Cancers of the anogenital tract as well as some head and neck cancers are caused by persistent infections with high-risk type human papillomaviruses (HPVs). Two viral oncogenes, E6 and E7, induce severe chromosomal instability associated with centrosome aberrations, anaphase bridges, chromosome lagging, and breaking. This occurs early in preneoplastic lesions, when the viral genome still persists in an episomal state. In most invasive cancers and also in a few high-grade dysplastic lesions, however, integration of high-risk HPV genomes into the host genome is observed. Integration seems to be a direct consequence of chromosomal instability and an important molecular event in the progression of preneoplastic lesions. Disruption or deregulation of defined critical cellular gene functions by insertional mutagenesis by integrated HPV genome fragments has been hypothesized as one major promoting factor in the pathogenesis of HPV-associated cancers. This hypothesis was based on the detection of HPV integration events in the area of tumor-relevant genes in few cases. Here, we reviewed >190 reported integration loci with respect to changes in the viral structure and the targeted genomic locus. This analysis confirms that HPV integration sites are randomly distributed over the whole genome with a clear predilection for genomic fragile sites. No evidence for targeted disruption or functional alteration of critical cellular genes by the integrated viral sequences could be found.

Persistent infections with high-risk (HR) human papillomaviruses (HPVs), e.g., HPV-16, HPV-18, HPV-31, HPV-33, and HPV-45 have been identified as an essential although not sufficient factor in the pathogenesis of anogenital and other epithelial carcinomas (1) HR-HPV genomes encode two proteins, E6 and E7, that interfere with important cellular control mechanisms of the cell cycle, apoptosis, and maintenance of chromosomal stability. The effects of E6 and E7 on p53 and pRB as well as on many other cellular proteins have been extensively investigated in the past and significant alterations of the regulation of the cell cycle could be attributed to the biochemical interaction of the two viral oncogenes to their respective cellular binding partners (2, 3). Moreover, recent studies demonstrated that the two viral oncoproteins cooperatively disturb the mechanisms of chromosome duplication and segregation during mitosis and induce thereby severe chromosomal instability (4).

HR-HPV genomes replicate as episomal molecules in the normal viral life cycle. Although the HPV genome is consistently retained in an episomal state in early dysplastic low-grade lesions, the whole viral genome or fragments thereof are covalently integrated into the chromosomal DNA of the host cell in some advanced HPV-associated precancers and the majority of HR-HPV-associated carcinomas (5, 6, 7, 8). These observations suggest that integration of viral genes in severe dysplastic lesions strongly enhance neoplastic progression to invasive carcinomas. A possible reason for the progression toward malignant lesions after HR-HPV integration might be structural changes of the viral genome that allow enhanced and deregulated expression of the viral oncogenes and thereby confer the additional neoplastic selective pressure. In addition to that, it has also been speculated that critical cellular genes are affected by integration of viral genome fragments and that interference of viral sequences with critical cellular sequences contributes essentially to the enhanced progression risk of HPV-induced preneoplasia into neoplastic lesions (9, 10, 11, 12).

It was shown that HPV E6- and E7-encoding cDNAs derived from integrated viral oncogene transcripts confer a much stronger transforming capacity in primary cells as compared with cDNAs derived from episome-derived transcripts. This was attributed to the longer half-life of transcripts derived from integrated HPV DNA, mediated by 3′-cellular sequences of the fusion transcripts (13). The relative expression levels of the viral oncogenes and their corresponding gene products appear to be directly influenced by the sequence context of individual integration sites. In addition, cis-acting regulatory sequences were shown to exert a strong influence on the expression level and regulation of the integrated viral oncogenes (14). Additional work demonstrated that in specific cervical cancer cell lines only one or few integrated genomes are transcribed, whereas many others within the same cells are transcriptionally silenced (15). In contrast, clinical samples harbor only few integration sites, with the majority thereof being actively transcribed (16). Taken together, these observations suggest that integration of the viral genome renders viral gene expression independent of viral control mechanisms and allows selection of cell clones with deregulated viral oncogene expression favoring the outgrowth of neoplastic cell clones. Thus, the current evidence clearly points to an important impact of cellular sequences on the integrated viral genomes; however, it remains unclear whether the influence of viral sequences on defined cellular genes similarly contributes to the progression of HPV-induced dysplasia. Various murine, avian, and feline retroviruses can transform cells either by affecting the regulation and/or disrupting the structure of tumor suppressing or oncogenic cellular genes (transforming retroviruses; Ref. 17). This process of insertional mutagenesis is random, usually affects many different genomic loci, and is highly inefficient with regard to the transformation efficacy of single infection events, features that seem to be shared by oncogenic HPVs. In some cases, HPV integration has been found to occur in or close to potentially tumor relevant genes, especially within or close to the MYC gene locus (9, 10, 18).

Schwarz et al. (19) identified an integrated genome copy of HPV-68 in the cervical carcinoma cell line ME180. The viral genome disrupts one allele of a novel tumor suppressor gene, APM-1. The nonaffected allele was lost in these cells, suggesting that lack of APM-1 function contributed to the pathogenesis of this particular cancer cell clone. In a recent report, Ferber et al. (11) described three cervical carcinoma cases in which integration was observed in the area of the telomerase gene. Strong up-regulation of hTERT expression was observed in one of these samples.

Many different assays have been applied to analyze genomic HPV integration sites. In situ hybridization using HPV-specific probes has given a rough estimate about the distribution of integrated HPV genomes in cell lines. Although an accumulation of integrated HPV genomes was observed at few loci, a general integration hot spot could not be identified (12, 20, 21, 22). Several PCR-based protocols have been developed that enable the analysis of HPV integration in clinical samples at larger scales. Direct methods to monitor integrated HPV genome copies imply that the HPV sequences are coamplified together with flanking cellular sequences using either enzyme digestion and adaptor ligation [detection of integrated papillomavirus sequences (DIPS) by ligation-mediated-PCR (23)] or religation followed by inverse PCR (24). In another protocol, fusion regions are amplified using HPV-specific primers and primers that bind to distinct restriction enzyme recognition sites [restriction-PCR (25)]. An additional method was referred to as amplification of papillomavirus oncogene transcripts (APOT) assay (7). Here, a modified 3′-rapid amplification of cDNA ends PCR using upstream HPV E7-specific and downstream oligo dT adaptor primers were applied to amplify HPV E7-specific transcripts either derived from integrated or episomal viral genome copies.

Up to now, in total, 192 individual HPV integration sites have been described in primary tumor samples and cell lines. Here, we summarize all available data on chromosomal HPV integration sites. The data suggest that integration of HR-HPV genomes occurs relatively late in the progression of high-grade cervical dysplasia. It appears that integration of HR-HPV genomes is a consequence of an overall destabilization process of the chromosomal integrity in replicating epithelial stem cells that express the viral E6-E7 oncogenes. The consequences of the structural alterations of the viral genome and the impact of cellular sequences on its transcriptional regulation seem to be more important than functional alteration of specific cellular genes by the integrated viral sequences.

Data Collection.

To collect data on chromosomal loci that are affected by integration of HR-HPV genomes, an extensive PubMed search was performed. All articles were included that presented data on either chromosomal localizations or exact nucleotide sequences of integration sites or viral cellular fusion regions. Several larger clinical studies have only looked at the HPV integration status but did neither provide locus nor sequence information (5, 6, 7, 8). These studies were not included in the analysis

Methods used to detect chromosomal loci hit by integration of HR-HPV genomes cover methods such as fluorescence in situ hybridization and genomic and RNA library techniques to PCR-based amplification of viral cellular genomic fusions or fusion transcripts. Only integration events that could be clearly mapped to a specific human sequence were included in the study, thereby omitting many integration events into repetitive genomic areas.

Database Analysis of Integration Sites.

Where sequence data were available, a BLASTN (26) database comparison of cellular sequences with the most recent update of the human genome sequence was performed.1 All mapping data were updated when necessary. Several integration sites were reassigned to different chromosomal bandings than those initially described.

Integration Database Internet Resource.

Table 2 is available as a continuously updated integration database.2

Overview of Studies and Samples.

In total, 25 studies were included in the analysis covering 192 individual integration events (Table 1). Eight studies used fluorescence in situ hybridization to map integration sites, the remaining 17 studies used different PCR-based protocols to generate sequence information of the respective loci. Twenty-one integration sites were derived from cell lines, 171 from clinical samples. The majority of integration events (157) has been described for cervical lesions, mainly cervical carcinomas, but also for CIN3 (9) and CIN2 (1) lesions. Six published integration sites were discovered in vulvar, 4 in vaginal lesions, and 1 in a penile carcinoma.

Furthermore, HPV integration loci of three head and neck as well as tonsillar cancer samples have been published. The prevailing HPV type in the studies is HPV-16 with 119 integrations, followed by HPV-18 (64), HPV-45 (3), HPV-33 (2), HPV-6a, HPV-1, HPV-67, and HPV-68 (each one). However, these numbers do not reflect the real distribution of HR-HPV in the respective lesions because most PCR-based methods have only been established for HPV-16 and HPV-18.

Twenty-three integration sites were mapped with in situ hybridization and 169 localizations derived from PCR-based methods providing sequence information; some of these samples have additionally been analyzed with fluorescence in situ hybridization techniques. The most frequently used PCR-based methods were the amplification of papillomavirus oncogene transcripts (APOT) assay (57), the restriction PCR method (47) and the DIPS assay (32), accounting for 136 mapped integration sites. Apart from that, PCR techniques involving enzyme digestion and religation (inverse PCR), ALU-PCR, and randomly primed PCR were used on a small number of samples as well as genomic and mRNA library techniques (Table 2).

Sequences at Integration Sites.

Several studies have looked at the exact integration site and analyzed the transition sequence between viral and cellular genome. With respect to the nucleotide sequence, all integration sites are different. Neither a specific cellular sequence motif has been observed, nor have recurrent integrations in a specific area happened at the similar nucleotides. Likewise, there is no constant disruption site in the viral genome, and the transitions from viral to cellular sequences can be found anywhere from early E1 to the late genes. Homologous recombination involving larger areas of similar nucleotide sequences does not seem to play a role in HPV integration. Geisen et al. (27) have described a human sequence that shows a mild degree of similarity to HPV E5 located on chromosome 7p13, but it has thus far not been reported to be a HPV integration target.

A sequence analysis of the fusion region between the viral and the cellular genome was possible in 40 cases (Table 2). Seven integrated HPV genomes were characterized on both fusion sides; for the remaining 33, only sequences from either the 5′- or the 3′-fusion region were available. In 27 cases, short overlapping sequences between one and six nucleotides could be found. Six samples showed a direct transition from viral to cellular sequence, and in seven other cases, filler sequences were found at the fusion site that neither derived from viral nor cellular sequences at the respective locus. Short identities in the fusion region seem to facilitate integration. In some cases, major chromosomal changes must have occurred upon integration, probably involving DNA loops that lead to the transfer of distant sequences to the integration site.

Deregulation of Cellular Genes by HPV Integration.

In several cases, HPV integration has occurred in or close to known genes, most frequently in intronic regions. Although coding regions are only rarely hit by HPV, gene expression and mRNA structure can be severely altered by insertion of the strong HPV promoter as well as additional splice donor and acceptor sites located on the HPV genome. The expression analyses of integrated HPV DNA have shown that transcribed and coding regions of genes are frequently cotranscribed with HPV E6 and E7 oncogenes.

Some of the genes disrupted by HPV integration are known to be involved in tumor development in other cancer entities, e.g., MYC, TP63, NR4A2, APM-1, FANCC, TNFAIP2, and hTERT. However, only few examples exist where a direct link between HPV integration and gene alteration was shown by functional data. In the case of the cell line ME180, HPV-68 integration was found in a novel tumor suppressor gene, APM-1(19). It could be shown that the unaffected allele was lost in that cell line and that APM-1 levels were reduced as compared with other cell lines. Transfection of HeLa and Caski cell lines with APM-1 led to reduced growth rates in colony-forming assays. Repeated integration in the area of a specific tumor relevant gene is rare; accumulation of integrated HPVs has been found in the greater area of the MYC locus; apart from that, integration in or close to FANCC, hTERT, and CEACAM5 has been described in two or three independent samples from different studies (10, 11, 18).

The highest number of integration events was observed at 8q24, a large chromosome banding that covers ∼30 Mb and, among others, harbors the MYC gene. 8q24 integration was observed in 12 clinical samples and the cervical cancer cell line HeLa (9, 10, 18). The integration sites are distributed over >500 kb around the MYC gene. Thus far, MYC expression analyses of the clinical samples that showed HPV integration in the MYC area have not been published. For HeLa, increased MYC-RNA levels were demonstrated by Northern blotting (9). We have previously isolated a fusion transcript from HeLa encompassing viral and cellular sequences derived from the 5′-noncoding MYC region (18). However, in contrast to Burkitt’s lymphoma, where structural aberrations of the MYC locus were clearly shown to be associated with the induction and maintenance of a malignant phenotype, this has not been demonstrated for HPV-induced carcinogenesis.

For FANCC, a transcript was identified in a clinical sample that showed the FANCC exon 6 fused to the HPV E6/E7 sequences (18). However, there is no functional evidence that integration at this locus has a major impact on the transformation process. One of three cases with integration in the hTERT locus showed indeed strong up-regulation of hTERT transcription (11). Albeit, given the frequently observed telomerase activation in cervical cancer independent of the integration status, one cannot exclude a coincidence of telomerase activation and HPV integration at that locus.

Taken together, this comprehensive set of data does not support the hypothesis that targeted modification of critical cellular genes plays a major role in the progression of HPV-induced preneoplasia. In contrast to the well-documented impact of E6 and E7 expression for HPV-induced transformation (28, 29, 30, 31, 32, 33), it has not been shown in a single case that the malignant phenotype of cells relies on the potentially critical changes induced by HPV integration.

Integration of HPV DNA in Fragile Sites.

Fragile sites are genomic regions prone to chromosome breaks that facilitate foreign DNA integration. Although some specific sequence motifs were identified for rare fragile sites, common fragile sites do not seem to be linked to a specific genomic sequence and span very large genomic areas (34) 

Looking at a larger scale, there seems to be an equal distribution of HPV integration sites in the human genome. All chromosomes were found to harbor integrated HPV genomes at various chromosomal bandings; however, several weakly preferred chromosomal regions were recognized, including 1q21, 2q22, 2q33, 3p21, 3p14, 3q28, 4q21, 5p15, 6p24, 8q24, 9q34, 12q13, 13q21-22, 14q24, and 17q23. They all encompass known fragile sites except for 3p21, 4q21, 5p15, 6p24, and 9q34.

Some studies have directly visualized the coincidence of fragile sites and HPV integration site (10, 25, 35). In other studies, exact chromosomal localizations were compared with mapped fragile sites in the database (18). Here, we reanalyzed all published loci for mapped fragile sites. A limitation of this approach is the rather imprecise mapping of fragile sites. Taking all data together, there is a high correlation between fragile sites and HPV integration sites. In 38% of the 192 integration sites, fragile sites are hit by HPV integration, and the number is probably much higher because some studies did not provide sufficient sequence information and not all of the fragile sites have been mapped thus far. Ten of 15 regions with at least three independent HPV integration events harbor known fragile sites, including the frequently targeted MYC locus (8q24). Matzner et al. (36) have analyzed integration of vector DNA containing a multidrug resistance gene in a breast cancer cell line under chemotherapy treatment. Here, cell clones grow out after random integration because an external gene confers the drug resistance. A significant overlap of multidrug resistance integration sites, fragile sites, and the clustered HPV integration sites (1p36, 1q21, 6q21, 9q34, 12q13 and 13q22) reviewed here was observed. In total, 62 of the 192 HPV integration loci correlated with the multidrug resistance integration loci described by Matzner et al. (36).

In conclusion, the cause for HPV integration clustering seems to be rather related to the accessibility of these fragile genomic areas than due to a selection of clones that harbor integrated HPV in regions with tumor relevant genes.

Role of Integration in HPV-Mediated Transformation.

The progression of HPV-induced lesions toward cancer reflects a classical selection scenario in which certain events lead to the clonal outgrowth of single cells in a heterogeneous cell population (Fig. 1). Deregulated expression of the HPV E6 and E7 genes in epithelial stem cells leads to major chromosomal instability in the respective cells at early stages of dysplasia. This instability becomes manifest in numerical centrosome aberrations, anaphase bridges, and chromosome breaks that over time result in aneuploidy (4, 37). Hopman et al. (38) have analyzed DNA ploidy and HPV integration by fluorescence in situ hybridization in a number of clinical samples and observed a high correlation of aneuploid cells with integrated HPV genomes in high-grade dysplastic lesions. Obviously, HPV integration is facilitated by repair processes activated in these chromosomally unstable cells. The association of DNA repair and viral integration has also been described for retroviruses (39). Recently, it has been shown in a large series of clinical samples that DNA aneuploidy clearly precedes HPV integration in the progression of HPV-associated cervical precancers,3 supporting the concept that integration occurs as a result of chromosomal repair mechanisms. Accordingly, HPV integration is most frequently observed in unstable areas of the genome that are also targeted by integration of foreign DNA molecules in other scenarios. Along with integration of HPV genomes or fragments thereof that presumably occur in parallel in multiple cell clones, selection processes seem to be initiated that finally result in preferred outgrowth of only one or few cell clones with optimized expression of the HR-HPV oncogenes (16). Finally, a malignant cell clone might emerge that accounts for the majority of the evolving tumor mass and that can also be found in local recurrences and distant metastases.4 Therefore, the detection of HPV integration points to progressing lesions and might be applied in various clinical applications: it can be a valuable individual tumor and recurrence marker. Detection of specific integration sites in biopsies, e.g., from lymph nodes or potential distant metastases, can be used as a tumor staging tool. Posttreatment detection of residual cells with identical integration patterns as the primary tumor indicates residual disease and might significantly influence the therapeutic decision taking.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Magnus von Knebel Doeberitz, Institute of Molecular Pathology, Department of Pathology, Im Neuenheimer Feld 220, Heidelberg D-69120, Germany. Phone: 49-6221-56-28-76; Fax: 49-6221-56-59-81; E-mail: [email protected]

1

Internet address: http://www.ncbi.nlm.nih.gov/BLAST/.

2

Internet address: http://www.med.uni-heidelberg.de/patho/pathomol/AG_onkogene_Papillomvirusinfektionen.html.

3

P. Melsheimer. DNA aneuploidy precedes integration of HPV16 E6/E7 oncogenes in intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix uteri, submitted for publication.

4

S. Vinokurova. Clonal composition of HR-HPV induced high grade cervical dysplasia and invasive carcinomas, manuscript in preparation.

Fig. 1.

Role of human papillomavirus (HPV) integration in the progression from normal epithelium to invasive carcinoma. L-SIL, low-grade squamous intraepithelial lesion; H-SIL, high-grade squamous intraepithelial lesion.

Fig. 1.

Role of human papillomavirus (HPV) integration in the progression from normal epithelium to invasive carcinoma. L-SIL, low-grade squamous intraepithelial lesion; H-SIL, high-grade squamous intraepithelial lesion.

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Table 1

Publications included in this study

AuthorMethodNumber and type of integrate-positive samples analyzed
Mincheva et al. (22) FISHa Hela, Caski, SiHa              b 
Canizzaro et al. (20) FISH C4-I, 1 CxCa 
Parton et al. (40) FISH SVD2 
Couturier et al. (41) FISH IC1, IC2, IC3, IC4 
Hori et al. (42) FISH cell line 
Smith et al. (43) FISH 6 cell lines 
Gilles et al. (44) FISH CK1, CK11 
Koopman et al. (21) FISH CSCC-1, CSCC-7, CC-8, CC-10A/B, CC-11 
Durst et al. (9) Genomic library SiHa, SW756, C4-1, HeLa, 1 CxCA 
Wagatsuma et al. (45) Genomic library 4 CxCa 
Kahn et al. (46) Genomic library 1 tonsillar carcinoma 
Choo et al. (47) HPV-random PCR Caski, 4 CxCa 
Reuter et al. (19) mRNA library ME180 
Thorland et al. (25) Restriction PCR 7 CxCa 
Kalantari et al. (24) Inverse PCR 5 CxCa 
Luft et al. (23) DIPS 17 CxCa, 1 VIN3 
Shera et al. (48) ALU PCR 5 CxCa 
Einstein et al. (49) Genomic library 1 CxCa 
Peitsaro et al. (50) APOT UT-DEC1 
Wentzensen et al. (18) APOT 55 CIN2-3, CxCa, VIN, VaIN 
Wiest et al. (51) APOT 2 head and neck cancers 
Thorland et al. (52) Restriction PCR 17 CxCa 
Ziegert et al. (16) DIPS/APOT 22 CIN3 and CxCa 
Ferber et al. (11) Restriction PCR 3 CxCa 
Ferber et al. (10) Restriction PCR 18 CxCa 
AuthorMethodNumber and type of integrate-positive samples analyzed
Mincheva et al. (22) FISHa Hela, Caski, SiHa              b 
Canizzaro et al. (20) FISH C4-I, 1 CxCa 
Parton et al. (40) FISH SVD2 
Couturier et al. (41) FISH IC1, IC2, IC3, IC4 
Hori et al. (42) FISH cell line 
Smith et al. (43) FISH 6 cell lines 
Gilles et al. (44) FISH CK1, CK11 
Koopman et al. (21) FISH CSCC-1, CSCC-7, CC-8, CC-10A/B, CC-11 
Durst et al. (9) Genomic library SiHa, SW756, C4-1, HeLa, 1 CxCA 
Wagatsuma et al. (45) Genomic library 4 CxCa 
Kahn et al. (46) Genomic library 1 tonsillar carcinoma 
Choo et al. (47) HPV-random PCR Caski, 4 CxCa 
Reuter et al. (19) mRNA library ME180 
Thorland et al. (25) Restriction PCR 7 CxCa 
Kalantari et al. (24) Inverse PCR 5 CxCa 
Luft et al. (23) DIPS 17 CxCa, 1 VIN3 
Shera et al. (48) ALU PCR 5 CxCa 
Einstein et al. (49) Genomic library 1 CxCa 
Peitsaro et al. (50) APOT UT-DEC1 
Wentzensen et al. (18) APOT 55 CIN2-3, CxCa, VIN, VaIN 
Wiest et al. (51) APOT 2 head and neck cancers 
Thorland et al. (52) Restriction PCR 17 CxCa 
Ziegert et al. (16) DIPS/APOT 22 CIN3 and CxCa 
Ferber et al. (11) Restriction PCR 3 CxCa 
Ferber et al. (10) Restriction PCR 18 CxCa 
a

FISH, fluorescence in situ hybridization; HPV, human papillomavirus; DIPS, detection of integrated papillomavirus sequences; APOT, amplification of papilloma virus oncogene transcripts.

b

italics: cell lines, CxCa, cervical carcinoma; CIN, cervical intraepithelial neoplasia; VaIN, vaginal intraepithelial neoplasia; VIN, vulvar intraepithelial neoplasia.

Table 2

Summary of all published HPV integration sites

NamePathologyHuman papillomavirusLocusFragile siteaGenebDetection methodReference no.Fusion regionc
int9 Cad 16 1p36 FRA1A WASF2 APOT  18   
V18 CA (Sq) 16 1p34  BMP8 Random PCR  47  3′ Ont 
FEH18L CL 18 1p22–31   FISH  43   
FEA CL 18 1q12–q21   FISH  43   
CC192 Ca (Sq) 16 1q21 FRA1F HS8015 Restriction PCR  25   
int73 Ca 16 1q21  RPS27 APOT  18   
CC10 CL 45 1q21–23   FISH  21   
F826 Ca 16 1q25   Inverse PCR  24  3′ Ont 
T5 Ca 16 1q25   DIPS  23   
MC360 Ca 18 1q31 FRA1K  Restriction PCR  11   
int69 CIN3 16 1q32  HS205126 APOT  18   
LU7 Ca 18 1q32.2 FRA1K CD34 Restriction PCR  11   
102 Ca 16 1q41 FRA1H  Restriction PCR  52   
T17 Ca 16 1q41   DIPS  23  3′ 0nt 
T32 Ca 18 1q42  HS285861 APOT/DIPS  16  3′ 1nt 
int66 Ca 18 1q43  CHS1 APOT  18   
T3 Ca 16   DIPS  23   
T4 Ca 16   DIPS  23   
IC4 CL 18 2p24   FISH  41   
int3 Ca 16 2p24   APOT  18   
T19 Ca 16 2q21  LRP1B APOT/DIPS  16   
T17 Ca 16 2q22   APOT/DIPS  16  3′ 2nt 
T1 Ca 16 2q22   DIPS  23   
HK9 Ca 18 2q22.1 FRA2F LRP1B Restriction PCR  11   
int70 Ca 16 2q23 FRA2K  APOT  18   
int29 Ca 16 2q24 FRA2K NR4A2 APOT  18   
int52 CIN3 16 2q31 FRA2G  APOT  18   
int71 Ca 16 2q32 FRA2H GLS APOT  18   
AC-8 Ca 18 2q32   ALU PCR  48  3′ filler 20nt 
int45 Ca 16 2q33 FRA2I AA084805 APOT  18   
SVD2 CL 2q33   FISH/mRNA lib  40   
H404 Ca 16 2q33   Genomic library  45   
T04 CIN3 16 2q34  HS25235 DIPS  16  3′ 2nt 
M15 Ca (Sq) 16 2q34–35  MAP-2 Random PCR  47  5′ filler 10nt 3′ 1nt 
CC-6 Ca 18 2q36   ALU PCR  48  3′ 3nt 
1.2a (probe) Ca 16 3p25     9   
CC-6 Ca 18 3p25   ALU PCR  48   
CC11 CL 67 t(3;13)(p23–26;q22–331)   FISH  21   
n.n. CL 18 3p21–22   FISH  42   
int65 Ca 18 3p21   APOT  18   
T14 Ca 16 3p21  MAP4 APOT/DIPS  16  3′ 2nt 
H705 Ca (Sq) 16 3p14 FRA3B  Genomic library  45   
61 Ca 16 3p14 FRA3B  Restriction PCR  52   
MC123 Ca 18 3p14 FRA3B FHIT Restriction PCR  11   
int72 Ca 16 3q21 FRA3F AI555655 APOT  18   
CC8 CL 45 3q26–29   FISH  21   
T31 Ca 16 3q27   APOT/DIPS  16   
T05 CIN3 16 3q27   DIPS  16  3′ 2nt 
F3155 Ca 16 3q28   Inverse PCR  24  5′ 1nt 
int32 VIN3 16 3q28 FRA3C  APOT  18   
int4 VINX 16 3q28 FRA3C TP63 APOT  18   
int26 Ca 18 3q28 FRA3C  APOT  18   
int2 Ca 16 4p16 FRA4A  APOT  18   
T13 Ca 18 4p15  PCDH7 APOT/DIPS  16  3′ 2nt 
T28 VaCa 16 4q21  BIKE DIPS  16  3′ 6nt 
int35 Ca 18 4q21   APOT  18   
int68 CIN3 16 4q21  PTPN13 APOT  18   
int18 VIN2 16 4q31  FRA4C APOT  18   
61 Ca 16 5p15.3   Restriction PCR  52   
MC11 Ca 18 5p15  HTERT Restriction PCR  10   
HK1 Ca 18 5p15  HTERT Restriction PCR  10   
HK2 Ca 18 5p15  HTERT Restriction PCR  10   
MC315 Ca 18 5p13.2 FRA5E SLC1A3 Restriction PCR  11   
HeLa CL 18 5p11–15   FISH/ISH  12   
        9   
        20   
UT-DEC-1 CL 33 5p14 FRA5E  APOT, genomic  50  3′ filler 16nt 
T3 HNSCC 16 5q14 FRA5E  APOT  51   
HK16 Ca 18 5q15 FRA5D  Restriction PCR  11   
int46 Ca 16 5q31 FRA5C KLHL3 APOT  18   
86 Ca 16 5q31 FRA5C FLJ23312 Restriction PCR  52   
24 Ca 16 5q35  KCNIP1 Restriction PCR  52   
int17 Ca 16 5q35 FRA5G  APOT  18   
int23 CIN3 16 6p   APOT  18   
F3165 Ca 16 6p25   Inverse PCR  24  5′ 4nt 
T8 HNSCC 16 6p24   APOT  51   
CC-2 Ca 18 6p24   ALU PCR  48  3′ filler 17nt 
T18 Ca 16 6p24  HS171942 APOT/DIPS  16  3′ 2nt 
T21 Ca 18 6p23  HS633327 APOT/DIPS  16  3′ 0nt 
CC171 Ca (Sq) 16 6p22 FRA6C  Restriction PCR  25   
NamePathologyHuman papillomavirusLocusFragile siteaGenebDetection methodReference no.Fusion regionc
int9 Cad 16 1p36 FRA1A WASF2 APOT  18   
V18 CA (Sq) 16 1p34  BMP8 Random PCR  47  3′ Ont 
FEH18L CL 18 1p22–31   FISH  43   
FEA CL 18 1q12–q21   FISH  43   
CC192 Ca (Sq) 16 1q21 FRA1F HS8015 Restriction PCR  25   
int73 Ca 16 1q21  RPS27 APOT  18   
CC10 CL 45 1q21–23   FISH  21   
F826 Ca 16 1q25   Inverse PCR  24  3′ Ont 
T5 Ca 16 1q25   DIPS  23   
MC360 Ca 18 1q31 FRA1K  Restriction PCR  11   
int69 CIN3 16 1q32  HS205126 APOT  18   
LU7 Ca 18 1q32.2 FRA1K CD34 Restriction PCR  11   
102 Ca 16 1q41 FRA1H  Restriction PCR  52   
T17 Ca 16 1q41   DIPS  23  3′ 0nt 
T32 Ca 18 1q42  HS285861 APOT/DIPS  16  3′ 1nt 
int66 Ca 18 1q43  CHS1 APOT  18   
T3 Ca 16   DIPS  23   
T4 Ca 16   DIPS  23   
IC4 CL 18 2p24   FISH  41   
int3 Ca 16 2p24   APOT  18   
T19 Ca 16 2q21  LRP1B APOT/DIPS  16   
T17 Ca 16 2q22   APOT/DIPS  16  3′ 2nt 
T1 Ca 16 2q22   DIPS  23   
HK9 Ca 18 2q22.1 FRA2F LRP1B Restriction PCR  11   
int70 Ca 16 2q23 FRA2K  APOT  18   
int29 Ca 16 2q24 FRA2K NR4A2 APOT  18   
int52 CIN3 16 2q31 FRA2G  APOT  18   
int71 Ca 16 2q32 FRA2H GLS APOT  18   
AC-8 Ca 18 2q32   ALU PCR  48  3′ filler 20nt 
int45 Ca 16 2q33 FRA2I AA084805 APOT  18   
SVD2 CL 2q33   FISH/mRNA lib  40   
H404 Ca 16 2q33   Genomic library  45   
T04 CIN3 16 2q34  HS25235 DIPS  16  3′ 2nt 
M15 Ca (Sq) 16 2q34–35  MAP-2 Random PCR  47  5′ filler 10nt 3′ 1nt 
CC-6 Ca 18 2q36   ALU PCR  48  3′ 3nt 
1.2a (probe) Ca 16 3p25     9   
CC-6 Ca 18 3p25   ALU PCR  48   
CC11 CL 67 t(3;13)(p23–26;q22–331)   FISH  21   
n.n. CL 18 3p21–22   FISH  42   
int65 Ca 18 3p21   APOT  18   
T14 Ca 16 3p21  MAP4 APOT/DIPS  16  3′ 2nt 
H705 Ca (Sq) 16 3p14 FRA3B  Genomic library  45   
61 Ca 16 3p14 FRA3B  Restriction PCR  52   
MC123 Ca 18 3p14 FRA3B FHIT Restriction PCR  11   
int72 Ca 16 3q21 FRA3F AI555655 APOT  18   
CC8 CL 45 3q26–29   FISH  21   
T31 Ca 16 3q27   APOT/DIPS  16   
T05 CIN3 16 3q27   DIPS  16  3′ 2nt 
F3155 Ca 16 3q28   Inverse PCR  24  5′ 1nt 
int32 VIN3 16 3q28 FRA3C  APOT  18   
int4 VINX 16 3q28 FRA3C TP63 APOT  18   
int26 Ca 18 3q28 FRA3C  APOT  18   
int2 Ca 16 4p16 FRA4A  APOT  18   
T13 Ca 18 4p15  PCDH7 APOT/DIPS  16  3′ 2nt 
T28 VaCa 16 4q21  BIKE DIPS  16  3′ 6nt 
int35 Ca 18 4q21   APOT  18   
int68 CIN3 16 4q21  PTPN13 APOT  18   
int18 VIN2 16 4q31  FRA4C APOT  18   
61 Ca 16 5p15.3   Restriction PCR  52   
MC11 Ca 18 5p15  HTERT Restriction PCR  10   
HK1 Ca 18 5p15  HTERT Restriction PCR  10   
HK2 Ca 18 5p15  HTERT Restriction PCR  10   
MC315 Ca 18 5p13.2 FRA5E SLC1A3 Restriction PCR  11   
HeLa CL 18 5p11–15   FISH/ISH  12   
        9   
        20   
UT-DEC-1 CL 33 5p14 FRA5E  APOT, genomic  50  3′ filler 16nt 
T3 HNSCC 16 5q14 FRA5E  APOT  51   
HK16 Ca 18 5q15 FRA5D  Restriction PCR  11   
int46 Ca 16 5q31 FRA5C KLHL3 APOT  18   
86 Ca 16 5q31 FRA5C FLJ23312 Restriction PCR  52   
24 Ca 16 5q35  KCNIP1 Restriction PCR  52   
int17 Ca 16 5q35 FRA5G  APOT  18   
int23 CIN3 16 6p   APOT  18   
F3165 Ca 16 6p25   Inverse PCR  24  5′ 4nt 
T8 HNSCC 16 6p24   APOT  51   
CC-2 Ca 18 6p24   ALU PCR  48  3′ filler 17nt 
T18 Ca 16 6p24  HS171942 APOT/DIPS  16  3′ 2nt 
T21 Ca 18 6p23  HS633327 APOT/DIPS  16  3′ 0nt 
CC171 Ca (Sq) 16 6p22 FRA6C  Restriction PCR  25   
Table 2A

Continued

Name Pathology Human papillomavirus Locus Fragile sitea Geneb Detection method Reference no. Fusion regionc 
H901 Ca 16 6p21.3   Genomic library 45 5′ 3nt 3′ 1nt 
int76 Ca 16 6q21 FRA6F  APOT  18   
191 Ca 16 6q21 FRA6F  Restriction PCR  52   
int21 VIN3 16 6q25 FRA6E TCP1 APOT  18   
MC123 Ca 18 6q26 FRA6E KIAA1838 Restriction PCR  11   
T25 Ca 16 7p22 FRA7B DGKB DIPS  16   
V15 Ca 16 7p22 FRA7B  Random PCR  47  5′ 1nt 3′ 0nt 
T6 Ca 18 7q31  FOXP2 DIPS  23  3′ filler 6nt 
MC315 Ca 18 7q31 FRA7G  Restriction PCR  11   
T13 Ca 16 7q31   DIPS  23   
int42 Ca 16 8p23  HS162183 APOT  18   
MC123 Ca 18 8p21  EPHX2 Restriction PCR  11   
CC5a Ca (Sq) 16 8p12   Random PCR  47  3′ 1nt 
int16 Ca 18 8p11.2  HS127775 DIPS, APOT  23  3′ 5nt 
        18   
C4-1 CL 18 8q21–22 FRA8B  FISH, APOT  22   
        18   
61 Ca 16 8q21.3 FRA8B RIPK2 Restriction PCR  52   
T29 Ca 18 8q24  FLJ10359 APOT/DIPS  16  3′ 1nt 
IC1 Ca 18 8q24   FISH  41   
IC2 Penile Ca 16 8q24.1   FISH  41   
IC3 Ca 16 8q24.1   FISH  41   
MC31 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
MC391 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
MC398 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
LU8 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
HK10 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
HeLa CL 18 8q24 FRA8C MYC FISH, APOT  12   
        9   
        20   
        18   
        11   
int41 Ca 16 8q24 FRA8C  APOT  18   
int25 Ca 18 8q24 FRA8C MYC APOT  18   
MC415 Ca 18 8q24.2 FRA8C/D MYC Restriction PCR  11   
94 Ca 16 9p24.1   Restriction PCR  52   
T23 Ca 18 9p22  NFIB APOT/DIPS  16  3′ 0nt 
int44 Ca 16 9p13   APOT  18   
CK11 CL 33 9p13   FISH  44   
int5 Ca 16 9q22 FRA9D FANCC APOT  18   
HK13 Ca 18 9q22 FRA9D FANCC Restriction PCR  11   
HeLa CL 18 9q31–34   FISH  9   
        20   
T22 Ca 18 9q34  HS323813 DIPS  6  3′ 2nt 
317 Ca 16 9q34  Notch1 Restriction PCR  52   
int36 Ca 16 9q34   APOT  18   
V1 VIN3 16 10p15   DIPS  23  3′ 2nt 
int19 Ca 16 10p15   APOT  18   
int79 Ca 16 10q22 FRA10D  APOT  18   
75 Ca 16 10q22 FRA10D  Restriction PCR  52   
int78 Ca 16 10q23 FRA10A FER1L3 APOT  18   
n.n. Tonsillar Ca 6a 10q24   genomic library  46   
int34 CIN2 16 10q26 FRA10F  APOT  18   
73 Ca 16 11p15.5  MUC5B Restriction PCR  52   
F338 Ca 16 11p13   Inverse PCR  24  5′ 4nt 3′ 3nt 
T15 Ca 16 11q14   DIPS  23  3′ 3nt 
SW756 CL 18 12q13 FRA12A  FISH  12   
        11   
SKv CL 16 12q13   FISH 53  
73 Ca 16 12q13   Restriction PCR  52   
int27 Ca 18 12q21  ALU APOT  18   
61 Ca 16 12q21.31  MYF5 Restriction PCR  52   
327 Ca 16 12q23.1  ELK3 Restriction PCR  52   
TC146 CL 16 13q14   FISH 54  
int50 VIN3 16 13q14  KPNA3 APOT  18   
SiHa CL 16 13q21 FRA13B ALU FISH, APOT 18  
        18   
int67 CIN3 16 13q21 FRA13B  APOT  18   
int30 Ca 16 13q21 FRA13B  APOT  18   
int58 Ca 16 13q21 FRA13B  APOT  18   
int10 Ca 16 13q21.1 FRA13B  APOT  18   
int57 CIN3 16 13q22   APOT  18   
80 Ca 16 13q22.2 FRA13C  Restriction PCR  52   
84 Ca 16 13q22.2 FRA13C  Restriction PCR  52   
CK1 CL 33 13q33–34   FISH  44   
T11 Ca 18 14   DIPS  23   
CSCC7 Ca 16 t(3;14)(p14.1 14.3;14)   FISH  21   
CSCC1 Ca 16 14q   FISH  21   
int55 Ca 18 14q13   APOT  18   
int1 Ca 16 14q24.1 FRA14C HS57811 APOT  18   
HK15 Ca 18 14q24.1 FRA14C  Restriction PCR  11   
Name Pathology Human papillomavirus Locus Fragile sitea Geneb Detection method Reference no. Fusion regionc 
H901 Ca 16 6p21.3   Genomic library 45 5′ 3nt 3′ 1nt 
int76 Ca 16 6q21 FRA6F  APOT  18   
191 Ca 16 6q21 FRA6F  Restriction PCR  52   
int21 VIN3 16 6q25 FRA6E TCP1 APOT  18   
MC123 Ca 18 6q26 FRA6E KIAA1838 Restriction PCR  11   
T25 Ca 16 7p22 FRA7B DGKB DIPS  16   
V15 Ca 16 7p22 FRA7B  Random PCR  47  5′ 1nt 3′ 0nt 
T6 Ca 18 7q31  FOXP2 DIPS  23  3′ filler 6nt 
MC315 Ca 18 7q31 FRA7G  Restriction PCR  11   
T13 Ca 16 7q31   DIPS  23   
int42 Ca 16 8p23  HS162183 APOT  18   
MC123 Ca 18 8p21  EPHX2 Restriction PCR  11   
CC5a Ca (Sq) 16 8p12   Random PCR  47  3′ 1nt 
int16 Ca 18 8p11.2  HS127775 DIPS, APOT  23  3′ 5nt 
        18   
C4-1 CL 18 8q21–22 FRA8B  FISH, APOT  22   
        18   
61 Ca 16 8q21.3 FRA8B RIPK2 Restriction PCR  52   
T29 Ca 18 8q24  FLJ10359 APOT/DIPS  16  3′ 1nt 
IC1 Ca 18 8q24   FISH  41   
IC2 Penile Ca 16 8q24.1   FISH  41   
IC3 Ca 16 8q24.1   FISH  41   
MC31 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
MC391 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
MC398 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
LU8 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
HK10 Ca 18 8q24 FRA8C MYC Restriction PCR  11   
HeLa CL 18 8q24 FRA8C MYC FISH, APOT  12   
        9   
        20   
        18   
        11   
int41 Ca 16 8q24 FRA8C  APOT  18   
int25 Ca 18 8q24 FRA8C MYC APOT  18   
MC415 Ca 18 8q24.2 FRA8C/D MYC Restriction PCR  11   
94 Ca 16 9p24.1   Restriction PCR  52   
T23 Ca 18 9p22  NFIB APOT/DIPS  16  3′ 0nt 
int44 Ca 16 9p13   APOT  18   
CK11 CL 33 9p13   FISH  44   
int5 Ca 16 9q22 FRA9D FANCC APOT  18   
HK13 Ca 18 9q22 FRA9D FANCC Restriction PCR  11   
HeLa CL 18 9q31–34   FISH  9   
        20   
T22 Ca 18 9q34  HS323813 DIPS  6  3′ 2nt 
317 Ca 16 9q34  Notch1 Restriction PCR  52   
int36 Ca 16 9q34   APOT  18   
V1 VIN3 16 10p15   DIPS  23  3′ 2nt 
int19 Ca 16 10p15   APOT  18   
int79 Ca 16 10q22 FRA10D  APOT  18   
75 Ca 16 10q22 FRA10D  Restriction PCR  52   
int78 Ca 16 10q23 FRA10A FER1L3 APOT  18   
n.n. Tonsillar Ca 6a 10q24   genomic library  46   
int34 CIN2 16 10q26 FRA10F  APOT  18   
73 Ca 16 11p15.5  MUC5B Restriction PCR  52   
F338 Ca 16 11p13   Inverse PCR  24  5′ 4nt 3′ 3nt 
T15 Ca 16 11q14   DIPS  23  3′ 3nt 
SW756 CL 18 12q13 FRA12A  FISH  12   
        11   
SKv CL 16 12q13   FISH 53  
73 Ca 16 12q13   Restriction PCR  52   
int27 Ca 18 12q21  ALU APOT  18   
61 Ca 16 12q21.31  MYF5 Restriction PCR  52   
327 Ca 16 12q23.1  ELK3 Restriction PCR  52   
TC146 CL 16 13q14   FISH 54  
int50 VIN3 16 13q14  KPNA3 APOT  18   
SiHa CL 16 13q21 FRA13B ALU FISH, APOT 18  
        18   
int67 CIN3 16 13q21 FRA13B  APOT  18   
int30 Ca 16 13q21 FRA13B  APOT  18   
int58 Ca 16 13q21 FRA13B  APOT  18   
int10 Ca 16 13q21.1 FRA13B  APOT  18   
int57 CIN3 16 13q22   APOT  18   
80 Ca 16 13q22.2 FRA13C  Restriction PCR  52   
84 Ca 16 13q22.2 FRA13C  Restriction PCR  52   
CK1 CL 33 13q33–34   FISH  44   
T11 Ca 18 14   DIPS  23   
CSCC7 Ca 16 t(3;14)(p14.1 14.3;14)   FISH  21   
CSCC1 Ca 16 14q   FISH  21   
int55 Ca 18 14q13   APOT  18   
int1 Ca 16 14q24.1 FRA14C HS57811 APOT  18   
HK15 Ca 18 14q24.1 FRA14C  Restriction PCR  11   
Table 2B

Continued

NamePathologyHuman papillomavirusLocusFragile siteaGenebDetection methodReference no.Fusion regionc
T7 Ca 16 14q24.2   DIPS  23   
T15 Ca 16 14q24.3   DIPS  23  3′ 0nt 
MC34 Ca 18 14q24 FRA14C RNGTT Restriction PCR  11   
T8 Ca 16 14q32   DIPS  23   
HKcHPV 16d-2 CL 16 14q32   FISH  12   
n.n. Ca 16 14q32.3  TNFAIP2 genomic lib.  49  duplication 5′ 11nt, 3′ 5nt 
int14 ValN3 18 15q12  HS150715 APOT  18   
int62 Ca 16 15q15  HS195730 APOT  18   
91 Ca 16 15q15   Restriction PCR  52   
LU3 Ca 18 15q23 FRA15A  Restriction PCR  11   
T3 Ca 16 16   DIPS  23   
CC-4 Ca 18 16p12   ALU PCR  48  3′ 3nt 
int61 Ca 16 16q22 FRA16B AFP APOT  18   
T15 Ca 16 16q24  CDH13 APOT/DIPS  16  3′ filler 9nt 
H022 Ca 16 17q11   Genomic library  45  5′ 6nt 3′ 5nt 
int33 Ca 16 17q12  HS23106 APOT  18   
AC-8 Ca 18 17q21  ERBB2 ALU PCR  48  3′ filler 11nt 
T16 Ca 18 17q23.2 FRA17B  DIPS  23  3′ 3nt 
T30 Ca 18 17q23   APOT/DIPS  16  3′ filler 4nt 
T24 Ca 18 17q23   DIPS  16  3′ 3nt 
T26 Ca 18 17q23  HS355936 APOT/DIPS  16   
CC226 Ca 16 17q23 FRA17B  Restriction PCR  25   
int13 Ca 18 17q23 FRA17B HS12677 APOT  18   
107 Ca 16 17q23.2 FRA17B DKFZP566I133 Restriction PCR  52   
207 Ca 16 17q23.2 FRA17B  Restriction PCR  52   
T9 Ca 16 17q25   DIPS  23  3′ 2nt 
ME180 CL 68 18q21  APM-1 mRNA library  19   
F2423 Ca 16 18q22   Inverse PCR  24  5′ 5nt 3′ 2nt 
HK11 Ca 18 19p13  PRKACA Restriction PCR  11   
LU2 Ca 18 19q13 FRA19A CEACAM5 Restriction PCR  11   
int54 CIN3 16 19q13 FRA19A CEACAM5 APOT  18   
265 Ca 16 20p12   Restriction PCR  52   
int8 Ca 16 20p12 FRA20B  APOT  18   
int6 Ca 16 20p11 FRA20A HS97790 APOT  18   
3.2a (probe) CA 16 20q13     9   
int15 Ca 18 21q21   APOT  18   
int20 ValN2 16 21q22   APOT  18   
HeLa CL 18 22q12–13   FISH  12   
        9   
        20   
CC10 CL 45 22q13   FISH  21   
T27 VaCa 16 Xp22  HSX11910 APOT/DIPS  16   
NamePathologyHuman papillomavirusLocusFragile siteaGenebDetection methodReference no.Fusion regionc
T7 Ca 16 14q24.2   DIPS  23   
T15 Ca 16 14q24.3   DIPS  23  3′ 0nt 
MC34 Ca 18 14q24 FRA14C RNGTT Restriction PCR  11   
T8 Ca 16 14q32   DIPS  23   
HKcHPV 16d-2 CL 16 14q32   FISH  12   
n.n. Ca 16 14q32.3  TNFAIP2 genomic lib.  49  duplication 5′ 11nt, 3′ 5nt 
int14 ValN3 18 15q12  HS150715 APOT  18   
int62 Ca 16 15q15  HS195730 APOT  18   
91 Ca 16 15q15   Restriction PCR  52   
LU3 Ca 18 15q23 FRA15A  Restriction PCR  11   
T3 Ca 16 16   DIPS  23   
CC-4 Ca 18 16p12   ALU PCR  48  3′ 3nt 
int61 Ca 16 16q22 FRA16B AFP APOT  18   
T15 Ca 16 16q24  CDH13 APOT/DIPS  16  3′ filler 9nt 
H022 Ca 16 17q11   Genomic library  45  5′ 6nt 3′ 5nt 
int33 Ca 16 17q12  HS23106 APOT  18   
AC-8 Ca 18 17q21  ERBB2 ALU PCR  48  3′ filler 11nt 
T16 Ca 18 17q23.2 FRA17B  DIPS  23  3′ 3nt 
T30 Ca 18 17q23   APOT/DIPS  16  3′ filler 4nt 
T24 Ca 18 17q23   DIPS  16  3′ 3nt 
T26 Ca 18 17q23  HS355936 APOT/DIPS  16   
CC226 Ca 16 17q23 FRA17B  Restriction PCR  25   
int13 Ca 18 17q23 FRA17B HS12677 APOT  18   
107 Ca 16 17q23.2 FRA17B DKFZP566I133 Restriction PCR  52   
207 Ca 16 17q23.2 FRA17B  Restriction PCR  52   
T9 Ca 16 17q25   DIPS  23  3′ 2nt 
ME180 CL 68 18q21  APM-1 mRNA library  19   
F2423 Ca 16 18q22   Inverse PCR  24  5′ 5nt 3′ 2nt 
HK11 Ca 18 19p13  PRKACA Restriction PCR  11   
LU2 Ca 18 19q13 FRA19A CEACAM5 Restriction PCR  11   
int54 CIN3 16 19q13 FRA19A CEACAM5 APOT  18   
265 Ca 16 20p12   Restriction PCR  52   
int8 Ca 16 20p12 FRA20B  APOT  18   
int6 Ca 16 20p11 FRA20A HS97790 APOT  18   
3.2a (probe) CA 16 20q13     9   
int15 Ca 18 21q21   APOT  18   
int20 ValN2 16 21q22   APOT  18   
HeLa CL 18 22q12–13   FISH  12   
        9   
        20   
CC10 CL 45 22q13   FISH  21   
T27 VaCa 16 Xp22  HSX11910 APOT/DIPS  16   
a

Fragile site correlates with integration locus, either by direct visualization or by database comparison.

b

Known gene or Unigene Cluster that correlates with integration locus.

c

Fusion region 5′ and 3′: xnt, identity between viral and cellular sequence; filler, sequence that neither derives from viral nor cellular sequence at that locus.

d

Ca, cervical carcinoma; APOT, amplification of papilloma virus oncogene transcripts; Sq, squamous cell; CL, cell line; FISH, fluorescence in situ hybridization; DIPS, detection of integrated papillomavirus sequences; CIN, cervical intraepithelial neoplasia; VIN, vulvar intraepithelial neoplasia; VaCa, vaginal carcinoma; HNSCC, head and neck squamous cell cancer; VaIN, vaginal intraepithelial neoplasia.

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