p53 Expression and Genetic Evidence for Viral Infection in Intraepithelial Neoplasia of the Uterine Cervix

Infections with high-risk strains of human papillomaviruses (HPVs) and with herpes simplex virus type 2 (HSV 2), as well as inactivation of the p53 tumor suppressor gene, are important cofactors in cervical carcinogenesis. We analyzed 41 paraffin-embedded cervical intraepithelial lesions, including 25 cases of low-grade cervical intraepithelia neoplasia (CIN), and 16 cases of high-grade CIN for the presence of HPV 16/18 and HSV 2 genomic sequences and for the nuclear accumulation of the p53 protein. HPV 16 DNA was detected in 24.% of low-grade CINs and in 43.7% of high-grade CINs. HPV 18 was found only in 8.% of low-grade CINs. None of the cases tested scored positive for HSV 2 DNA. Nuclear accumulation of p53 was found in 4% of low-grade CINs, and in 31.2% of high-grade CINs, including 57.1% of the lesions that were positive for HPV 16. These results indicate that HPV 16 infection was over sixfold more common than HPV 18 infection and that p53 overexpression was significantly associated with high-grade lesions.     

Detection of HPV DNA in the uterine cervical lesions by polymerase chain reaction and in situ hybridization]

Human papillomavirus (HPV) is found in close association with carcinogenesis of the uterine cervix. We applied a new in vitro gene amplification technology, the polymerase chain reaction (PCR) to detect HPV 16 and 18 in cervical exfoliated cells. HPV infections were detected in 5 (16%) of 31 women with no pathological lesions of the uterine cervix (normal), 16 (24%) of 67 with cervical intraepithelial neoplasia (CIN) and 6 (38%) of 16 with invasive cervical cancer. Moreover, 10% formalin-fixed and paraffin-embedded tissue sections were prepared from the uterine cervix of these 27 women with PCR-proven HPV infection and were examined for the histological localization of HPV-DNA by in situ hybridization with biotin-labeled DNA probes of HPV types 6/11, 16/18 and 31/33/35. HPV-DNA type 16/18 was detected in 3 of 5 normal women, 2 of 4 CINs I, 2 of 3 CINs II, 6 of 9 CINs III and 6 of 6 invasive cervical cancers. HPV-DNA type 6/11 was detected in 6 of 6 condylomas. Viral DNA sequence was detected in the superficial cells of CIN I and II, and it was distributed through entire thickness layer of undifferentiated cells derived from CIN III and squamous cell carcinoma. In addition, the staining intensity became weak as the lesion progressed. These differences between lesions might be due to the difference in the viral form in the nuclei, ie whether an episomal or integrated form. Thus, an in situ hybridization technique with a biotin-labeled DNA probe as well as the PCR method is useful for the detection of HPV in clinical samples.     

Frequent allelic imbalance of tumor suppressor gene loci in cervical dysplasia.

In addition to human papillomavirus (HPV) infection, loss of heterozygosity (LOH) at tumor suppressor gene loci has been frequently observed in cervical cancer. Thus, it may be assumed that detection and characterization of specific LOH profiles in preneoplastic lesions, in addition to HPV typing, might facilitate assessment of progression risk of cervical dysplasia. In this study, the type and frequency of allelic imbalance (allelic loss or allelic reduction) were analyzed in 24 unrelated cervical lesions using 14 polymorphic microsatellite markers at different tumor suppressor gene loci. No allelic loss was observed in four condylomatous lesions, whereas 2 of 13 (15%) CIN I lesions displayed allelic loss at 3p25 and 5q11-13. In high-grade lesions, however, allelic loss occurred in four of six (66%) cases at multiple chromosomal regions (3p14-25, 5p15, 5q11, 5q21, 11p15, and 17q21). Allelic reduction was observed in 4 of 13 (30%) low-grade lesions and 3 of 6 (50%) high-grade lesions. LOH was confined to lesions infected by high-risk HPV types. These data suggest that chromosomal instability is an early event in cervical carcinogenesis. The detection of LOH on multiple chromosome 3p loci in 50% of high-grade lesions suggests that a specific marker panel encompassing this region might enable better assessment of which lesions are likely to regress, persist, or progress.     

Relationship between HPV typing and abnormality of G1 cell cycle regulators in cervical neoplasm

OBJECTIVE: In tumorigenesis, loss of function of the G1 pathway (p16-CDK4/cyclinD1-pRB pathway (RB pathway) and p14-MDM2-p53 pathway (p53 pathway)) is a theoretically essential event. The simultaneous analysis of all components of the RB and p53 pathway may be able to explain cervical tumorigenesis. However, there are no reports in which all components of the G1 pathway and HPV typing were examined simultaneously in cervical cancer. METHODS: We examined HPV typing and the status of the G1 pathways simultaneously by PCR-SSCP, multiplex PCR, methylation-specific PCR, and immunohistochemical techniques in cervical neoplasia. A total of 105 samples (normal, 10; cervical intraepithelial neoplasm (CIN), 42; invasive cancer (IC), 53) were included. RESULTS: Abnormality of the RB pathway tended to be more frequent in ICs (60.4%) than in CINs (31.0%) (P = 0.069). The primary target was p16 (CIN, 14.3%; IC, 43.4%; P = 0.032). Abnormality of the p53 pathway was detected in ICs (56.6%) and in CINs (40.5%) (P = 0.1494). In particular, strong expression of MDM2 was higher in ICs (32.1%) than in CINs (7.1%) (P = 0.0045). Abnormalities of the RB and p53 pathways were higher in low-risk and negative HPV than in high-risk HPV (81.3% vs 51.4%, P = 0.0657; 81.3% vs 45.9%, P = 0.0328). Seven HPV-negative cases had abnormalities in the RB or p53 pathways. CONCLUSION: In conclusion, abnormality of the G1 pathway may be one of the important mechanisms for carcinogenesis of low-risk and negative HPV cases.     

Genetic changes during the multistage pathogenesis of human papillomavirus positive and negative vulvar carcinomas.

OBJECTIVE: To identify the molecular alterations found in 30 human papillomavirus (HPV) positive (n = 15) and negative (n = 15) vulvar carcinomas (VC) and their associated preinvasive lesions (VIN [vulvar intraepithelial neoplasia]) and normal epithelium to determine a common molecular pathogenesis of HPV positive and negative VC. METHODS: Loss of heterozygosity (LOH) at seven 3p chromosomal regions (3p12, 3p14.2, 3p14.3-21.1, 3p21.3, 3p22-24, 3p24.3, 3p25), 13q14 (RB) and 17p13.1 (p53) loci, and TP53 gene mutations in microdissected archival tissues were investigated. RESULTS: Fourteen of fifteen HPV positive VC had HPV 16 DNA sequences. The fractional regional loss index (FRL), an index of total allelic loss at all chromosomal regions analyzed, was greater in the HPV negative VCs than in the HPV positive tumors (FRL = 0.55 versus 0.32; P = .048) and was also greater in the HPV negative high-grade VINs as compared with the HPV positive lesions (0.29 versus 0.02; P = .002). Overall, LOH at any 3p region was frequent (80%) in both groups of cancers and in their associated VIN lesions. Although TP53 gene mutations were present in a minority of VCs (20%), allelic losses at the TP53 locus were frequently present, especially in HPV negative VCs, as compared with the HPV positive tumors (62% versus 15%; P = .02). CONCLUSION: A greater number of molecular alterations are found in HPV negative VCs compared with HPV positive tumors. Allelic losses at 3p are common early events in vulvar carcinogenesis in HPV negative cancers detected at a high rate in the corresponding high-grade precursor lesions (VIN II/III). TP53 gene mutations with associated 17p13.1 LOH are more common in HPV negative cancers.     

Cervical intraepithelial neoplasia: prognosis by combined LOH analysis of multiple loci

OBJECTIVE: Cervical intraepithelial neoplasias (CIN) show markedly variable clinical behavior. Clinically, it is important to distinguish CIN lesions with different behaviors and identify those likely to persist and progress. The purpose of this study is to explore whether CIN lesions with different clinical behaviors can be stratified by analysis of loss of heterozygosity (LOH) at multiple loci. METHODS: One hundred sixty-four cases of CIN (54 CIN1, 59 CIN2 and 51 CIN3) were screened for LOH at 12 microsatellite markers including 10 from 3p14, 3p21-22, 6p21 and 11q23. LOH was correlated with clinical follow-up data and high-risk HPV infection. RESULTS: In a pilot study of 71 cases of CIN, screening of 12 microsatellite markers identified four (D3S1300, D3S1260, D11S35, and D11S528) at which LOH was significantly associated with disease persistence/progression. These four markers were further investigated in a larger cohort, which brought the total number of cases examined to 164. Combined analysis of LOH at the above four loci permitted the identification of 22-47% of CIN lesions depending on the histological grade, which showed disease persistence/progression. LOH at these loci was significantly associated with HPV16 infection. Bioinformatic analysis identified several candidate genes including the fragile histidine triad gene and progesterone receptor gene that may be the target of deletions. CONCLUSIONS: LOH at D3S1300, D3S1260, D11S35 and D11S528 was significantly associated with cins that showed persistence/progression, and combined LOH analyses at these loci could be used to identify such cases.     

Analysis of transforming gene regions of human papillomavirus type 16 in normal cervical smears

Summary Exfoliated cells from the uterine cervix of 102 Hungarian women with no cytological abnormality were screened using the polymerase chain reaction (PCR) for human papillomavirus (HPV) type 16 infection. Twenty-nine patients with histologically confirmed cervical intraepithelial neoplasia (CIN) served as reference cases. PCR was performed with 2 different HPV 16 specific oligonucleotide primer pairs flanking a 300 and a 200 base-pair fragment from the early 6 (E6) and early 7 (E7) genes, position 215–514 and 605–805. The specimens exhibited the same proportions of type 16 sequences specific for the tested regions. 8.8% (9/102) of normal samples showed amplification for HPV type 16 E6 and E7 regions, while 48.3% (14/29) of CIN biopsies were positive for the same gene sequences.     

Sequence variations of the late upstream region of HPV16 in cervical intraepithelial neoplasm and invasive carcinoma

Abstract. Pang T, Hu X, Ponten J. Sequence variations of the late upstream region of HPV16 in cervical intraepithelial neoplasm and invasive carcinoma.
HPV16 is the most common type of human papillomavirus (HPV) seen in cervical squamous cell carcinoma. A 78-bp promotor element at nt 4118–4196 called late upstream region (LUR), critical for the expression of late genes, has been identified recently. Late genes encode viral capsid proteins that coat viral DNA to form particles and serve as antigen. To elucidate whether there are any sequence variations within LUR of HPV16 and any difference of these sequence variations between cervical invasive squamous cell carcinoma (CIC) and cervical intraepithelial neoplasia (CIN), we sequenced HPV16 LUR from 50 cases of HPV16-positive CIC and CIN. We found that variation frequency in the late upstream region ranged from 0 to 4.2 except for two cases in which variation frequency was as high as 22.8%. Eight of 24 CINs and 17 of 26 CICs contained two or more variations (33% vs. 65%, P < 0.025). The results suggested that the sequence variations occurred more often in LUR of HPV16 than in other regions of HPV16 and the variations in HPV16 LUR might play a role in the process of carcinogenesis of cervical carcinoma.     

Expression of human papilloma virus (HPV) and P16ink4a in cervical intraepithelial neoplasia (CIN) and papilloma

p16ink4a Is a tumor-supressor gene and a key regulator of the cell cycle. The neoplastic cervical epithelium (squamous and cylindric) intensely expresses the cyclin-dependent kinase inhibitor p16ink4a. It was shown that the expression of p16ink4a in the squamous cervical cancer was induced by HPV. The aim of our study was to reveal the frequency of expression of p16ink4a and of HPV in the different grades of CIN and in the papilomatous cervical lesions. We used biopsy material (n=11) and cone biopsies (n=10), collected from women with different grades of CIN and with papillomatous lesions, having different grades of koilocytotic dysplasia. The biopsy material, collected from one woman with squamous cervical cancer was also studied. Using the immunohistochemical procedure we determined the expression of p16ink4a and HPV in the changed squamous cervical epithelium. RESULTS: We found that the neoplastic epithelium in CIN II and CIN III intensely expressed p16ink4a. We observed positive immune reaction for HPV in only 22.7% from the cases with papillomatous lesions, having koilocytic dysplasia. In conclusion we can state that p16ink4a could be used as a marker for the exact determination of CIN lesions in the cervix uteri. The koilocytic dysplasia, determined histologically was not always HPV-positive.     

Detection of human papillomavirus DNA in human cervical lesions by tissue in situ nucleic acid hybridization

Cervical cancer is one of the most common female cancers in Taiwan. Certain types of human papillomavirus (HPV) are frequently detected in the epithelial precancerous and cancerous lesions of the cervix. By the use of tissue in situ hybridization, we investigated the relationship of various types of HPV (group I, HPV-6 & 11, group II, HPV-16 & 18, group III, HPV-31, 33 & 35) with cervical condyloma, carcinoma as well as precancerous lesions. Group I HPV DNAs were mainly found in cervical condylomatous lesions (2/2) of the cervix and cervical intraepithelial neoplasia I (CIN I) (2/4), but were only occasionally found in CIN II (1/4), CIN III (1/9) or non-keratinized squamous cell carcinoma (1/15). HPV DNAs of groups II and III were mainly detected in lesions of CIN III (5/9) and invasive squamous cell carcinoma (large cell, keratinized type: 4/7; large cell, non-keratinized type: 11/15). HPV DNA sequences were invariably detectable only in the cell nuclei of condyloma or dysplastic epithelium or invasive carcinoma. However, they could not only be detected in the upper layer dysplastic cells and koilocytes but also in the well and poorly differentiated cervical cancer cells. The distribution of HPV DNA positive cells in the carcinomas fell into four different patterns: (1) upper zone and non-invasive regions of the carcinoma (11/22, 50%), (2) basal zone and invasive regions (2/22, 9%), (3) randomly scattered (7/22, 32%), and (4) extensively distributed over the whole tumor lesions (2/22, 9%). Thus, our results are consistent with a strong correlation between the presence of HPV-16, 18, 31, 33 and 35 and malignant conversion of cervical epithelial cells.     

Loss of Fhit expression as a potential marker of malignant progression in preinvasive squamous cervical cancer

OBJECTIVE: In a previous study using the same cases of squamous cervical neoplasia and microinvasive carcinoma (MICA) we found an association between FHIT gene deletion and infection with high-risk HPV (HR HPV). The purpose of this study was to evaluate Fhit protein expression by immunohistochemistry in order to determine whether FHIT gene deletion or infection with HR HPV correlated with aberrant protein expression and grade of lesion. METHODS: A total of 74 archival LLETZ biopsy cases consisting of 23 cervical intraepithelial neoplasia grade 1 (CIN1), 28 CIN3, and 23 MICA cases were selected for Fhit immunostaining. The results of this study on Fhit immunostaining were analyzed in relation to our previous findings using Epi-Info and SPSS-PC statistical analysis software. RESULTS: Fifty percent (14/28) of CIN3 lesions and 78% (18/23) of MICA lesions had a marked reduction or absence of Fhit protein expression (P = <0.001, strength of association, Cramers' V, 0.632). CIN1 lesions were found to have moderate to strong cytoplasmic expression of Fhit. Seventy percent of cases in this study with reduced/absent Fhit protein expression were also positive for FHIT gene loss of heterozygosity (LOH) (P = 0.04, strength of association, phi, 0.254). A significant statistical relationship was found between Fhit protein expression and HPV 16 infection in combined CIN1, CIN3, and MICA cases (P = <0.001). Eighty-seven percent of cases with reduced/absent Fhit protein expression were positive for HPV 16 (strength of association, phi, 0.552). Ninety percent of HPV 16 and 31 positive cases had reduced/absent Fhit expression. CONCLUSION: Our findings suggest an association between HPV infection and FHIT gene abnormalities raising the possibility of a mechanistic role for the FHIT gene as a cofactor with HPV in triggering the development of cervical cancer.     

Chromosome 4 deletions are frequent in invasive cervical cancer and differ between histologic variants

OBJECTIVE: Patterns of discontinuous deletion of chromosome 4 have been described in histologic variants of lung carcinomas and may represent different "hotspot" targets for gene-environment interactions. Since similar environmental risks exist for cervical cancer, we investigated patterns of discontinuous deletion in two major histologic variants. METHODS: Thirteen archival cases of squamous cell cancer (SCCA) and 11 cases of adenocarcinoma (AC) were precisely microdissected. Matched normal and tumor DNA were used for polymerase chain reaction (PCR) based loss of heterozygosity (LOH) analyses using 19 polymorphic markers spanning chromosome 4. Human papillomavirus (HPV) detection was determined by PCR using general and type-specific primers (HPV 16, 18). Differences in LOH between histologic tumor types and chromosomal regions were determined using Fisher's exact test. RESULTS: Loss at any chromosome 4 locus occurred in 92% of all tumors studied, with the majority of deletions occurring on the long arm of the chromosome. Four discrete minimal regions of discontinuous deletion (R) were identified. For these regions, LOH frequencies were 76% (R1, 4q34-q35), 48% (R2, 4q25-q26), 36% (R3, 4p15.1-p15.3), and 26% (R4, 4p16). Loss in SCCA predominated at 4q (4q34-q35; 83%) and in AC at 4p (4p15.3; 50%). Overall LOH on the p arm was significant in AC (82%) compared to SCCA (31%) (P = 0.02). HPV detection was similar in SCCA (85%) and AC (73%), and HPV 16/18 subtypes were similarly represented in both histologies. CONCLUSIONS: Chromosome 4 deletions are frequent in cervical carcinomas. Different patterns of deletion between SCCA and AC may represent gene regions targeted by different gene-environment interactions in these tumor subtypes.     

Association of human leukocyte antigen and T cell message with human papillomavirus 16–positive cervical neoplasia in Japanese women

To investigate whether an association exists between human leukocyte antigen (HLA) haplotype and cervical neoplasia within the Japanese population, we analyzed the human papillomavirus (HPV) genotypes, the HLA class I specificities and class II alleles, and the T-cell responses in the lesions of patients with cervical neoplasia. Eighty-one patients, consisting of 62 cervical intraepithelial neoplasia (CIN) lesions and 19 invasive cervical cancers (ICC), were examined. The frequencies of HPV infection in the CIN I/II and CIN III/ICC groups were 68.0% (17/25) and 80.4% (45/56), respectively. All patients and 138 local Japanese controls were analyzed for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1. For major histocompatibility complex (MHC) class II HLA-DRB1 alleles, the frequency of DRB1*0901 was significantly elevated in HPV 16-positive CIN III/ICC patients compared with controls (59.3% versus 29.7%, P = 0.0031, OR = 3.44). Similarly for the HLA-DQB1 alleles, a significant increase in the DQB1*03032 frequency was observed in HPV 16-positive CIN III/ICC patients compared with controls (59.3% versus 28.3%, P = 0.0018, OR = 3.69). In the analysis of the T-cell responses in the lesions, Fas ligand was detected at a decreased frequency in HPV 16-positive CIN III/ICC patients with the HLA-DRB1*0901-DQB1*03032 haplotype. The presence of helper T cell-specific messenger RNAs in the cervical lesions supports an association among MHC class II, helper T cells, the immune response to HPV, and the development of cervical carcinoma. Accordingly, a specific MHC class II haplotype, DRB1*0901-DQB1*03032, may be a risk factor for cervical carcinoma in the Japanese population.     

Diagnosis of cervical intraepithelial neoplasia and human papillomavirus infection: punch biopsy versus cervical smear

Summary In 102 patients referred to our colposcopy clinic because of one to three Papanicolaou smears indicating cervical intraepithelial neoplasia (CIN) and/or abnormal colposcopy, routine smears and colposcopically directed punch biopsies were taken simultaneously. For detection and typing of human papillomavirus (HPV)-DNA in situ hybridization was performed in all biopsies and in 46 of the cervical smears. In cases of dysplastic lesions the number of HPV 16/18 (40.5%) and 31/33 (42.9%) was markedly higher than HPV 6/11 (16.6%) infection rate. In cases where simultaneous in situ hybridization in biopsy specimen and cervical smears was performed 21.7% showed a HPV negative smear and a positive biopsy, in 6.5% the results were the other way round. In 34.9% of cases with CIN I and 9.5% of cases with CIN II verified by punch biopsy the cytological smear did not indicate dysplasia. Our data show that mild and moderate CIN lesions of the cervix as well as HPV infection are detected more frequently by a combination of cervical smear and colposcopically directed punch biopsy than by cervical smear alone.     

Overexpression of p16INK4a as an indicator for human papillomavirus oncogenic activity in cervical squamous neoplasia

Overexpression of p16(INK4a) has been observed when retinoblastoma protein is inactivated by high-risk human papillomavirus (HPV) oncoprotein E7. We investigated overexpression of p16(INK4a) and HPV infection in cervical squamous neoplasia to evaluate the oncogenic potential among various HPV subtypes. The high-risk HPV was detected by PCR in 69.8% (37/53), 97.5% (39/40), 91.7% (44/48), and 100% (16/16) of cervical intraepithelial neoplasia (CIN)1, CIN2, CIN3, and squamous cell carcinoma (SCC), respectively. The p16(INK4a) overexpression was investigated immunohistochemically using a p16(INK4a)-specific monoclonal antibody (clone E6H4). In high-risk HPV positive cases, 32.4% (12/37) of CIN1, 82.1% (32/39) of CIN2, 93.2% (41/44) of CIN3, and all (16/16) SCC showed p16(INK4a) overexpression. The incidence of p16(INK4a) overexpression was significantly different between CIN1 and CIN2, suggesting that the disorder of cell cycle regulation by HPV frequently occurred from CIN2. As for CIN1 cases, p16(INK4a) overexpression was observed more frequently in HPV16 and HPV52 than in HPV51 and HPV35. Using p16(INK4a) as a bio marker of HPV oncogenic activity, we demonstrate that the level of pRb dysfunction by high-risk HPV varied from subtypes and was getting more frequent from CIN2.     

Correlation of the histologic appearance of intraepithelial neoplasia of the cervix with human papillomavirus types. Emphasis on low grade lesions including so-called flat condyloma

Cervical condylomas and intraepithelial neoplasia (CIN) were correlated with human papillomavirus (HPV) types and analyzed for the presence of abnormal mitotic figures. Colposcopically directed cervical biopsies were divided in half and processed for routine microscopy and Southern blot hybridization. Of 83 specimens from 71 patients, 70 (84%) contained HPV-DNA sequences. The HPV distribution was as follows: HPV 16 in 6/25 flat condylomas (FC), 2/8 CIN I, 8/18 CIN II, 12/14 CIN III; HPV 18 in 1/25 FC; HPV 31 in 3/25 FC, 3/18 CIN II, and 1/14 CIN III; HPV 6/11 in 12/18 exophytic condylomas (EC), 5/25 FC, 2/8 CIN I, and 3/18 CIN II. Uncharacterized HPVs were identified in 4/18 EC, 5/25 FC, 2/8 CIN I, and 1/18 CIN II. A similar heterogeneous distribution of HPV types was found in flat condylomas and CIN I. A more homogeneous distribution was noted in the exophytic condylomas and high grade CIN lesions, with HPV 6/11 found in the former and predominantly HPV 16 in the latter. Abnormal mitotic figures were predominantly seen in the high grade CIN lesions. Based on our findings, we would recommend that the term flat condyloma be abandoned and that low grade flat lesions of the cervix be graded according to CIN criteria.     

p53 Polymorphism (codon-72) has no correlation with the development and the clinical features of cervical cancer

Abstract. Nishikawa A, Fujimoto T, Akutagawa N, Iwasaki M, Takeuchi M, Fujinaga K, Kudo R. p53 polymorphism (codon-72) has no correlation with the development and the clinical features of cervical cancer.
Recent analysis of the codon-72 polymorphism of the p53 gene, the allele encoding proline or arginine, suggested that the homozygous Arg/Arg genotype is a significant risk factor for cervical cancer associated with human papillomavirus (HPV). We investigated the polymorphism of p53 in cervical condylomas, cervical intraepithelial neoplasias (CINs), and cervical cancers, evaluating clinical implications of the polymorphism of p53 in development of cervical neoplasms. DNA from 87 cervical cancer tissues, 28 CIN tissues, and seven cervical condyloma tissues were examined for the presence of HPV DNA by the consensus PCR method and the p53 polymorphism was analyzed by PCR using an allele-specific primer. The frequencies of p53Pro, p53Arg, and p53 Pro/Arg were 14.3%, 57.1%, and 28.6% in condyloma patients; 21.4%, 39.3%, and 35.7% in CIN patients; and 10.3%, 44.8%, and 42.5% in cervical cancer patients, respectively. No statistically significant differences in the distribution of p53 genotypes were found among the patients with these diseases, regardless of HPV status. Furthermore, there was no clear correlation between the polymorphism of p53 and age, histopathologic type, clinical stage, or lymph node metastasis. Nor was there any evidence of a correlation between the p53 genotype and the outcome for patients with HPV-positive uterine cervical cancer.     

Serologic response to human papillomavirus 16 among Australian women with high-grade cervical intraepithelial neoplasia

This study evaluated the detection of human papillomavirus (HPV) 16 antibody in HPV 16-associated cervical intraepithelial neoplasia (CIN) in Australian women. Seroreactivity to HPV 16 L1 virus-like particles was assessed in patients with CIN 2 (n= 169) and CIN 3 (n= 229) lesions previously tested for the presence of HPV DNA. Seropositivity was significantly commoner in women with HPV 16 DNA-positive lesions (98/184) than in women with no HPV DNA in the lesion (15/47) or with HPV of types other than 16 in the lesion (43/167) (P= 0.0004). In addition, seropositivity was observed in 33% (55/169) of women with CIN 2 and 46% (106/229) of women with CIN 3, in keeping with the lower fraction of CIN 2 (57/169) than CIN 3 (127/229) biopsies positive for HPV 16 DNA. HPV 16 seropositivity is most common in women with HPV 16-associated CIN, but many patients with HPV-associated CIN 3 are seronegative, and HPV 16 seropositivity is common in women with CIN associated with other HPV types. Overall, HPV 16 serology is a poor predictor of presence of HPV 16-associated CIN 3 in patient population studied.     

Human papillomavirus genotypes associated with cervical neoplasia in India

The aim of this study was to determine the prevalence of human papillomavirus (HPV) genotypes in tissue with cervical neoplasias in patients from south and east India. Cross-sectional cervical tissue was obtained from 100 patients from south India and 30 patients from east India who had a biopsy for clinically invasive cervical cancer or cervical intraepithelial neoplasia (CIN) in a tertiary care hospital in India. DNA amplification was done with biotinylated PGMY 09/11 primers, and the line blot assay was used to determine the HPV genotype. HPV DNA was detected in 95% of invasive cancers (113/119) and 91% of CINs (10/11). A single HPV type was found in 100 women (77%), and mixed infections were found in 23 women (18%). HPV 16 (60%) and HPV 18 (14%) were the most frequent types, but 16 other types (26, 31, 33, 35, 42, 45, 51, 52, 53, 56, 58, 61, 62, 64, 81, and 82) were also identified. HPV 16 was present in 63% of patients from south India and in 50% of patients from east India, while HPV 18 was present in 12% and 20%, respectively. There are several high-risk HPV types associated with cervical neoplasias of which types 16 and 18 are the most common.     

组蛋白H3乙酰化和HPV感染的相关性及其对CINⅠ转归的影响

目的:探讨组蛋白H3乙酰化状态与宫颈HPV感染的相关性,及其分别与CINⅠ级转归的关系。方法:(1)选择2006年1月～2008年1月我院治疗的正常宫颈、CINⅠ、CINⅡ～Ⅲ、宫颈癌组织各30例,用免疫组化技术检测其组蛋白H3乙酰化表达水平;(2)对2006年1月～2008年1月仁济医院阴道镜下活检确诊为CINⅠ级的161例患者,用免疫组化技术检测组织中组蛋白H3乙酰化表达的水平,采用凯普技术检测宫颈HPV感染分型。结果:(1)CIN病变组组蛋白H3乙酰化水平与正常宫颈组和宫颈癌组的差异有统计学意义(P0.01)。CINⅠ和CINⅡ～Ⅲ组差异有统计学意义(P0.05);(2)组蛋白H3乙酰化表达水平增加,进展为CINⅡ级以上的发生率进行性升高,(+++)组最高达80%,差异有统计学意义(P0.05);(3)宫颈高危型HPV16/18感染的CINⅠ级,其组蛋白H3乙酰化表达水平明显高于低危型和非16/18高危型(P0.05);进展为CINⅡ级以上发生率与低危型和非16/18高危型的差异有统计学意义(P0.05);(4)不同的治疗方案对CINI级转归的影响不同,LEEP术后随访6月无1例复发,HPV转阴率77.94%(P0.05)。结论:组蛋白H3乙酰化水平和HPV感染类型与CINI级转归密切相关。