Matching intended use and type of HPV test in research and clinical practice
Geraets, D.T.
2015
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Geraets, D. T. (2015). Matching intended use and type of HPV test in research and clinical practice.
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1.1
1.1
1.1
1.1
BACKGROUND
BACKGROUND
BACKGROUND
BACKGROUND
1.1.1
1.1.1
1.1.1
1.1.1
Short introduction
Short introduction
Short introduction
Short introduction
Infection of cervical epithelium with a human
papillomavirus (HPV) can lead to the development of
cervical intraepithelial neoplasia (CIN) and ultimately
cervical cancer. Technologies that can detect and
distinguish different human papillomaviruses are
important to determine their involvement in disease, to
evaluate the efficacy of HPV vaccines, to monitor
prevalence of HPV genotypes in immunized cohorts,
and to identity women at risk for having high-grade
CIN within cervical cancer screening programs. Over
125 commercial HPV tests have been developed, with
differences in design and performance. In this thesis we
evaluated the performance of a number of established
and novel technologies for the identification of HPVs in
relation to their intended use.
1.1.2
1.1.2
1.1.2
1.1.2
C
Cervical cancer
C
C
ervical cancer
ervical cancer
ervical cancer
Cervical cancer is the fourth most common malignancy
among women worldwide, with 528,000 new cases and
266,000 deaths occurring each year (1). Squamous cell
carcinoma (SCC; 80%) and adenocarcinoma (ADC;
15%) are the main histological types (2), while
adenosquamous and neuroendocrine carcinomas
account for less than 5% of cervical cancers (3).
ADC develops from adenocarcinoma in-situ (AIS).
Precursors of SCC are classified as cervical
intraepithelial neoplasia (CIN) grade 1, 2, and 3
(including carcinoma in-situ). All precursor lesions can
regress, persist or progress. However, the possibility of
regression decreases with increasing CIN grade. The
risk of progression from CIN3 to invasive cervical
cancer (ICC) is estimated between 30-50% (4-7). The
concept of cervical carcinogenesis is summarized in
Figure 1
Figure 1:
Figure 1:
Figure 1:
Figure 1: The concept of HPV-mediated cervical carcinogenesis and the according morphological appearance. HPV
gains access to the basal cells of squamous epithelium, followed by an ordered expression pattern of viral genes leading
to the production and release of new virions. Deregulated expression of E6 and E7 oncoproteins and viral genome
integration are associated with malignant transformation, leading to genomic instability, (epi)genetic changes, and
ultimately invasive cervical cancer. The outcomes of HPV exposure are represented as a transient infection (no
pathology), a productive infection (productive CIN; CIN1 and a subset of CIN2), and a transforming infection
(transforming CIN; remaining subset of CIN2 and CIN3). The majority of transforming CIN and cervical cancers are
suggested to arise from an hrHPV infection of embryonic squamo-columnar junction (SCJ) cells (adapted from (8) and
(9)).
1.1.3
1.1.3
1.1.3
1.1.3
H
H
H
Human papillomaviruses
uman papillomaviruses
uman papillomaviruses
uman papillomaviruses
PVs are naked viruses with a circular, double-stranded
DNA genome of about 7600-8000 base-pairs (bp)
contained in a protein capsid. The genome is divided
into three regions, i.e., the long control region (LCR),
the early (E) coding region, and the late (L) coding
region. The LCR regulates viral gene expression and
replication. The E region contains six or more early
open reading frames (ORFs), i.e., E1, E2, E4, E5, E6, E7,
which encode proteins required for viral gene
expression, replication and survival. The late (L) region
encodes the two viral structural proteins, i.e., L1 and L2.
By convention, the similarity across the highly
conserved L1 ORF was adapted as the basis for
taxonomic classification of PVs (10). A PV “type” is
defined as a complete PV genome, whose L1 ORF
Squamous epithelium Superficial zone Midzone Basal layer Basement membrane DermisInfectious viral particles
Productive CIN Transforming CIN Cancer
Cancer Type of hrHPV
infection Productive (permissive) infection Transforming (non-permissive) infection Morphological
appearance CIN1/2 CIN2/3