Landscape of HPV mediated events as potential biomarkers in

diverse carcinomas
Amit Kumar Gupta, Manoj Kumar*
Bioinformatics Centre, CSIR-Institute of Microbial Technology, Sector 39A, Chandigarh-160036, India
Email: amitg@imtech.res.in, manojk@imtech.res.in
Results

Introduction
The human papillomaviruses (HPVs) are circular, doublestranded DNA genome of approximately 8.0 kb in length.
They are extremely associated with different carcinomas.
Persistent HPVs infection and associated consequences are
valuable determinants of multistage carcinogenic progression.
Multiple events pertinent to HPV mediated diseases can act as
potential biomarkers are mainly viral DNA integration, viral
methylation and cellular miRNAs expression. These could
improve the reliability of cancer screening and prevention.
Despite of numerous experimental studies, there is a paucity of
computational resources with a unique focus on cancer
progression and therapeutically potential biomarkers. Moreover,
it is still unclear and less known about the viral mediated
processes.
The HPVbase is the first web knowledgebase to provide highly
interactive and manually curated resource for the clinically
significant viral and cellular biomarkers.

90

HPV16

HPV18

HPV33

HPV45

80

Number of Integration Sites

70

60

50

40

30

20

10

0
HPV16

Chr1
64

Chr2
74

Chr3
86

Chr4
36

Chr5
53

Chr6
48

Chr7
30

Chr8
54

Chr9
80

Chr10
22

Chr11
31

Chr12
23

Chr13
48

Chr14
33

Chr15
22

Chr16
20

Chr17
42

Chr18
25

Chr19
36

Chr20
28

Chr21
27

Chr22
8

ChrX
49

ChrY
1

HPV18

18

17

13

13

10

10

46

10

12

11

10

HPV33

HPV45

Graph depicting chrommosomal distribution of HPVs

integration sites on human genome.

Figure delineating frequency of major host genes disrupted due

to viral integration events.

Representing number of integration sites

distributed at distinct cytoband positions.

Distribution of methylation sites among

different types of HPV.

Objectives
The goal of study is to provide a comprehensive web-based
platform of clinically significant potential biomarkers such as
integration events, methylation pattern in different
epidemiological conditions and cellular miRNAs aberrant
expressions in the etiology of oncogenesis.

Distribution of integration sites among diverse

cancer types.

Materials And Methods

Circos plot representing genome-wide integration pattern of HPV16 into human genome with chromosomal
cytobands and disrupted gene information. From inside to out, the innermost ring with rainbow color lines (specific
for each chromosomes) linking HPV16 genomic coordinates to human idiogram (chromosome numbers in a
clockwise direction, and small red segment within each chromosome indicating the centromere) delineating
genomic integration sites. Dark bands within chromosomes depicting integration hot spots. The second ring
represents cytoband information. At last, outermost circle shows the host genes (in blue color) disrupted due to
viral integration.

(( PubMed(

Literature(search(
HPV'type'
HPV'region'
Viral'Integrant/'breakpoints'
Chromosome'Number'
Cytoband'
Cellular'breakpoint'
Target'genes'
Fragile'sites'
Specimen/sample'type'
Sample'size'
Cancer'type/histology'
DetecDon'Technique'
References'

Cancer'type'
mirbase'ID'

Bar diagram to represent chromosome wise

distribution of differentially regulated miRNAs in
HPVs associated carcinomas. (a) Upregulated,
(b) Downregulated.

Venn diagram showing number of aberrantly expressed

miRNAs in diverse carcinomas. (a) Upregulated, (b)
Downregulated, (c) up and down regulated miRNAs in CC,
(d) up and down regulated miRNAs in HNSCC and (e) up and
down regulated miRNAs in vulvar carcinoma.

Conclusion

mature'miR'ID'
miRNAs'
cytoband'
Chromosome'coordinates'

To support biomarker discovery and systematically utilize existing knowledge, we have developed a web-based integrative resource HPVbase for the comparative
analysis of multiple events i.e. HPV integrations, methylation patterns and cellular miRNAs expression. Thus, in turn this exhaustive platform could be useful to
assist and facilitate reliable cancer diagnostics and prognosis.

Target'genes'

References'

DetecDon'technique'

Sample'size'

Sample'/specimen'type'

Cancer'type/stage'

Genomic'sequence'

Length'

MethylaDon'status'

MethylaDon'Sites'

Genomic'region'

HPV'type'

References'

Acknowledgement
Council of Scientific and Industrial Research (CSIR), India and
Department of Biotechnology (DBT), Government of India.

References

zur Hausen, H. Papillomaviruses and cancer: from basic studies to clinical application. Nat. Rev. Cancer 2, 342350 (2002).
Schiffman, M. & Wentzensen, N. Human papillomavirus infection and the multistage carcinogenesis of cervical cancer. Cancer Epidemiol. Biomarkers Prev. 22, 553560 (2013).
Jeon, S. & Lambert, P. F. Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proc. Natl. Acad.
Sci. U S A 92, 16541658 (1995).
Wentzensen, N., Vinokurova, S. & von Knebel Doeberitz, M. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower
genital tract. Cancer Res. 64, 38783884 (2004).
Clarke, M. A. et al. Human papillomavirus DNA methylation as a potential biomarker for cervical cancer. Cancer Epidemiol. Biomarkers Prev. 21, 21252137 (2012).
Wang, X. et al. microRNAs are biomarkers of oncogenic human papillomavirus infections. Proc. Natl. Acad. Sci. U S A 111, 42624267 (2014).
Kumar Gupta, A. and Kumar, M. HPVbase- a knowledgebase of viral integrations, methylation patterns and microRNAs aberrant expression: As potential biomarkers for Human papillomaviruses mediated
carcinomas. Sci. Rep. 5, 12522 (2015).