we were able to amplify bacterial DNA from 94% of the cervical/ vaginal samples and 87% of the uterine samples. The amplification of bacterial DNA decreased markedly between the uterus and fallopian tubes/ovaries; we were only able to amplify bacterial DNA from 50% and 61% of fallopian tubes and ovaries, respectively.…”

“…Firmicutes, Spirochaetes, Actinobacteria ( Atopobium ), Bacteroidetes ( Bacteroides and Porphyromonas ) and Proteobacteria species were enriched in patients with EC. Interestingly, the simultaneous presence of a Porphyromonas species and Atopobium vaginae in vaginal swabs, combined with a vaginal pH greater than 5, had a sensitivity of 100% and specificity of 60% to detect EC . Vaginal dysbiosis has been shown to cause PID and, as mentioned previously, there is a possible relationship between PID and EC .…”

“…In our study, the bacterial burden was different in different body parts, and we were able to amplify bacterial DNA from 94% of the cervical/vaginal samples and 87% of the uterine samples. The amplification of bacterial DNA decreased markedly between the uterus and fallopian tubes/ovaries; we were only able to amplify bacterial DNA from 50% and 61% of fallopian tubes and ovaries, respectively . This might be secondary to decreased bacterial burden or to other factors such as sampling.…”

“…Interestingly, the simultaneous presence of a Porphyromonas species and Atopobium vaginae in vaginal swabs, combined with a vaginal pH greater than 5, had a sensitivity of 100% and specificity of 60% to detect EC. 53 Vaginal dysbiosis has been shown to cause PID 54 and, as mentioned previously, there is a possible relationship between PID and EC. 51 In our study, patients with EC had a microbial composition similar to PID-causing agents such as Escherichia (Proteobacteria) and Bacteroides.…”

“…The amplification of bacterial DNA decreased markedly between the uterus and fallopian tubes/ovaries; we were only able to amplify bacterial DNA from 50% and 61% of fallopian tubes and ovaries, respectively. 53 This might be secondary to decreased bacterial burden or to other factors such as sampling. At this time, we have no evidence to suggest that tubal ligation impairs circulation of bacteria or bacterial toxins between the lower and upper genital tract or whether that modifies EOC risk.…”