Cervical cancer subtypes harbouring integrated and/or episomal HPV16 portray distinct molecular phenotypes based on transcriptome profiling of mRNAs and miRNAs

Abstract Background: Cervical cancer is a gynecologic cancer type that develops in the cervix, accounting for 8% mortality of all female cancer patients. Infection with specific human papillomavirus (HPV) types is considered the most severe risk factor for cervical cancer. In the context of our socioeconomic conditions, an increasing burden of this disease and high mortality rate prevail in Bangladesh. Although several researches related to the epidemiology, HPV vaccination, and treatment modalities were conducted, researches on the mutation profiles of marker genes in cervical cancer in Bangladesh remain unexplored. Methods: In this study, five different genomic regions within the top three most frequently mutated genes (EGFR, KRAS and PIK3CA) in COSMIC database with a key role in the development of cervical cancers were selected to study the mutation frequency in Bangladeshi patients. In silico analysis was done in two steps: nucleotide sequence analysis and its corresponding amino acid analysis.Results: DNA from 46 cervical cancer tissue samples were extracted and amplified by PCR, using 1 set of primers designed for EGFR and 2 sets of primers designed for two different regions of both PIK3CA and KRAS gene. In total, 39 mutations were found in 28 patient samples. Eleven different mutations (23.91%), twenty-four different mutations (52.17%) and four mutations (8.7%) were found in amplified EGFR, PIK3CA and KRAS gene fragments, among which 1 (EGFR) was common in seven patient samples and 2 (PIKCA) were found in more than 1 patient. Our study shows that except for KRAS, the frequency of observed mutations in our patients is higher than those reported earlier in other parts of the world. Most of the exonic mutations were found only in the PIK3CA and EGFR genes.Conclusions: The study can be used as a basis to build a mutation database for cervical cancer in Bangladesh with the possibility of targetable oncogenic mutations. Further exploration needs to establish future diagnostics, personalized medicine decisions, and other pharmaceutical applications for specific cancer subtypes.

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Viral E6 is overexpressed via high viral load in invasive cervical cancer with episomal HPV16

BMC Cancer ◽

10.1186/s12885-017-3124-9 ◽

2017 ◽

Vol 17 (1) ◽

Cited By ~ 8

Author(s):

Die Hong ◽

Jia Liu ◽

Ying Hu ◽

Xiaonan Lu ◽

Baohua Li ◽

...

Keyword(s):

Cervical Cancer ◽

Viral Load ◽

Invasive Cervical Cancer ◽

High Viral Load ◽

Episomal Hpv16

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Multi-omics subtyping of hepatocellular carcinoma patients using a Bayesian network mixture model

10.1101/2021.12.16.473083 ◽

2021 ◽

Author(s):

Polina Suter ◽

Eva Dazert ◽

Jack Kuipers ◽

Charlotte K.Y. Ng ◽

Tuyana Boldanova ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Bayesian Network ◽

Molecular Characterization ◽

Mixture Model ◽

Clinical Stage ◽

Molecular Characteristics ◽

Clustering Methods ◽

Cancer Subtypes ◽

Molecular Phenotypes

Comprehensive molecular characterization of cancer subtypes is essential for predicting clinical outcomes and searching for personalized treatments. We present bnClustOmics, a statistical model and computational tool for multi-omics unsupervised clustering, which serves a dual purpose: Clustering patient samples based on a Bayesian network mixture model and learning the networks of omics variables representing these clusters. The discovered networks encode interactions among all omics variables and provide a molecular characterization of each patient subgroup. We conducted simulation studies that demonstrated the advantages of our approach compared to other clustering methods in the case where the generative model is a mixture of Bayesian networks. We applied bnClustOmics to a hepatocellular carcinoma (HCC) dataset comprising genome (mutation and copy number), transcriptome, proteome, and phosphoproteome data. We identified three main HCC subtypes together with molecular characteristics, some of which are associated with survival even when adjusting for the clinical stage. Cluster-specific networks shed light on the links between genotypes and molecular phenotypes of samples within their respective clusters and suggest targets for personalized treatments.

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Integration of human papillomavirus type 16 in cervical cancer cells

Open Medicine ◽

10.1515/med-2015-0001 ◽

2014 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Zivile Gudleviciene ◽

Daiva Kanopiene ◽

Ausra Stumbryte ◽

Raminta Bausyte ◽

Edgaras Kirvelaitis ◽

...

Keyword(s):

Cervical Cancer ◽

Invasive Cervical Cancer ◽

Additional Test ◽

Human Papillomavirus Type 16 ◽

Non Invasive ◽

E2 Gene ◽

Episomal Hpv16 ◽

The Status ◽

Cervical Cancer Cells

AbstractCervical cancer remains an important cause of women morbidity and mortality. The progression of cervical pathology correlates with the HPV integration into the host genome. However, the data on the viral integration status in cervical dysplasias are controversial. The aim of the current study was to evaluate the status of HPV integration in two types of cervical pathology – invasive and non invasive cervical cancer (e.g. carcinoma in situ). 156 women were included in the study: 66 women were diagnosed with invasive cervical cancer (CC) and 90 with non invasive cervical cancer (carcinoma in situ, CIS). 74.2% [95% PI: 63.64÷84.76] of specimens collected from women with diagnosed CC and 85.6% [95% PI: 85.53÷92.85] of CIS specimens were positive for HPV. The most prevalent HPV genotype in both groups was HPV16. To evaluate HPV integration, three selected HPV16 E2 gene fragments were analyzed by PCR. In the majority of CC and CIS specimens the amplification of all three HPV16 E2 gene fragments was observed. The episomal HPV16 form was detected in the majority of CC and CIS specimens. The deletion of all three HPV16 E2 gene fragments was detected in 9.4% of CC specimens and 2.2% of CIS specimens. Finally, integration status could not be used as diagnostical additional test to distinguish between invasive and non invasive cervical cancer.

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Defining Molecular Phenotypes of Human Papillomavirus–Associated Oropharyngeal Squamous Cell Carcinoma

Otolaryngology ◽

10.1016/j.otohns.2009.04.014 ◽

2009 ◽

Vol 141 (3) ◽

pp. 382-389 ◽

Cited By ~ 35

Author(s):

Paul M. Weinberger ◽

Ziwei Yu ◽

Panteleimon Kountourakis ◽

Clarence Sasaki ◽

Bruce G. Haffty ◽

...

Keyword(s):

Cervical Cancer ◽

Squamous Cell Carcinoma ◽

Human Papillomavirus ◽

Growth Factor ◽

Protein Expression ◽

Cell Carcinoma ◽

Squamous Cell ◽

Expression Patterns ◽

Molecular Phenotypes ◽

P16 Expression

OBJECTIVE: The purpose of this study was to determine if oropharyngeal squamous cell carcinoma (OSCC) classified into three groups based on human papillomavirus (HPV) 16 DNA presence and p16 expression display different protein expression patterns. STUDY DESIGN: Cross-sectional study. SETTING: A laboratory-based study of patients with OSCC treated at a tertiary care academic medical center. SUBJECTS AND METHODS: Paraffin-embedded OSCC specimens from 77 patients classified into the three-class model (HPV negative, HPV inactive [HPV16+/p16–], and HPV active [HPV16+/p16 +]) were queried for the expression of 14 tumor progression proteins using AQUA (HistoRx, New Haven CT). Protein expression between groups was assessed by analysis of variance. Global expression patterns were determined by unsupervised hierarchical clustering. RESULTS: There were significant differences in expression of β-catenin ( P = 0.009), epidermal growth factor receptor ( P = 0.009), and vascular endothelial growth factor ( P = 0.028) between groups. HPV-active tumors had overexpression of β-catenin. Hierarchical clustering showed HPV-negative and HPV-inactive tumors displayed association patterns distinct from HPV-active tumors. CONCLUSIONS: Tumors classified by HPV DNA presence and p16 expression have different molecular phenotypes. This is the first demonstration of overexpression of β-catenin (also found in HPV-caused cervical cancer) in HPV-active OSCC. HPV-active OSCC may share a similar ontogeny to HPV-caused cervical cancer.

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Mutational profiles of marker genes of cervical carcinoma in Bangladeshi patients

10.21203/rs.3.rs-39793/v2 ◽

2020 ◽

Author(s):

Shahana Sharmin ◽

Fatima Tuj Zohura ◽

Md. Sajedul Islam ◽

Anika Shimonty ◽

Md. Abdullah-Al-Kamran Khan ◽

...

Keyword(s):

Cervical Cancer ◽

Hpv Vaccination ◽

Gynecologic Cancer ◽

Treatment Modalities ◽

Nucleotide Sequence Analysis ◽

Marker Genes ◽

Cancer Tissue ◽

Cancer Type ◽

Tissue Samples ◽

Cancer Subtypes

Abstract Background: Cervical cancer is a gynecologic cancer type that develops in the cervix, accounting for 8% mortality of all female cancer patients. Infection with specific human papillomavirus (HPV) types is considered the most severe risk factor for cervical cancer. In the context of our socioeconomic conditions, an increasing burden of this disease and high mortality rate prevail in Bangladesh. Although several researches related to the epidemiology, HPV vaccination, and treatment modalities were conducted, researches on the mutation profiles of marker genes in cervical cancer in Bangladesh remain unexplored. Methods: In this study, five different genomic regions within the top three most frequently mutated genes (EGFR, KRAS and PIK3CA) in COSMIC database with a key role in the development of cervical cancers were selected to study the mutation frequency in Bangladeshi patients. In silico analysis was done in two steps: nucleotide sequence analysis and its corresponding amino acid analysis.Results: DNA from 46 cervical cancer tissue samples were extracted and amplified by PCR, using 1 set of primers designed for EGFR and 2 sets of primers designed for two different regions of both PIK3CA and KRAS gene. In total, 39 mutations were found in 26 patient samples. Eleven different mutations (23.91%), twenty-four different mutations (52.17%) and four mutations (8.7%) were found in amplified EGFR, PIK3CA and KRAS gene fragments, among which 1 (EGFR) was common in seven patient samples and 2 (PIKCA) were found in more than 1 patient. Our study shows that except for KRAS, the frequency of observed mutations in our patients is higher than those reported earlier in other parts of the world. Most of the exonic mutations were found only in the PIK3CA and EGFR genes.Conclusions: The study can be used as a basis to build a mutation database for cervical cancer in Bangladesh with the possibility of targetable oncogenic mutations. Further exploration needs to establish future diagnostics, personalized medicine decisions, and other pharmaceutical applications for specific cancer subtypes.

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Pro-metastatic gene expression, immune evasion and an altered HPV spectrum characterize an aggressive subtype of cervical cancer

10.1101/2020.04.02.019711 ◽

2020 ◽

Author(s):

Ankur Chakravarthy ◽

Stephen Henderson ◽

Cindy Dong ◽

Nerissa Kirkwood ◽

Maxmilan Jeyakumar ◽

...

Keyword(s):

Cervical Cancer ◽

Immune Evasion ◽

Effective Means ◽

Tumour Microenvironment ◽

Invasive Disease ◽

Cancer Subtypes ◽

Papillomavirus Infection ◽

Genomic Aberrations ◽

Disease Understanding ◽

Aggressive Subtype

AbstractCervical cancer is caused by carcinogenic human papillomavirus infection and represents one of the leading causes of cancer death worldwide. Effective means of tumour classification are required for better disease understanding. We performed an integrated multi-omic analysis of 655 cervical cancers, using epigenomic and transcriptomic signatures to discover two distinct cervical cancer subtypes we named “typical” and “atypical”. Typical tumours were largely HPV16-driven and frequently displayed an ‘immune-hot’ tumour microenvironment. Atypical tumours were associated with poor prognosis; they were more likely to be driven by HPVs from the HPV18-containing α7 clade, displayed distinct genomic aberrations, greater evidence of past immunoediting and a microenvironment associated with immune-evasion and failure of anti-PD1 checkpoint inhibition. The finding that atypical tumours encounter stronger anti-tumour immune responses during development may explain the lower frequency at which α7 HPV infected-lesions progress from pre-invasive disease. However those escaping this selection pressure evolve into aggressive tumours (independent of HPV-type) in which more intensive adjuvant treatment may be warranted.

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Impact of viral and host DNA methylations on HPV16-related cervical cancer pathogenesis

Tumor Biology ◽

10.1177/1010428317699799 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831769979 ◽

Cited By ~ 5

Author(s):

Shrinka Sen ◽

Paramita Mandal ◽

Amrapali Bhattacharya ◽

Sudip Kundu ◽

Rahul Roy Chowdhury ◽

...

Keyword(s):

Cervical Cancer ◽

Dna Methyltransferases ◽

Viral Integration ◽

Dna Hypomethylation ◽

Significant Linear Trend ◽

Hpv16 E6 ◽

Cpg Motifs ◽

Cancer Pathogenesis ◽

Episomal Hpv16 ◽

Negative Controls

Epigenetic alterations within human papillomavirus (HPV) and host cellular genomes are known to occur during cervical carcinogenesis. Our objective was to analyse the influence of (1) methylation within two immunostimulatory CpG motifs within HPV16 E6 and E7 genes around the viral late promoter and their correlation, if any, with expression deregulation of host receptor (TLR9) and DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) and (2) global DNA methylation levels within CpGs of the repetitive Alu sequences, on cervical cancer (CaCx) pathogenesis. Significantly higher proportions of CaCx samples portrayed methylation in immunostimulatory CpG motifs, compared to HPV16-positive non-malignant samples, with cases harbouring episomal HPV16 showing decreased methylation compared to those with viral integration. A significant linear trend of TLR9 upregulation was recorded in the order of HPV–negative controls < HPV16-positive non-malignant samples < HPV16-positive CaCx cases. TLR9 upregulation in cases with episomal HPV16 was again higher among those with non-methylated immunostimulatory CpG motifs. Comparison of cases with HPV–negative controls revealed that DNMT3A was significantly downregulated only among integrated cases, DNMT3B was significantly overexpressed among both categories of cases, although at variable levels, while DNMT1 failed to show any deregulated expression among the cases. Global host DNA hypomethylation, also showed a significant linear increasing trend through the progressive CaCx development stages mentioned above and was most prominently higher among cases with episomal HPV16 as opposed to viral integration. Thus, HPV16 and host methylations appear to influence CaCx pathogenesis, with differential molecular signatures among CaCx cases with episomal and integrated HPV16.

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