Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1080 Molecular Pathogenesis of Cervical Carcinoma Analysis of Clonality, HPV16 Sequence Variations and Loss of Heterozygosity BY XINRONG HU ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2001
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Molecular Pathogenesis of Cervical Carcinoma160985/FULLTEXT01.pdfPathology presented at Uppsala University in 2001 Abstract Hu, X. 2001. Molecular Pathogenesis of Cervical Carcinoma:
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Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Medicine 1080
Molecular Pathogenesis of
Cervical CarcinomaAnalysis of Clonality, HPV16 Sequence Variations
and Loss of Heterozygosity
BY
XINRONG HU
ACTA UNIVERSITATIS UPSALIENSISUPPSALA 2001
1
Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) inPathology presented at Uppsala University in 2001
Abstract
Hu, X. 2001. Molecular Pathogenesis of Cervical Carcinoma: Analysis ofClonality, HPV16 Sequence Variations and Loss of Heterozygosity. ActaUniversitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations fromthe Faculty of Medicine 1080. 76pp. Uppsala. ISBN 91-554-5127-6
A previous model of morphological pathogenesis assumed that cervical carcinomais of monoclonal origin and progresses through multiple steps from normal epitheliumvia CINS into invasive carcinomas. The aim of this study was to investigate themolecular mechanism of pathogenesis of cervical neoplasia.
In the clonality study, we found that 75% (6/8) of informative cases of cervicalcarcinoma had identical patterns of loss of heterozygosity (LOH) in the multiplesynchronous lesions, while the remaining cases had different LOU patterns. In anextensively studied "golden case", the multiple carcinoma and cervical intraepithelialneoplasia (CIN) lesions could be divided into several different clonal groups by theX-chromosome inactivation patterns, HPV 16 mutations and LOH patterns. Thebiggest clonal family included one CIN II, one CIN III and four carcinoma samples,while four other monoclonal families of carcinoma did not include CIN lesions. Theseresults suggested that cervical carcinoma can be either monoclonal or polygonal andcontains clones developing either directly or via multiple steps. In the study of HPVtypes and HPV16 variations, the results confirmed that specific HPV types are thecause of cervical carcinoma but failed to support the previous opinion that HPV16 E6variants are more malignant than the prototype. We established a novel classificationcalled oncogene lineage of HPV16, and found that additional variations of HPV 16oncogenes might be a weak further risk factor for cervical carcinoma. In the study ofLOH, we found that interstitial deletion of two common regions of chromosome 3p,i.e., 3p2l.1-3p2l.3, and 3p22, was an early event in the development of cervicalcarcinoma. The results showed that the hMLH1 gene, located in 3p22 and showingLOH in 43% of the studied cases, was not involved in the development of cervicalcarcinoma because neither the expression level of protein nor the gene sequence wasaltered in these cases.
In summary, a suggested model of molecular pathogenesis of cervical carcinoma isas follows. Specific types of HPV infect one or more committed stem cells in thebasal layer of the epithelium. Fully efficient LOH events turn one (monoclonal origin)or more (polyclonal origin) HPV-infected stem cells into carcinoma cells without CINsteps. Less efficient LOH events would lead to CIN steps where some other unknownfactors require to be added to facilitate the formation of carcinoma. In the absence ofLOH events no carcinoma develops from the HPV-infected stem cells.
(125-128) and microsatellite repeat polymorphism of the AR (androgen receptor)
gene (129) have been used. For somatic mutation analysis, genetic deletions,
chromosomal translocations and specific point mutations are often detected. The
immunoglobulin assay is used for analysis of B- lymphocyte tumors and T-cell
receptor gene assay is used for T-cell tumors. Genetic EBV termini, HIV and HPV
integration sites have been used to analyze the clonality status of the tumors harboring
the corresponding virus.
1.3.1.2 Polymorphism of inactivation of X-chromosome linked androgen receptor
gene
Because of the fact that up to 90% of the cases turn out to be informative for the
androgen receptor gene, the polymorphism of this gene is used the broadest for the
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clonality analysis of tumors. Thus, here is introduced the working principle of this
analysis.
One X-chromosome, the one from the mother or the one from the father in an
embryonic stem cell is randomly inactivated by methylation of CpG sites at a stage
with about 50 cells in the female embryo to avoid double dosage of the genes on X-
chromosomes. The inactivation pattern of the X-chromosome in a stem cell is stably
inherited by subsequent descendants forming a cell lineage (130-132). Therefore, a
female body including cervical epithelium develops into a mosaic of Xm- and Xp-
inactivated cells. Cervical carcinoma cells derived from a committed epithelial stem
cell with a certain Xm- or Xp-inactivation pattern are equipped with the same pattern
as their progenitor, and this pattern serves as the clonality sign of the carcinoma.
Located at the first exon of the human androgen receptor gene, a highly polymorphic
microsatellite consisting of a short tandem repeat, [CAG]n (n=11-13), is about 100bp
away from HpaII and HhaI (methylation sensitive) restriction sites. This
polymorphism of the microsatellite allows the use of enzyme cleavage of DNA and
PCR-fragments in an assay to identify the X-chromosome inactivation pattern of the
cells tested (133, 134). Figure 1 shows how the analysis works and how the
interpretation is done. However, the interpretation of the clonality information for a
XX Embryonic stem cell
XX XX Random inactivation
XX XX.XX XX Mosaic of cell lineage
Enzymatic digestion
Bands of PCR product
Monoclonal Polyclonal Monoclonal
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Fig. 1. Technique of X-chromosome inactivation analysis. Before digestion with
methylation sensitive restriction enzyme HpaII, the informative sample gives two
bands. After digestion, the active allele of an X-chromosome linked gene is destroyed.
Only the inactivated allele is amplified and will give a band. One band indicates the
presence of one type of cell population in the analyzed sample (monoclonality). Two
bands indicate more than one type of cell populations in the analyzed sample
(polyclonality).
few samples with the same X-chromosome inactivation pattern in an individual
requires further markers.
To get reliable and reproducible results, one has to take notice of some facts (135).
In larger cell populations, the average numbers of paternally- and maternally-
inherited inactivated X-chromosomes is close to 50:50 due to the random inactivation
of the X-chromosomes, but in small cell populations, it would be possible to find
skewing towards one allele to an extent that meets the criteria for clonal derivation.
This kind of skewing is different from tissue to tissue in the same patient and
probably from case to case. So in every case, the tumor sample must be compared
with matched controls from the same patient to test the heterozygosity for the marker.
Fine microdissection to separate the tumor cells and normal cells as much as possible
is one of the requirements. The sample size is also a limiting factor. The lower the cell
number, the higher is the probability to detect a monoclonal pattern based on patch
size mosaic in normal cells. More than 100 cells each in multiple microdissected
samples from different tumor areas and from controls are required. The sample
number from the same patient is one among other impact factors. As many samples as
possible should be taken to represent the whole situation of the tumor. Good
purification of DNA samples and optimal enzymatic digestion of the samples are
always important factors.
1.3.1.3 Clonality features of cervical neoplasms
Evidence shows that cervical neoplasia can be monoclonal or polyclonal. More
cases with monoclonal origin than cases with polyclonal origin have been reported.
This actually depends on the type of cervical neoplasm analyzed. The lower grade of
the cervical neoplasia (toward CIN I) has higher frequency of polyclonality.
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With inactivation polymorphism of the X-chromosome linked androgen receptor
gene as the clonality marker, some efforts on clonality analysis of cervical neoplasia
have been made. Park et al. demonstrated that 100% of CIN III (25/25) and 68% of
CIN II (54/79) are monoclonal, while 32% of CIN II (25/79) are polyclonal (136).
Enomoto et al. found that 100% CIN III (30/30) are monoclonal and found 1 case of
CIN II to be polyclonal. Six cases of cervical invasive carcinoma were found to be
monoclonal and their synchronous CIN lesions shared the clonality composition with
the corresponding invasive carcinoma (137). In another study, Enomoto et al. found
all 13 cases of cervical squamous cell carcinoma and 6 cases of adeneocarcinoma to
be monoclonal (138). Based on the finding of a 100% monoclonality in cervical
carcinoma (12/12) including two early invasive carcinomas, Guo et al. pointed out
that genetic events are critical in the transition of pre-malignant epithelia to invasive
cancer in cervical carcinogenesis and that monoclonality of human tumors is not a
late event during the process of clonal competition or selection (139). In a series of
studies, however, Guo et al. found that among 22 cases of cervical invasive carcinoma
and synchronous CIN lesions two thirds of these cases were monoclonal, while the
remaining CINs were polyclonal (140). Later on, they found that 25% of cervical
invasive carcinoma ((2/8) were polyclonal (141). In line with these results, Ko et al.
reported that 33.3% of cervical invasive carcinoma cases (6/18) are polyclonal (142).
These reports indicate that the pathogenesis of cervical carcinoma is probably even
more complicated than that of many other types of cancers involving selection of sub-
clones of different clonal composition. In a study with 64 cases of cervical neoplasms,
Chuaqui et al. showed that invasive carcinoma and CIN III had high percentages of
cases with monoclonality and identical LOH patterns on chromosome 6q, while CIN I
and II had low percentages of cases with monoclonality and identical LOH patterns
on chromosome 6q, suggesting that CINs develop into invasive carcinoma through
progression from polyclonal lesions to monoclonal lesions (Table 1) (143).
PGK is also an X-chromosome linked gene. Sawada et al. used the X-
chromosome inactivation polymorphism of PGK to analyze the clonality of 25 cases
of cervical invasive and metastatic carcinoma. They found that all analyzed cases
were monoclonal and the same allele of the PGK gene was inactivated in the primary
invasive carcinoma and the metastatic carcinoma in each case (144).
LOH is another commonly used clonality marker (145). However, LOH patterns
are not always identical in all cases in other studies. A distinct type of cervical
carcinoma, adeno-squamous cell carcinoma, contains an adenocarcinoma component
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Table 1. Monoclonal patterns as seen in analysis of the AR inactivationand identical LOH patterns on chromosome 6q in cervical neoplasms(ref. 143). AR: X-chromosome linked androgen receptor geneinactivation.
ICC (%) CIN III (%) CIN II (%) CIN I (%)
AR 92 93 20 0
6q 55 40 37 10
and a squamous cell carcinoma component in the same case. Kersemaekers et al.
performed LOH analysis on nine chromosomes, i.e., chromosomes1, 2, 3, 6, 11, 15,
17, 18, and X, in two cases of adeno-squamous cell carcinoma. Many genetic
alterations were the same in each component in both cases, which indicates that the
adeno-squamous cell carcinoma most likely has one cell origin. But the presence of
some differences of genetic changes associated with the component in one cases favor
a diversion of different development (146). With the combination of LOH analysis
and X-chromosome inactivation analysis, Guo et al. found two of eight cases of
cervical invasive carcinoma to be of polyclonal origin (141).
Park et al. even associated the clonality status with HPV types in cervical
neoplasia (136). All cases of 24 high-grade CIN and 47 out of 71 cases of low-grade
CIN were found to be monoclonal and contain HPV types 16, 18, 33, 35, 45, 56, 58 or
65. In contrast, 22 of 71 cases of low-grade CIN were polyclonal and contained other
types of HPV. Their findings suggest that the histopathological entity termed low-
grade CIN consists of two different types of lesions that are biologically distinct.
1.3.1.4 Clonality status of some other common human tumors
Most cases of other kinds of human tumors show monoclonality (147-151). This
favors the theory that genetic defects cause most tumors in a model of multiple steps.
Simultaneously randomly occurring multiple genetic events in multiple cells are very
rare. One progenitor cell that undergoes a series of genetic changes required for the
initiation of lesions will give rise to a monoclonal neoplasia. So monoclonality is
believed to be a hallmark of neoplastic proliferation. In some tumors, clonality
22
analysis has been used as a tool to diagnose the tumor, to exclude hyperplasia or
responsive proliferation, and to monitor the response to treatment (148, 152, 153).
However, there are a significant number of reported cases of different kinds of tumors
with polyclonality. In 11 cases of multiple squamous cell carcinomas of the
aerodigestive tract the p53 mutations and LOH patterns were stable during tumor
progression, and different p53 mutations or LOH patterns in multiple tumor areas
were observed in each case (154). In a study of bilateral breast carcinoma, four of 12
cases were scored as being of polyclonal origin (155). Yamamoto et al. found that two
of eight cases of multiple human hepatocellular carcinomas were monoclonal (had
intrahepatic metastases) and six of eight were polyclonal (showed independent
multicentric occurrence) (156). Sporadic medullary thyroid carcinoma has often been
found to result from a mutational event occurring at the single cell level and therefore
should be monoclonal, however, 10 of 11 such cases showed polyclonal patterns
(157). Polyclonal origin in some cases can also be seen in other tumors such as
“Kaposi” sarcoma (158), benign breast tumors (159, 160), and multifocal urothelial
papillary tumors (161).
While the origin of tumors, whether from one cell or many, has been a source of
fascination for experimental oncologists for many years, in recent years there has
been an explosion of information. Although these results have apparently confirmed
the monoclonal origin of tumors, there are some studies in which this conclusion just
cannot be made. The potential impact of such considerations as the patch size of a
normal clonal cell population and clonal evolution on the determination of clonality
has largely been ignored, with the result that a number of these determinations are
confounded. It is clear, for many reasons, that more efforts should be put into the
techniques of analysis (162).
1.3.2 HPV16
HPV16 is the most commonly seen type of HPV in cervical squamous cell
neoplasia, so this chapter mainly describes the features of HPV16.
1.3.2.1 The structure of the HPV16 genome and the function of HPV16 genes
The DNA sequence of the HPV16 genome contains 7905bp (61). HPV16 has a
long terminal region (LTR) and eight genes including six early genes and two late
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genes. The six early genes are E6 (495bp, nt 65-559), E7 (315bp, nt 544-858), E1
(1955bp, nt 859-2813), E2 (1128bp, nt 2725-3852), E4 (287bp, nt 3332-3619), and
E5 (296bp, nt 3804-4100). The two late genes are L2 (1523bp, nt 4134-5657) and L1
(1630bp, nt 5527-7155). The LTR is 815bp long located between E6 and L1. Fig.2
shows the structure of the HPV16 genome. E6, E7 and E5 are viral oncogenes
encoding proteins with growth-stimulatory and transforming properties.
The E6 protein is an approximately 150 amino acid protein that is localized to the
nuclear matrix, as well as to non-nuclear membrane (163). E6 is not normally capable
of inducing transformation by itself, but has been shown to induce immortalization of
primary human keratinocytes in conjunction with E7 (164), as well as to promote
anchorage-independent growth of rat cells (165). Binding and degrading cellular p53,
E6 intervenes with the cell cycle and functions as an anti-apoptosis factor (104). E6
can also destabilize chromosomes (166), enhance foreign DNA integration and
mutagenicity (167) and activate telomerase (168).
The E7 protein is a 98 –amino acid protein that is located in the cytoplasm of cells
(169). Expression of E7 alone in epithelial cells is sufficient for transformation, but
E7-mediated transformation is much more efficient when co-expressed with the HPV
E6 protein (170). E7 can bind and inactivate Rb protein and Rb-related pocket
E6
E7
E1
E2
E4L2
L1
LTR
Fig. 2. The genome of HPV16
24
proteins to deregulate the cell cycle (101, 171). To intervene with the cell cycle, E7
also inhibits cyclin-dependent kinase inhibitors (172) and activates cyclins E and A
(173). Like E6 protein, E7 is able to enhance foreign DNA integration and
mutagenicity (174).
The E5 protein is a small hydrophobic protein located in cytoplasmic and plasma
membranes (175, 176). It complexes with a variety of other trans-membrane proteins,
such as the epidermal growth factor receptor, platelet-derived growth factor β-
receptor, and colony-stimulating factor-1 receptor (175). The E5 protein also binds to
adenosine triphosphatase (ATPase) in membrane (177). The HPV16 E5 protein
possesses weak transforming activity and induces a protein kinase-mediated, PKC-
independent, activation of membrane-associated protein kinase (178, 179). Its
transient induction in mouse 3T3 cells or immortalized human keratinocytes results in
suppression of the cyclin-dependent kinase inhibitor p21 and in the induction of c-jun
expression (180), and enhances endothelin-1-induced keratinocyte growth (181). The
expression pattern of E5 is less well established, but like E6 and E7, it is also
correlated with abnormal cervical cytology and can be detected in all stages of
development of cervical carcinoma (182, 183).
The E2 gene codes for two proteins with a transcriptional regulatory function. The
E2 protein has a transcriptional activation domain in the N-terminus and a DNA
binding domain in its C-terminus. The E2 gene can be expressed in two forms, a
complete protein and a short protein with only the DNA binding domain (184). Both
E2 and E1 proteins are necessary and sufficient in vivo for efficient viral DNA
replication. The ability of E2 and E1 to complex with each other appears to be
essential for efficient viral DNA replication (185, 186). E1 may play a role to
maintain HPV in episomal form, while E2 may regulate expression of E6 and E7
(163). Mutation of E2 increases immortalization capacity (187). The E4 protein
localizes to cytoplasmic inclusion granules and results in the collapse of the epithelial
cell intermediate filament network (188, 189). E4 expression is abundant in CIN and
condyloma, but the significance of this is unknown. L1 protein is the major capsid
protein and L2 is the minor one. Both L1 and L2 constitute the viral coat protein that
surrounds the viral DNA genome to assemble a complete infectious HPV particle
(190). LTR is a region of the genome adjacent to the E6 open reading frame. It does
not encode any protein but rather contains promoters and enhancers that influence
viral gene transcription (191).
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1.3.2.2 HPV16 variants in progression of cervical carcinoma
HPV variants are defined as those HPV DNA sequences differing from each other
by less than 2% of nucleotides (71). Variations refer to any change of nucleotides
compared to the “prototype” nucleotides at the same positions. Based on the
variations in E6, L1 and LTR, HPV16 has been classified into six classes: E-350T, E-
350G, As, AA, Af1, and Af2. The geographical distribution of HPV16 variant classes
by continents is shown in table 2 (192). This classification can not reflect the
Table 2. Distribution of HPV16 variant classes by continent (Ref. 192)
and Guiling Li . The Chinese friends who shared or share a corridor with me, for the
friendship: Xuxia Wu–liang Liu, Ling Ling, Kiu Huang, Xiaoli Liu, Yi Wang, Li Li,
Yuman Zhang, Hao He, Sizhong Bu and Shao Hong.
Former group members: Anna Asplund, Ling Gao, Helena Bäckvall, Cecilia
Wassberg and Natalia Mazurenko, for wonderful co-operation, nice group meetings,
free talks and laughs, delicious food and stimulating alcohol at the group dinner
parties. Anna Asplund is also a nice co-author.
58
Current group members in Monica´s group for the nice scientific presentations at
the group meeting.
Other co-authors: F Kisseljov, Sonja Andersson and Erik Wilander, for the co-
operation.
All other colleagues who work in the department of Genetics and Pathology, for
the great help.
Finally and particularly, my lovely daughter Xian Hu, my lovely son Ruiwen Hu,
my beloved wife Tianyun Pang and my parents, for their forever love and strong
support. Pang is also a nice co-author.
59
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