Compositional and Functional Differences between Microbiota and Cervical Carcinogenesis as Identified by Shotgun Metagenomic Sequencing

Recent studies have reported the potential role of microbiomes in cervical disease. However, little is known about the microbiome composition and function in cervical carcinogenesis. We aimed to identify the compositional and functional alterations of cervical microbiomes in cases of cervical carcinogenesis of Korean women using shotgun metagenomic sequencing. In this study, using shotgun sequencing, we sequenced the cervical metagenomes of cervical intraneoplasia 2/3 (n = 17), cervical cancer (n = 12), and normal controls (n = 18) to identify the microbial abundances and enriched metabolic functions in cervical metagenomes. At the genus level, the microbiota of cervical cancer were differentially enriched with genera Alkaliphilus, Pseudothermotoga, and Wolbachia. Cervical intraepithelial neoplasia (CIN) 2/3 were enriched with Lactobacillus, Staphylococcus, and Candidatus Endolissoclinum. The normal group was enriched with Pseudoalteromonas and Psychrobacter. Further characterization of the functionalities of the metagenomes may suggest that six Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologies (KOs) that are involved in 10 pathways are associated with an increased risk of CIN2/3 and cervical cancer. Specifically, cervical metagenomes were enriched in the course of peptidoglycan synthesis and depleted by dioxin degradation and 4-oxalocrotonate tautomerase. The Cluster of Orthologous Groups (COG) category ‘Defense mechanisms’ was depleted in cervical cancer patients. Our findings based on shotgun metagenomic sequencing suggest that cervical microbiome community compositions and their metagenomics profiles differed between cervical lesions and normal subjects. Future studies should have larger sample sizes and/or aggregate their results to have sufficient power to detect reproducible and significant associations.

Download Full-text

LC/MS-Based Polar Metabolite Profiling Identified Unique Biomarker Signatures for Cervical Cancer and Cervical Intraepithelial Neoplasia Using Global and Targeted Metabolomics

Cancers ◽

10.3390/cancers11040511 ◽

2019 ◽

Vol 11 (4) ◽

pp. 511 ◽

Cited By ~ 7

Author(s):

Imran Khan ◽

Miso Nam ◽

Minji Kwon ◽

Sang-soo Seo ◽

Sunhee Jung ◽

...

Keyword(s):

Cervical Cancer ◽

Cervical Intraepithelial Neoplasia ◽

Metabolic Pathways ◽

Multivariate Logistic Regression Analysis ◽

Intraepithelial Neoplasia ◽

Cervical Carcinogenesis ◽

Cervical Cancers ◽

Hpv Status ◽

Increased Risk ◽

Risk Of Cancer

Cervical cancer remains one of the most prevalent cancers among females worldwide. Therefore, it is important to discover new biomarkers for early diagnosis of cervical intraepithelial neoplasia (CIN) and cervical cancer, preferably non-invasive ones. In the present study, we aimed to identify unique metabolic signatures for CINs and cervical cancers using global and targeted metabolomic profiling. Plasma samples (69 normal, 55 CIN1, 42 CIN2/3, and 60 cervical cancer) were examined by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS) coupled with multivariate statistical analysis. Metabolic pathways were analyzed using the integrated web-based tool MetaboAnalyst. A multivariate logistic regression analysis was conducted to evaluate the combined association of metabolites and human papillomavirus (HPV) status with the risk of cervical carcinogenesis. A total of 28 metabolites exhibiting discriminating levels among normal, CIN, and cervical cancer patients (Kruskal–Wallis test p < 0.05) were identified in the global profiling analysis. The pathway analysis showed significantly altered alanine, aspartate, and glutamate metabolic pathways (FDR p-value < 0.05) in both the discovery and validation phases. Seven metabolites (AMP, aspartate, glutamate, hypoxanthine, lactate, proline, and pyroglutamate) were discriminated between CINs and cervical cancer versus normal (area under the curve (AUC) value > 0.8). The levels of these metabolites were significantly high in patients versus normal (p < 0.0001) and were associated with increased risk of developing CIN2/3 and cervical cancer. Additionally, elevated levels of the seven metabolites combined with positive HPV status were correlated with substantial risk of cancer progression. These results demonstrated that metabolomics profiling is capable of distinguishing CINs and cervical cancers from normal and highlighted potential biomarkers for the early detection of cervical carcinogenesis.

Download Full-text

The Role of Early Colposcopy in the Management of Females with First Episode Anogenital Warts

International Journal of STD & AIDS ◽

10.1177/095646249400500511 ◽

1994 ◽

Vol 5 (5) ◽

pp. 343-345 ◽

Cited By ~ 2

Author(s):

K A Ward ◽

J R Houston ◽

B E Lowry ◽

R D Maw ◽

W W Dinsmore

Keyword(s):

Intraepithelial Neoplasia ◽

Hpv Infection ◽

Cervical Cytology ◽

First Episode ◽

Low Grade ◽

High Grade ◽

Anogenital Warts ◽

Cervical Smear ◽

Cervical Lesions ◽

Increased Risk

212 females attending a genitourinary medicine (GUM) clinic with first episode anogenital warts were screened by cervical cytology and colposcopy/histology for the presence of cervical epithelial abnormalities in keeping with infection by the human papillomavirus (HPV infection) and/or cervical intraepithelial neoplasia (CIN). The prevalence of cervical epithelial abnormalities detected by cervical cytology alone was 32%, rising to 56% after colposcopic examination. However, the majority of cervical lesions detected by colposcopy alone were of low grade (HPV infection and/or CIN I). Histologically confirmed high grade cervical lesions (CIN II or CIN III) were detected more frequently in those females in whom cervical cytological examination indicated dyskaryosis in keeping with any grade of CIN, compared to females without dyskaryotic changes on cervical smear ( P<0.05, chi-squared test with Yates' correction). Early colposcopy is indicated for females with anogenital warts in the presence of a cervical smear showing dyskaryosis in keeping with any grade of CIN, because of the statistically significant increased risk of detecting a potentially progressive high grade cervical lesion. In females without dyskaryotic changes on cervical smear, the value of early colposcopy is uncertain and warrants larger more long-term trials.

Download Full-text

Mycoplasma Co-Infection Is Associated with Cervical Cancer Risk

Cancers ◽

10.3390/cancers12051093 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1093 ◽

Cited By ~ 2

Author(s):

Cameron Klein ◽

Kandali Samwel ◽

Crispin Kahesa ◽

Julius Mwaiselage ◽

John T. West ◽

...

Keyword(s):

Cervical Cancer ◽

Mycoplasma Hominis ◽

Mycoplasma Genitalium ◽

Metagenomic Sequencing ◽

Cervical Lesions ◽

Sexually Transmitted ◽

Cervical Cancer Risk ◽

Immunodeficiency Virus ◽

The Relationship ◽

Ureaplasma Spp

Tanzania faces one of the highest cervical cancer burdens in the world. Recent work has suggested that the bacterial family Mycoplasmataceae is associated with higher levels of human papillomavirus (HPV), human immunodeficiency virus (HIV), and pre-cancerous cervical lesions. Mycoplasmataceae infection in Tanzania is not well understood, especially when considering the differences between sexually transmitted species of Mycoplasmataceae. To establish the prevalence of common Mycoplasmataceae cervical infections and evaluate their relationship with risk factors for cervical cancer, 1160 Tanzanian women responded to an epidemiological questionnaire and were tested for HIV, HPV, cervical lesions, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma spp., and Lactobacillus iners. A subset of 134 women were used for 16s metagenomic sequencing of cervical DNA to establish the relative abundance of Mycoplasmataceae and Lactobacillus present. PCR detection of bacteria at the cervix found Ureaplasma spp. in 51.4% of women, M. hominis in 34%, M. genitalium in 2.3%, and L. iners in 75.6%. M. hominis and M. genitalium infection were significantly more prevalent among women with HPV and HIV. M. hominis prevalence was similar despite severity of cervical lesions; however, abundance of M. hominis increased significantly in women with cervical lesions. These results emphasize the importance of understanding the relationship between M. hominis and HPV-related cervical pathogenesis.

Download Full-text

Residual or Recurrent Precancerous Lesions After Treatment of Cervical Lesions in Human Immunodeficiency Virus–infected Women: A Systematic Review and Meta-analysis of Treatment Failure

Clinical Infectious Diseases ◽

10.1093/cid/ciy1123 ◽

2019 ◽

Vol 69 (9) ◽

pp. 1555-1565 ◽

Cited By ~ 7

Author(s):

Pierre Debeaudrap ◽

Joelle Sobngwi ◽

Pierre-Marie Tebeu ◽

Gary M Clifford

Keyword(s):

Systematic Review ◽

Cervical Cancer ◽

Human Immunodeficiency Virus ◽

Treatment Failure ◽

Post Treatment ◽

High Grade ◽

Cervical Lesions ◽

Pooled Prevalence ◽

Increased Risk ◽

Immunodeficiency Virus

Abstract Background Screening and treating premalignant cervical lesions (cervical intraepithelial neoplasia 2+ [CIN2+]) is an effective way to prevent cervical cancer, and recommendations exist for the monitoring of treatment success. Yet, there is no specific recommendation for human immunodeficiency virus (HIV)-infected women, who are at a known, increased risk of cervical cancer. Methods A systematic review was performed by searching MEDLINE, EMBASE, and Web of Science for studies published from January 1980 through May 2018. Eligible studies described the prevalence of histologically- and/or cytologically-defined lesions in HIV-infected women at least 6 months post-treatment. The primary endpoint was treatment failure, defined as the presence of residual and/or recurrent high-grade CIN2+/high-grade squamous intraepithelial lesions post-treatment. The pooled prevalence in HIV-infected women and the odds ratios (ORs) for HIV-infected compared to HIV-uninfected women were estimated using random-effects models. Results Among 40 eligible studies, the pooled prevalence of treatment failure in HIV-infected women was 21.4% (95% confidence interval [CI] 15.8–27.0). There was no significant difference in the treatment failure prevalence for cryotherapy (13.9%, 95% CI 6.1–21.6) versus loop electrosurgical excision procedure (13.8%, 95% CI 8.9–18.7; P = .9), but the treatment failure prevalence was significantly higher in women with positive (47.2%, 95% CI 22.0–74.0) than with negative (19.4%, 95% CI 11.8–30.2) excision margin (OR 3.4, 95% CI 1.5–7.7). Treatment failure was significantly increased in HIV-infected versus HIV-uninfected women, both overall (OR 2.7, 95% CI 2.0–3.5) and in all sub-group analyses. Conclusions There is strong evidence for an increased risk of treatment failure in HIV-infected women, in comparison to their HIV-negative counterparts. The only significant predictor of treatment failure in HIV-infected women was a positive margin status, but further data is needed on long-term outcomes after ablative treatment in HIV-infected women.

Download Full-text

Discovery of candidate gene expression signatures in peripheral blood for the screening of cervical cancer

Biomarkers in Medicine ◽

10.2217/bmm-2019-0247 ◽

2020 ◽

Vol 14 (2) ◽

pp. 109-118 ◽

Cited By ~ 2

Author(s):

Qiuling Ma ◽

Yong Shao ◽

Wei Chen ◽

Cheng Quan ◽

Yanhui Zhu ◽

...

Keyword(s):

Gene Expression ◽

Cervical Cancer ◽

Real Time ◽

Real Time Pcr ◽

Peripheral Blood ◽

Area Under The Curve ◽

Intraepithelial Neoplasia ◽

Sequencing Analysis ◽

Quantitative Real Time Pcr ◽

Cervical Lesions

Aim: To investigate whether cervical cancer (CC) and cervical intraepithelial neoplasia (CIN) can be screened by analyzing gene expression profiling of peripheral blood. Methods: RNA-sequencing analysis of blood was performed on 11 CC patients, 21 CIN patients and 19 healthy controls (H). Fifty-nine genes were validated by quantitative real-time PCR using blood samples from 46 H, 83 CC and 32 CIN patients. Results: There were significant differences in the expression levels of six genes between CC and H, five genes between CIN and H and four genes between CC and CIN (p < 0.05). Four genes discriminated cervical lesions from H with a sensitivity of 82.61%, a specificity of 87.83% and an area under the curve of 0.8981. Three genes discriminated CC from CIN with a sensitivity of 53.13%, a specificity of 96.39% and an area under the curve of 0.7786. Conclusion: Our findings provided a promising noninvasive quantitative real-time PCR diagnostic assay of CC and CIN.

Download Full-text

The ratio of serum Angiopoietin-1 to Angiopoietin-2 in patients with cervical cancer is a valuable diagnostic and prognostic biomarker

PeerJ ◽

10.7717/peerj.3387 ◽

2017 ◽

Vol 5 ◽

pp. e3387 ◽

Cited By ~ 5

Author(s):

Ping Yang ◽

Na Chen ◽

Dongyun Yang ◽

Janet Crane ◽

Shouhua Yang ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Cancer ◽

Progression Free Survival ◽

Intraepithelial Neoplasia ◽

Roc Curves ◽

Enzyme Linked Immunosorbent Assay ◽

Advanced Tumor Stage ◽

Cervical Lesions ◽

Advanced Tumor ◽

Angiopoietin 1

Objectives Angiopoietins have been found to play essential roles in tumor angiogenesis. The present study was aimed at investigating the diagnostic and prognostic values of serum angiopoietin 1 and 2 (sAng-1 and sAng-2) in cervical cancer. Methods The sAng-1 and sAng-2 concentrations were analyzed in 77 women with cervical cancer, 44 women with cervical intraepithelial neoplasia (CIN) and 43 women without cervical lesions by enzyme-linked immunosorbent assay. The diagnostic values of sAng-1, sAng-2 and sAng-1/sAng-2 were evaluated by receiver operating characteristic (ROC) curves. The Ang-1 and Ang-2 expression in cervical cancer tissues as well as microvessel density (MVD), were assessed by immunohistochemistry. Results The concentration of sAng-2 gradually increased and the sAng-1/Ang-2 ratio was gradually decreased from normal control to CIN, then to squamous cell cancer, and the sAng-1/sAng-2 ratio was also significantly decreased in adenocarcinoma. The area under ROC curves of sAng-2 and sAng-1/sAng-2 ratio for discriminating cervical cancer from normal were 0.744 and 0.705, respectively. Decreased sAng-1/sAng-2 was significantly associated with advanced tumor stage, poor differentiation, lymph-vascular space invasion and high MVD. sAng-2 was positively correlated with the Ang-2 expression in cervix epithelia. A high sAng-1/sAng-2 ratio was associated with a longer progression-free survival and a longer overall survival in cervical cancer patients. Conclusions These findings suggest that sAng-2 and the sAng-1/sAng-2 ratio may be valuable diagnostic and prognostic biomarkers for cervical cancer.

Download Full-text

Dietary Inflammatory Index and Its Relationship with Cervical Carcinogenesis Risk in Korean Women: A Case-Control Study

Cancers ◽

10.3390/cancers11081108 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1108 ◽

Cited By ~ 2

Author(s):

Sundara Raj Sreeja ◽

Hyun Yi Lee ◽

Minji Kwon ◽

Nitin Shivappa ◽

James R. Hebert ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Risk ◽

Multinomial Logistic Regression ◽

Gynecologic Oncology ◽

Cervical Carcinogenesis ◽

Korean Women ◽

Dietary Inflammatory Index ◽

Inflammatory Index ◽

Cervical Cancer Risk ◽

Increased Risk

Several studies have reported that diet’s inflammatory potential is related to chronic diseases such as cancer, but its relationship with cervical cancer risk has not been studied yet. The aim of this study was to investigate the association between Dietary Inflammatory Index (DII®) and cervical cancer risk among Korean women. This study consisted of 764 cases with cervical intraepithelial neoplasia (CIN)1, 2, 3, or cervical cancer, and 729 controls from six gynecologic oncology clinics in South Korea. The DII was computed using a validated semiquantitative Food Frequency Questionnaire (FFQ). Odds ratios and 95% CI were calculated using multinomial logistic regression. Higher DII scores were associated with higher cervical carcinogenesis risk. A significant association was observed between the DII and risk among CIN2/3 [Odds Ratio (OR) = 3.14; 95% Confidence Intervals (CI) = 1.57–6.29] and cervical cancer patients (OR = 1.98; 95% CI = 1.01–3.88). Among Human Papilloma Virus (HPV)-positive women, a significant association was found between DII and cervical carcinoma risk with CIN2/3 (OR = 5.65; 95% CI = 1.38–23.2). Moreover, women with CIN2/3 and cervical cancer showed a significant association with proinflammatory diet in people without of physical activity (OR = 3.79; 95% CI = 1.81–7.93). These findings suggest that high intake of proinflammatory diets is associated with increased risk of cervical carcinogenesis among women with CIN2/3. Further evaluation in future studies to confirm this association is warranted.

Download Full-text

Distribution of cervical lesions in high-risk HPV (hr-HPV) positive women with ASC-US: a retrospective single-center study in China

Virology Journal ◽

10.1186/s12985-020-01455-2 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Zhiling Wang ◽

Ying Gu ◽

Hui Wang ◽

Junyu Chen ◽

Yawen Zheng ◽

...

Keyword(s):

Cervical Cancer ◽

Viral Load ◽

High Risk ◽

High Viral Load ◽

Single Infection ◽

Multiple Infections ◽

Trend Test ◽

Cervical Lesions ◽

Increased Risk ◽

High Risk Hpv

Abstract Background To investigate distributions of cervical lesions and factors associated with the severity of the cervical lesions in high-risk HPV (hr-HPV) positive women with atypical squamous cells of undetermined significance (ASC-US) cytology. Methods Clinical information of 250,000 women who underwent HPV and cytological test was collected from January 2012 to January 2019. The association between the severity of the cervical lesions and hr-HPV genotypes, hr-HPV viral load, and ages, were analyzed in hr-HPV-positive/ASC-US women. Results 3459 hr-HPV-positive/ASC-US women were enrolled in this study. Overall, 43.51% of women with ASC-US had normal histological results, 34.35% had high-grade squamous intraepithelial lesion (HSIL), and 1.30% had cervical cancer. The rate of HSIL or worse (HSIL+) in women with single HPV16 infection (63.09%) was the highest, followed by HPV33 (57.50%), HPV51 (36.11%), HPV58 (36.11%), HPV52 (28.28%), HPV18 (26.37%), HPV66 (19.35%), HPV39 (18.92%), HPV53 (15.00%), and HPV56 (8.51%). Detection rate of HSIL+ in low, intermediate and high viral-load groups were 15.87% (n = 30), 34.91% (n = 74) and 40.68% (n = 214) (Cochran-Armitage Trend test χ2 = 35.03, p < 0.0001). Compared with the 51–60-year-old group (21.65%), the women in ≤ 30 (40.52%), 31–40 (39.67%), and 41–50 (34.22%) year-old groups had significantly higher risk of HSIL+. The women in ≤ 51–60 (2.68%) and > 60 (3.41%) year-old groups were at increased risk for cervical cancer, compared with the ≤ 30-year-old group (0.61%). Conclusions ASC-US women with HPV 16/18/33/51/52/58 single infection and multiple infections, as well as high HPV viral loads, have high risk of HSIL+.

Download Full-text

Clinical Significance of the Interaction between Human Papillomavirus (HPV) Type 16 and Other High-Risk Human Papillomaviruses in Women with Cervical Intraepithelial Neoplasia (CIN) and Invasive Cervical Cancer

Journal of Oncology ◽

10.1155/2020/6508180 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Arsenio A. Spinillo ◽

Mattia M. Dominoni ◽

Anna A. C. Boschi ◽

Cecilia C. Sosso ◽

Giacomo G. Fiandrino ◽

...

Keyword(s):

Cervical Cancer ◽

High Risk ◽

Residual Disease ◽

Invasive Cervical Cancer ◽

Intraepithelial Neoplasia ◽

Human Papillomaviruses ◽

Multiple Infections ◽

Cervical Lesions ◽

Hpv 16 ◽

The Impact

The aim is to evaluate the clinical consequences of coinfection between HPV 16 and other high-risk HPVs among women with a histological diagnosis of CIN or invasive cervical cancer. A total of 2985 women, with a diagnosis of either CIN or cancer (<IB) on cervical or cone biopsy, were included. HPV genotypes were identified using the INNO-LiPA HPV genotyping assay, version EXTRA, on cervical scraping, before the colposcopic evaluation and the colposcopic biopsies or conization. In the overall population, HPV16 interacted positively with HPV18 (RR = 2, 95% CI 1.5–2.6) and negatively with HPV33, 51, 52, and 66, in log-linear analysis. There was an excess of CIN3 diagnoses among subjects coinfected with HPV16 and HPV18 or HPV52, although the absolute number of cases was relatively small. In a logistic model, the odds ratio of CIN3+ associated with coinfection of HPV16 and HPV18 (OR = 3.8, 95% CI 2.5–5.7, p = 0.004 compared to single HPV16) or HPV52 (OR = 3.6, 95% CI 2.6–5.1, p = 0.009 compared to single HPV) was higher than that associated with single HPV 16 infections. Finally, multiple infections had no effect on residual disease and did not influence the recurrence of high-grade CIN during a median follow-up of 25 months (IR 17–41). HPV16 interacted positively with HPV18 and negatively with HPV33, 51, 52, and 66 supporting the notion that HPV16 interacts mostly negatively with other HR-HPVs in CIN lesions. Among specimens coinfected with HPV16 and 18 or 52, there was an excess of CIN3+ although the impact on the prevalence of severe cervical lesions was limited.

Download Full-text

Interplay between the human gut microbiome and host metabolism

10.1101/561787 ◽

2019 ◽

Cited By ~ 1

Author(s):

Alessia Visconti ◽

Caroline I. Le Roy ◽

Fabio Rosa ◽

Niccolo Rossi ◽

Tiphaine C. Martin ◽

...

Keyword(s):

Gut Microbiome ◽

Metabolic Pathways ◽

Taxonomic Composition ◽

Metagenomic Sequencing ◽

Human Gut ◽

Metabolic Potential ◽

Microbial Ecosystem ◽

Microbiome Composition ◽

Shotgun Metagenomic Sequencing ◽

Key Species

AbstractThe human gut is inhabited by a complex and metabolically active microbial ecosystem regulating host health. While many studies have focused on the effect of individual microbial taxa, the metabolic potential of the entire gut microbial ecosystem has been largely under-explored. We characterised the gut microbiome of 1,004 twins via whole shotgun metagenomic sequencing (average 39M reads per sample). We observed greater similarity, across unrelated individuals, for functional metabolic pathways (82%) than for taxonomic composition (43%). We conducted a microbiota-wide association study linking both taxonomic information and microbial metabolic pathways with 673 blood and 713 faecal metabolites (Metabolon, Inc.). Metabolic pathways associated with 34% of blood and 95% of faecal metabolites, with over 18,000 significant associations, while species-level results identified less than 3,000 associations, suggesting that coordinated action of multiple taxa is required to affect the metabolome. Finally, we estimated that the microbiome mediated a crosstalk between 71% of faecal and 15% of blood metabolites, highlighting six key species (unclassified Subdoligranulum spp., Faecalibacterium prausnitzii, Roseburia inulinivorans, Methanobrevibacter smithii, Eubacterium rectale, and Akkermansia muciniphila). Because of the large inter-person variability in microbiome composition, our results underline the importance of studying gut microbial metabolic pathways rather than focusing purely on taxonomy to find therapeutic and diagnostic targets.

Download Full-text