The role of human papillomavirus infection in breast cancer

Breast cancer is the leading female cancer and the third most common cause of cancer deaths worldwide. Many studies have suggested a possible link between breast cancer pathogenesis and viral infection, particularly mouse mammary tumour virus, simian virus 40, Epstein–Barr virus, and human papillomavirus (HPV). A significant number of recent studies have reported that approximately 29% of human breast cancer tissues were positive for high-risk HPV subtypes, especially HPV subtypes 16, 18, or 33. In contrast, several other investigations did not detect any HPV subtypes in either breast cancer tissue or normal breast tissue from patients diagnosed with breast cancer. Given these conflicting data and the established complexity of the association between HPV with other cancers, a definitive relationship between human breast cancer and HPV infection has not been determined. Recent advances in laboratory methodologies aim to overcome the inherent challenges in detecting HPV in breast cancer tissue. There is an urgent need to obtain additional evidence in order to assess the possibility of breast cancer prevention using HPV vaccines.     

No evidence of Human papillomavirus DNA sequences in invasive breast carcinoma

Breast cancer is one of the most frequently diagnosed cancers in women in France, but its aetiology remains unknown. Viruses including Epstein-Barr virus (EBV), a human equivalent of murine mammary tumour virus (MMTV) and human papillomavirus (HPV) have been detected in benign breast tissues and breast tumours and are considered to be involved in the aetiology of breast cancer. The aim of this study was to determine the prevalence of high-risk oncogenic HPVs in breast carcinoma from French patients. Fifty unselected DNA samples extracted from invasive breast carcinoma tissues were analysed. Polymerase chain reaction (PCR) was performed to amplify both consensus GP5 + /GP6 + HPV sequences and specific sequences for HPV types 16, 18, 33, 45 and 6-11. No HPV-DNA sequences were detected in our series of 50 samples. These data argue against the role of oncogenic HPV in the pathogenesis of breast cancer.     

ＨＰＶ感染种系型别与宫颈癌变的相关性研究

目的　研究妇女下生殖道人乳头瘤病毒（ＨＰＶ）感染的种系型别分布,探讨不同基因型ＨＰＶ与子宫颈癌变的相关性。方法　对我院门诊４７６例宫颈ＨＰＶ感染的患者以第二代杂交捕获（ＨＣ-Ⅱ）试验检测１３种高危型ＨＰＶ,同时采用核酸分子快速导流杂交基因分型技术（ＨｙｂｒｉＭａｘ）进行２１种ＨＰＶ-ＤＮＡ亚型分析,分析ＨＰＶ感染型别与宫颈癌变的相关性。结果　４７６例患者中,ＨｙｂｒｉＭａｘ法检测１３种高危型ＨＰＶ的阳性率为８４.９％,ＨＣ-Ⅱ法为８５.７％,两种方法的总符合率为９５.８％,Ｋａｐｐａ指数（ＫＩ）为０.８３。ＨＰＶ亚型感染频度由高到低依次为１６、５８、５２、１１、３３、１８、６８、３１、６、３９、５３、６６、ＣＰ８３０４、５１、５６、４５、５９、４４和４２型,宫颈癌／ＨＳＩＬ组最常见的前６位型别由高到低为１６（１６.４％）、５８（１１.３％）、５２（８.０％）、３３（３.８％）、１８（３.４％）和３１（２.５％）,ＬＳＩＬ组为１６（８４％）、５８（４.６％）、１８（３.４％）、３３（３.４％）、３９（２.９％）和６８（２.９％）,正常组织／炎症组为１６（５.５％）、１１（５.０％）、５８（４.２％）、６（２.９％）、３１（２.１％）和１０（２.１％）。正常组织／炎症组、ＬＳＩＬ组、宫颈癌／ＨＳＩＬ组中两种以上ＨＰＶ亚型感染者分别占２２.７％、３３.７％和５５.３％,最后一组明显高于前两组,差异有统计学意义（Ｐ＜０．０５）。结论　哈尔滨地区妇女下生殖道感染ＨＰＶ型别以１６、５８、５２、１１、３３、１８型较为多见,其中１６、５８、５２、３３和１８型的致癌性较强。ＨＰＶ-ＤＮＡ分型检测在宫颈癌变的临床诊断和预后判断方面具有重要意义。     

No Detection of ‘High-risk’ Human Papillomaviruses in a Group of Iranian Women with Breast Cancer

The presence of viral DNA in breast cancer cells is controversial. However, some studies have revealed apossible role for the human papillomavirus in the pathogenesis of breast cancer. The aim of the present studywas to investigate the presence of HPV-DNA in breast tissue in a group of Iranian women with and withoutbreast cancer and identification of the detected HPV types. Paraffin-embedded specimens from 65 malignantbreast cancer cases and 65 cases with benign breast lesions were investigated for presence of HPV-DNA by nestedpolymerase chain reaction. We found HPV-DNA in 22 (33.8%) of the breast cancer specimens. All non-cancerousspecimens were negative. Low and high-risk HPV types, including HPV-6 (26.2%), HPV-16 (1.5%), HPV-35(1.5%), HPV-52 (1.5%), and HPV-11 (1.5%) were detected in our study. HPV-6 was the most prevalent typein the breast cancer specimens. Although high-risk HPV types have been shown to have a major role in cervixcancer, there have been no data that support the same relevance for other types of malignancies. Furthermore,presence of low-risk HPV types in malignancies still is a matter of debate. The data presented in this studyindicates a strong need for epidemiological studies correlating different HPV types in human breast cancer.     

Prevalence of Human Papillomavirus subtypes 16 and 18 among Yemeni Patients with Cervical Cancer

Background: The Human Papillomavirus (HPV) is a DNA tumor virus that causes epithelial proliferation. There are more than 100 HPV subtypes, of which 13 subtypes are regarded as high risk subtypes that can cause cancers of epithelial mucosal surfaces. High risk human papilloma viruses (HR-HPV) subtypes 16 and 18 plays a major role in the etiology of cervical cancer worldwide. Therefore, the aim of this study was to screen for the existence of HPV16 and HPV18 among Yemeni women with cervical lesions. Methodology: Formalin fixed paraffin wax processed tissue blocks were retrieved for 200 patients (150 were previously diagnosed with cervical cancer and the remaining 50 were diagnosed with different benign conditions). Results: Of the 200 cervical cancer tissue specimens, HR-HPV 16 was identified in 74/200 (37%) samples and couldn’t be recognized in 126/200(63%) tissue samples. HR-HPV 18 was identified in 32/200 (16%) specimens and couldn’t be recognized in 168/200(84%) tissue specimens. Conclusion: HR-HPV subtypes were prevalent among Yemeni women with cervical cancer, with significant increase of HR-HPV subtype 16 over the HR-HPV subtype 18.     

Evidence for an association of human papillomavirus infection and colorectal cancer.

AIM: To investigate the presence of human papillomavirus (HPV) in colorectal carcinomas and the correlation of the viral infection with prognostic factors for the disease outcome. METHODS: Seventy-two patients with primary colorectal adenocarcinoma were studied. From each patient two tissue samples were collected: one sample of the tumor and one sample of normal colorectal tissue from an area located 15 cm away from the tumor. Samples of colorectal mucosa obtained from 30 individuals without malignant disease were also studied as control group. Tissues were initially analyzed through MY/GP nested polymerase chain reaction (PCR) and through GP5+/GP6+ auto-nested PCR. Specific primer sets targeting the E6/E7 region of the HPVs 6, 11, 16, 18, 31, 33, 45 were used for typing. Direct DNA sequencing was conducted to confirm positive PCR results. RESULTS: HPV DNA was detected in colorectal specimens of 60 patients with cancer (83.3%), but in none of the tissues from the non-malignant control group (p<0.001). Twenty-three cancer patients had HPV DNA detected in both the tumor and the matched normal tissue, 23 had HPV only in the tumor, and 14 had HPV only in the normal colorectal tissue. HPV16 was the viral type most frequently detected, being present in 41 out of 60 positive cases (68.3%). No correlation between the presence of the virus and specific prognostic predictors for the disease outcome was observed. CONCLUSION: HPV is present in the colon and rectum of most patients with colorectal adenocarcinoma, suggesting that this virus may be related to the pathogenesis of colorectal cancer.     

肺鳞癌与人乳头瘤病毒相关性研究

目的:了解肺鳞癌组织中人乳头瘤病毒存在情况,并分析人乳头瘤病毒与肺癌发生部位、性别因素、角化程度、吸烟因素的关系.方法:采用地高辛标记的DNA探针对肺癌组织进行原位杂交检测,同时结合临床资料分析多种因素的相关性.结果:肺鳞癌组织,鳞状上皮生化组织、粘膜慢性炎组织HPV检出率分别为48.4%,27.4%,5.6%,各组比较差异显著(P＜0.01),中心型肺癌与周围型肺癌组织HPV检出率分别为50.6%和4.4%,两组比较差异显著(P＜0.01).男女两组HPV检出率分别为46.1%和54.3%,差异无显著性(P＞0.05).吸烟组HPV检出率为50.6%,非吸烟组为43.9%,差异不显著(P＞0.05).结论:肺癌组织中存在一定比例HPV感染,HPV感染与肺鳞癌关系密切,中心型肺癌与HPV感染密切相关,HPV感染与性别及吸烟因素未发现明显相关性.人乳头瘤病毒感染可能与肺癌发生发展有关.     

人乳头瘤病毒16、18型在乳腺癌组织中的表达

目的：探讨人乳头瘤病毒（ＨＰＶ）１６、１８型感染与人乳腺癌病因学的关系。方法：采用免疫组化法（ＳＰ）检测ＨＰＶ１６、１８Ｅ６蛋白在１０例正常乳腺组织,４５例乳腺癌组织中的表达并对癌组中１３例ＨＰＶ１６、１８Ｅ６蛋白阳性材料进行ＨＰＶ１６、１８ＤＮＡ原位杂交检测。结果：癌组中ＨＰＶ１６、１８Ｅ６阳性率为５３．３％（２４／４５）,而正常乳腺组织中均为阴性表达。ＨＰＶ１６、１８ＤＮＡ阳性率为３８．５％（     

Lack of Evidence for a Relationship between High Risk Human Papillomaviruses and Breast Cancer in Iranian Patients

Background: Whether there is any relationship between human papilloma virus (HPV) and breast carcinoma is not clear. Some previous studies have indicated a possible role in oncogenesis in the breast. In this study, we therefore analyzed the presence of HPV infection in breast tissues of Iranian women from Yazd city. Materials and Methods: In a cross-sectional study, formalin-fixed paraffin-embedded tissues from 87 patients with breast cancer and 84 cases with breast fibrocystic lesions (control group) were selected from a tissue archive. Grade of tumors and fibrocystic tissues were determined by two pathologists. The nested-PCR method was performed for detection of HPVs in samples. HPV genotypes were determined by sequencing and the phylogenetic tree depicted by MEGA software. Results: Of the 87 women with breast cancer, 22.9% (20 isolates) had positive results for HPV DNA. In the control group no HPV was detected. The HPV genotypes in positive samples were HPV-16 (35%) HPV-18 (15%), HPV-6 (45%) and HPV-11 (5%). The data did not approved a significant correlation between tissue pathology of breast cancer and the HPV genotype frequency. Conclusions: The data did not provide any evidence for a role of high risk HPV types in oncogenesis in the breast.     

Human papillomavirus detected in female breast carcinomas in Japan

To investigate the aetiological role of human papillomavirus (HPV) in breast cancer, we examined the presence, genotype, viral load, and physical status of HPV in 124 Japanese female patients with breast carcinoma. Human papillomavirus presence was examined by PCR using SPF10 primers, and primer sets targeting the E6 region of HPV-16, -18, and -33. The INNO-LiPA HPV genotyping kit was used to determine genotype. Human papillomavirus DNA was detected in 26 (21%) breast carcinomas. The most frequently detected HPV genotype was HPV-16 (92%), followed by HPV-6 (46%), HPV-18 (12%), and HPV-33 (4%). In 11 normal epithelium specimens adjacent to 11 HPV-16-positive carcinomas, 7 were HPV-16-positive. However, none of the normal breast tissue specimens adjacent to HPV-negative breast carcinomas were HPV-positive. The real-time PCR analysis suggested the presence of integrated form of viral DNA in all HPV-16-positive samples, and estimated viral load was low with a geometric mean of 5.4 copies per 10(4) cells. In conclusion, although HPV DNA was detected in 26 (21%) breast carcinomas and, in all HPV-16-positive cases, the HPV genome was considered integrated into the host genome, their low viral loads suggest it is unlikely that integrated HPV is aetiologically involved in the development of Japanese breast carcinomas that we examined.     

Relation between HPV-DNA and expression of p53, bcl-2, p21WAF-1, MIB-1, HER-2/neu and DNA ploidy in early cervical carcinoma: correlation with clinical outcome

The purpose of the present study was to analyze the relation between the expression of p53, bcl-2, p21WAF1, MIB-1, HER-2/neu, DNA ploidy and HPV16 or 18 infections with clinical parameters. HPV-DNA was evaluated in 171 early cervical carcinomas treated from 1965 to 1990 and detected by PCR (polymerase chain reaction) on paraffin specimens obtained before therapy was started. HPV-DNA of any type was detected in 78% (86/110) of all tumors, HPV16 was the predominant type and was seen in 56% (62/110), HPV18 in 8% (9/110) and HPV35 in 21% (23/110). Patients with HPV16 or 18 were significantly (P=0.011) younger than patients with tumors not containing these two HPV subtypes. Lymph node metastases were seen more frequently (P=0.047) in tumors expressing HPV16 or 18. Tumor size was associated with the HPV-type. The frequency of DNA aneuploidy was lower in high-risk HPV tumors than in tumors with other HPV subtypes (P=0.014). MIB-1 expression was highly significantly (P=0.00007) associated with presence of HPV16 or 18. The cancer-specific survival rate was lower for patients with HPV16 and 18 positive tumors, but the difference was not statistically significant. The overall 5-year survival rate of the complete series was 91%. In conclusion, the HPV DNA subtype was a prognostic factor in early stage cervical cancer and it was associated with age, positive lymph nodes, tumor size, DNA ploidy and the proliferation marker MIB-1.     

人乳头状瘤病毒16 型DNA 在乳腺癌组织中表达的研究

 目的　探讨人乳头状瘤病毒 (HPV) 1 6型感染与人乳腺癌病因学的关系。方法　采用原位分子杂交技术检测本地区人口女性乳腺癌和正常乳腺组织中的 HPV1 6型 DNA。结果　乳腺癌和正常乳腺组织中 HPV1 6型 DNA的阳性率分别为 52 .0 %和 2 0 .0 % ,多种组织学类型的乳腺癌组织中有 HPV1 6型 DNA的存在且以整合型感染为主。结论　本地区女性乳腺组织中有HPV1 6型 DNA感染的存在 ,HPV1 6型感染与本地区乳腺癌的发生、发展密切相关。     

Identification of human papillomavirus DNA gene sequences in human breast cancer

Human papilloma viruses (HPVs) are accepted as being carcinogenic in human cervical and anogenital cancers. The suspicion that HPVs may also have a role in human breast cancer is based on the identification of HPVs in human breast tumours and the immortalisation of normal human breast cells by HPV types 16 and 18. For this investigation, DNA that had been previously extracted and fresh frozen at -70 degrees C from 50 unselected invasive ductal breast cancer specimens were screened by polymerase chain reaction (PCR) for HPV type 16, 18 and 33 gene sequences. We show that HPV 18 gene sequences are present in DNA extracted from breast tumours in Australian women. Overall, 24 (48%) of the 50 samples were HPV positive. Overall no correlations with tumour grade, patient survival, steroid receptor status, ERB-2, p53 expression and mutation were observed. Human papilloma viruses may have a role in human breast cancer. We speculate that HPVs may be transmitted by hand from the female perineum to the breast.     

Relation between human papillomavirus (HPV) and cancer of uterine cervix

HPV-DNA fragments were detected in biopsy specimens (29 cases of cancer of uterine cervix, 2 cervical dysplasia and 9 normal cervix) using DNA hybridization technique. It was demonstrated that 52% of biopsy specimens of the cancer of uterine cervix was positive for HPV 16 DNA probe, while 9% was positive for HPV 18 DNA probe. 11% of non-cancerous biopsy specimens had a positive result for HPV 16 DNA probe. It was also demonstrated that the positive rate of HPV 16 DNA was 75% in grossly cauliflower and nodular type tumors but only 25% in erosion type. It seems that the positive rate of HPV 16 DNA is correlated to gross appearance of the tumor. The positive rates of HPV 16 DNA were different in 6 provinces in China. It was 64% in Shanxi Province, a high incidence area but 36% in Sichuan Province, a low incidence area. These results suggest that the carcinogenesis of cancer of the uterine cervix, be related to HPV infection.     

High-risk human papillomavirus infections in breast cancer in Syrian women and their association with Id-1 expression: a tissue microarray study

High-risk human papillomaviruses (HPVs) could be important risk factors for breast carcinogenesis and metastasis. Based on this hypothesis, we recently studied the effect of E6/E7 onco-proteins of high-risk HPV type 16 in two non-invasive human breast cancer cell lines, BT20 and MCF7; we reported that E6/E7 converts these cell lines to invasive cells. This is accompanied by an overexpression of Id-1, which is an important regulator of breast metastasis. In this investigation, we examined the presence of high-risk HPVs (16, 18, 31, 33 and 35) and the expression of their E6 onco-protein as well as their correlation with Id-1 gene expression, using polymerase chain reaction (PCR) and tissue microarray (TMA) analysis, respectively, in a cohort of 113 Syrian breast cancer patients. We found that high-risk HPV types 16, 18, 31, 33 and 35 are present in 8.84, 9.73, 7.07, 55.75 and 37.16% of our samples, respectively, which represent invasive breast cancers. Overall, 69 (61.06%) of the 113 samples are HPV positive; among these specimens 24 tissues (34.78%) are coinfected with more than one HPV type. Furthermore, we report that the expression of the E6 onco-protein of these high-risk HPVs is correlated with Id-1 overexpression in the majority of invasive breast cancer tissue samples. Our data suggest that high-risk HPV infections are associated with human breast cancer progression in Syrian women.     

人乳头状瘤病毒18型DNA在乳腺癌组织中的表达

目的：探讨人乳头状瘤病毒（ＨＰＶ）１８型感染与人乳腺癌病因学之间的关系。方法：采用生物素标记的分子原位杂效技术检测柳州地区女性乳腺癌、导管内乳头状瘤和正常乳腺组织中ＨＰＶ １８ ＤＮＡ。结果：乳腺癌、导管内乳头状瘤和正常乳腺组织中ＨＰＶ １８ ＤＮＡ的阳性率分别为４８．０％、３０．０％和１６．７％。多种组织学类型的乳腺癌组织中有ＨＰＶ １８ ＤＮＡ的存在且以整合型感染为主。癌组中淋巴结转移组ＨＰＶ     

宫颈癌细胞DNA含量和HPV16的对比研究

作者对３３例宫颈癌患者的活检组织进行了ＤＮＡ含量和ＨＰＶ１６检测。结果显示：宫颈癌细胞ＤＮＡ异倍体率为６６．７％，ＨＰＶ１６阳性率３３．３％。异倍体患者ＨＰＶ１６阳性率显著高于二倍体患者（Ｐ＜０．０５）；在异倍体病例中，不同倍体类型者ＨＰＶ１６阳性率明显不同，其顺序为多异倍体＞非整倍体＞四倍体＞近二倍体。ＨＰＶ１６阳性者的ＤＩ、ＳＰＦ、＞２Ｃ％均显著高于ＨＰＶ１６阴性者（Ｐ＜０．０１）。该结果提示，ＨＰＶ１６不仅与宫颈癌的发生关系密切，而且和癌细胞ＤＮＡ含量、增植特性、肿瘤恶性度也有一定关系。     

乳腺浸润性导管癌组织中HPV16DNA与p53蛋白表达的研究

 目的 检测人乳腺浸润性导管癌组织中HPV16DNA和p53蛋白，探讨HPV16型感染和p53蛋白表达与人乳腺癌之间的关系。方法 采用分子原位杂交和免疫组化技术检测和分析50例乳腺浸润性导管癌、30例正常乳腺组织中HPV16DNA和p53蛋白二者之间的表达关系。结果 癌组中HPV16DNA阳性和HPV16DNA阴性两组阃p53蛋白的表达均有显著性差异（P〈0．01），HPV16DNA阳性组显示与p53蛋白表达呈负相关（P〈0．02）。结论 HPV16感染后导致野生型p53的降解可能涉及HPV16感染后人乳腺上皮细胞癌变的病理发生过程。     

Papillomavirus infection of the lower genital tract: detection of viral DNA in gynecological swabs

A total of 311 smears from the lower genital tract were examined by the filter in situ hybridization method to identify human papillomavirus (HPV) DNA. Of these 311 smears, 229 came from clinically and cytologically negative patients and served as a control group. In this group HPV-DNA was detected in 5 cases (2.2%). Of 82 cytologically positive cases (25 confirmed by histology) 56 (68%) contained HPV-DNA. A high prevalence of HPV 6/11 and absence of HPV 16/18 was found in cases with cytological signs of permissive HPV infection. In mild and moderate dysplasia all viruses occurred at almost the same frequency. In severe dysplasia/carcinoma in situ HPV 16/18 was found 5 times more frequently than HPV 6/11. HPV 16/18 was identified in all 4 invasive cancer cases. Cervical irrigation of colposcopically suspect areas was performed in 15 cytologically and HPV-DNA positive cases using the hydrodynamic filtration method. In 12 cases only the cells obtained from the colposcopically positive areas contained HPV-DNA. The sensitivity and reproducibility of the filter in situ hybridization was shown by: comparing the results obtained by HPV-DNA hybridization using Southern blot analysis of tumor biopsies; analysing the correlation of cytologic diagnosis and presence of HPV-DNA in follow-up examinations, and diagnosing presence or absence of HPV-DNA in parallel filters from the same patients.