Human papillomaviruses and breast cancer: A systematic review and meta‑analysis
- Authors:
- Published online on: December 22, 2023 https://doi.org/10.3892/ol.2023.14208
- Article Number: 75
-
Copyright: © Karachalios et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Breast cancer (BC) is globally considered as a marked disease burden (1). It is not only the most prevalent, accounting for one third of cancer cases in female patients, but the breast is also the malignancy site associated with the majority of cancer-related deaths in developed and developing countries (2–4). BC incidence rates have steadily increased internationally over the last 10 years by ~20% (4,5). According to the Global Cancer Observatory of the International Agency for Research on Cancer of the World Health Organization, a total of 2,261,419 new BC cases were newly diagnosed in 2020, and a total of 684,996 deaths were attributed to BC. Among neoplastic diseases, the incidence of BC ranked 1st worldwide, even surpassing that of lung cancer (2,206,771 new cases in 2020) (6).
A vast variety of genetic, environmental and lifestyle parameters have been described over time as possible risk factors which likely contribute to mammary gland tumorigenesis (7,8). Viral etiology of breast carcinoma has been addressed in numerous studies, but still remains controversial (9). Several viruses, including bovine leukemia virus, Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus (EBV), mouse mammary tumor virus (MMTV), simian vacuolating virus 40 (10), human mammary tumor virus (11), cytomegalovirus (CMV) (12), herpes simplex virus-1 (HSV), human herpes virus type-8 (13) have been regarded as potential breast oncogenic factors a number of years ago. In 1944, the discovery that MMTV caused BC in mice led researchers to investigate a possible viral contribution to BC (14). In 1990, it was reported that HPVs are capable of immortalizing healthy mammary epithelial cells and decrease their need on growth factors (15). Since Di Lonardo first demonstrated in 1992 the potential relationship between HPV infection and BC by detecting HPV-16 DNA in ~30% of breast and lymph node samples (16), an increasing number of studies have reported the detection of HPV DNA in patients with BC (4,17–19). HPV+ breast tumors exhibit more aggressive characteristics than HPV−breast tumors, such as occurring at younger age, having a higher grade of malignancy, showing an estrogen receptor−status and having a higher Ki67 index (20).
The current published literature on HPV types and BC is divergent, as the prevalence of HPV infection in BC specimens varies (range, 0–86.21%) (5,21). The study designs, population differences and HPV detection techniques chosen are variable, and thus, provide inconsistent results (15). The purpose of the present systematic review and meta-analysis was to address the prevalence of HPV DNA in BC tissues compared with that in healthy and benign mammary specimens obtained from controls, thus determining the possible association between HPV infection and breast tumorigenesis.
Materials and methods
Data sources and search strategy
PubMed (http://www.ncbi.nlm.nih.gov/pubmed) and SCOPUS (http://www.elsevier.com/solutions/scopus) databases were searched for published, full-text English journal articles including case-control studies of >19 years of age, adult female individuals published between January, 1 2003 and January, 7 2023 and which evaluated the association between HPV DNA and BC. Relevant studies were identified using combinations of the terms ‘HPV’ or ‘human papillomavirus’ in combination with ‘breast cancer’, ‘breast carcinoma’ or ‘mammary carcinoma’. The reference lists of pertinent articles were further manually searched for potentially eligible studies. The ‘Related Citations’ tool in PubMed was also applied whenever a suitable article was included. The exact search strings for every database can be found in Data SI. The search was designed using the Systematic Review Accelerator (22). The present systematic review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (23).
Inclusion and exclusion criteria
The inclusion criteria were: i) Case-control studies; ii) adult patients aged >19 years histologically diagnosed with BC, irrespective to tumor stage, grade and histologic type; iii) controls with a histologic confirmation of normal breast tissue or benign breast disorders; and iv) HPV DNA detected by polymerase chain reaction (PCR). The exclusion criteria were: i) Non-case-control studies including books or book chapters, conference abstracts, theses, press articles, expert, narrative and systematic reviews, editorials/letters to the editor, medical hypotheses, case reports and case series as well as cohort studies; ii) presence of concomitant disease site(s) with precancerous or cancerous lesions; iii) HPV genome extracted from samples other than breast tissue, such as milk and blood; iv) patients and/or non-patients with prior neoplasia, surgery for malignancy, radiation or cytotoxic therapy; v) absence of healthy/benign controls/specimens; vi) co-presence of other oncogenic viruses; vii) HPV presence detected by methods other than PCR; and viii) low quality papers, as identified by the use of Critical Appraisal Skills Program Checklists (24).
Study screening and selection
Two investigators, CK and SP, independently selected the articles which met the inclusion criteria. Once the initial title/abstract screening was completed, the full texts of the included studies from that stage were reviewed by the aforementioned investigators to determine if they should be included. Discrepancies were resolved by consulting a third investigator, KD. The aforementioned stage was completed with the assistance of the automation tools Screenatron and Disputatron (22).
Data extraction
Study characteristics and data outcomes from every study were recorded in a data extraction form. Data extraction was independently conducted by two researchers, CK and SP. A third researcher, CMS, was consulted to resolve disagreements through open discussion. The following data regarding study characteristics and outcomes were extracted from every included study: First author, publication year, country of origin, type of samples, number of BC samples, most prevalent BC histological type, mean/median patient age, number of HPV+ BC samples and most prevalent HPV type in patients with BC.
Quality assessment
The quality of included studies was evaluated using the Critical Appraisal Skills Program Case Control Study Checklist (Table SI) (24). This list was divided into three sections and contained 11 questions on validity, effect and generalizability of the study. Every question could be answered with a ‘Yes (Y)’, a ‘No (N)’, or an ‘I can't tell (?)’. Every ‘Y’ counted as 1 point, while ‘N’ and ‘?’ counted as 0 points. A score range of 0–4 indicated low quality, 5–7 indicated moderate quality and 8–11 high quality. Only high and moderate quality papers were included in the present meta-analysis. CK and SP independently evaluated the quality of the included studies. Disagreements were resolved by discussion with CMS and KD.
Statistical analysis
Odds ratios (ORs) with 95% confidence intervals (CIs) were implemented as measures of strength association for every case-control study. Heterogeneity of the included studies was analyzed using the Q-test, which quantitatively evaluates whether such heterogeneity affected the results. Heterogeneity was quantified using the I2-test. According to the Cochrane Handbook for Systematic Reviews of Interventions (version 6.3) (25), an I2 range of 0–40% implied that heterogeneity might not be significant, an I2 range of 30–60% may have represented moderate heterogeneity, an I2 range of 50–90% may have represented substantial heterogeneity and an I2 range of 75–100% indicated considerable heterogeneity of studies. When studies demonstrated moderate heterogeneity (I2>50%), the random-effects model was used for analysis. Therefore, due to the several differences of subjects among the included case-control studies, such as ethnicity of participants and PCR methodology, data analysis was performed using the random-effects model. The meta-analysis was conducted using MedCalc (version 20.210; MedCalc Software Ltd.), which combined effect size and created a forest plot. To evaluate the influence of individual studies on the overall estimate, sensitivity analysis was performed. Egger's linear regression test was used to evaluate potential publication bias. P<0.05 was considered to indicate a statistically significant difference.
Results
Collection and selection of studies
A PRISMA flowchart of the study selection is depicted in Fig. S1. A total of 159 records, 142 from PubMed and 17 from SCOPUS databases, were initially identified. Using the Deduplicator tool (23), five duplicates were removed by browsing titles and abstracts. No further records were manually retrieved from reference lists. The remaining 154 articles were assessed for eligibility, and 79 of them were excluded using the title and abstract because they were not pertinent to the search. The remaining 75 articles were then assessed for eligibility, and 52 records were excluded based on the aforementioned exclusion criteria (Table SII) (4,9,10,14,19,26–73). The final step of eligibility criteria implementation (Table SIII) resulted in a total of 23 original case-control studies being included in the present meta-analysis (Table SIV).
Baseline characteristics of the included studies and assessment of risk of bias
The 23 included studies involved a total of 3,243 breast tissue samples, collected between 2004 and 2022 from nine countries worldwide (Table SIV) (3,7,18,21,74–92). A total of six continental regions (Asia, Europe, Oceania, North Africa and South America) were represented. Iran was the major representative (n=6; 26.09%). Five studies did not mention mean patient age, and two studies mentioned median age instead. The mean patient age of the remaining 16 studies was 51.34 years of age (years of age range, 35.2–59.0). The specimen types used for HPV detection were as follows: A total of 11 studies (47.83%) used formalin-fixed paraffin-embedded (FFPE) tissues, one study (4.35%) used fresh tissues, six studies (26.09%) used fresh frozen tissues, one study (4.35%) used frozen tissues and the rest four studies (17.39%) used paraffin-embedded (PE) tissues. In all of the case-control studies, 445 tissues in the BC group (2,027 cancer specimens) and 109 tissues in the control group (1,216 normal and benign specimens) were found to be HPV+. Therefore, the overall HPV prevalence in the present systematic review was 17.08% (n=554/3,243), the HPV DNA prevalence in patients with BC was 21.95% (n=445/2,027), and the HPV DNA prevalence in controls was 8.96% (n=109/1,216). Invasive ductal carcinoma (IDC) was the most prevalent BC type reported (n=17/23; ~74%). The range of IDC prevalence was 31.08–97.33%. The oncogenic HPV-16 high-risk type was the most frequently detected HPV type (n=9/23; 39.13%) (21). Assessment of risk of bias was performed with the assistance of the ‘Tool to Assess Risk of Bias in Case Control Studies’ contributed by the CLARITY Group at McMaster University (Table SIII). A total of seven studies had a low risk of bias, 15 studies a moderate risk of bias and only one study had a serious risk of bias.
Meta-analysis
The results of the pooled analysis for the 23 included studies are summarized in the forest plot (Fig. S2). The random-effects model was applied since I2=69.57% (95% CI, 51.89–80.75) (93). The summary OR was 3.83 (95% CI, 2.03–7.25; P<0.001). Since heterogeneity was substantial due to a Q value of 62.43 with 19 degrees of freedom and P<0.0001, the impact of publication bias was examined by conducting Egger's linear regression test. The P-value of the Egger's test was 0.26 (P>0.05), confirming the absence of publication bias.
Discussion
Summary of evidence
The present systematic review and meta-analysis suggested that there is a statistically significant difference between the prevalence of HPV DNA extracted from BC specimens and that of HPV DNA isolated from breast tissue samples of female patients with either benign breast disorders or healthy breasts (Table SV). Studies published in the last 20 years confirm the controversial nature of the alleged association of HPV with BC. There are reports which favor the impact of HPVs in BC oncogenesis (21,75,78,80–82,84,89), while other studies have confirmed a limited or nonexistent role of HPVs in the development of BC (3,7,18,74,76,77,79,83,85–88,90–92).
Interpretation of results
The current meta-analysis confirms the wide variations existing among the included studies. Various reasons have been described for the aforementioned discrepancy, which not only affects the possibility of an association of HPV with BC, but also the distribution of the HPV genotypes: Geographic region(s) of the samples, genetic background, cultural variations such as variable sexual practices and patterns, sample types such as fresh versus FFPE samples, age of the selected populations, sensitivity of the detection methods used, condition of the preserved samples that can hamper DNA quality, the histological type of BCs (IDC versus ductal adenocarcinoma in situ), the absence of an international standard assay for HPV genotyping and the unintentional contamination of samples with the genome of other potentially oncogenic viruses, such as EBV, MMTV, CMV and HSV (2,4,7,13,31,94–98).
The mean patient age in the present systematic review was 51.34 years. Although BC incidence increases with advancing age, HPV prevalence decreases as time goes by (7). Younger women usually tend to be more sexually active than older ones, risking infection with HPV (83). As a result, the average age of women with HPV+ BC is notably lower than that of women with HPV−BC (96). Estrogen expression, which is higher in younger women compared with that in older counterparts, acts as a co-factor to HPV infection, modulating oncogenesis (78). The need to vaccinate young girls against HPV is evident.
A total of ~50% of the studies included in the present systematic review have isolated HPV DNA from FFPE specimens. Technical aspects can also modify the detection rate of the HPV genome and expression in BC. DNA extracted from PE tissues is of poor quality due to partial degradation (2,7). When HPV DNA is extracted from PE tissues, HPV detection rates can be overestimated compared with those from fresh tissues (15). Moreover, the commercial kits used for DNA extraction and amplification by PCR, as well as the specific type of PCR used in every study, nested or quantitative PCR, differed among the included studies. Furthermore, it is considered a challenge to completely eliminate the possibility of specimen contamination with other oncogenic viruses, such as EBV (10), which could lead to carcinogenesis caused by these viruses and not by HPV (98). Moreover, the low viral loads detected in breast specimens impede the identification of HPV DNA in patients with BC (99). When cell transformation is completed, viral replication seizes and the viral genome is incorporated into the host genome with HPV DNA copies being reduced following integration (3). The ‘concentration’ of HPV, that is copy number of HPV/mg of tumor, in breast tumors appeared to be lower than its concentration in cervical cancer, which may make the detection of HPV in BC harder, despite amplification by PCR (100).
Another marked finding of the present systematic review is that the most prevalent HPV subtypes in patients with BC reported in four studies published in the last 10 years were low-risk HPVs (LR-HPVs) (75,78,82,83). These studies showed that 43.17% of patients with BC were LR-HPV DNA+ (117/271). All of the included studies originated from lower income countries of the Middle East and South America. Future studies could investigate the potential role of LR-HPVs in breast carcinogenesis, and define the association of potential risk factors, such as low socioeconomical status, with the development of LR-HPV+ BC.
Comparison with previous published literature
The overall HPV prevalence in the present systematic review was 17.08% (554/3243), the HPV DNA prevalence in patients with BC was 21.95% (445/2027), and the HPV DNA prevalence in controls was 8.96% (109/1216). These results are mainly in agreement with an Iranian systematic review which analyzed 61 Iranian studies and concluded that HPV prevalence in BC was 14% (101). By contrast, the aforementioned numerical findings of the present review are lower than those of a systematic review from Iran which examined 11 studies from around the globe and concluded that the HPV DNA prevalence in 858 Iranian patients with BC from six Iranian studies was 23.6% (102). In 2018, another meta-analysis from Belgium, which included 40 studies and a total of 4,762 patients with BC, estimated a 20% pooled prevalence of HPV in BC tissue specimens (99). A previous systematic review from Brazil examined 29 studies from five continents and concluded that HPV DNA prevalence in patients with BC was 23.0 and 12.9% in 1,932 cases and 279 controls, respectively (100). Li et al (15) conducted a meta-analysis of 21 studies from 17 countries and four continents, and revealed that the overall HPV prevalence in 1,184 BC cases was 24.49%. It is unclear whether the implementation of HPV vaccination has led to a possible decrease of HPV+ BC.
Limitations
The limitations of the present systematic review and meta-analysis include discrepancies of the included studies in their design, PCR methodology, such as exact PCR conditions and primers used, and HPV genotyping techniques. Moreover, the present review did not include older studies published prior to 2004. Studies with a substantial number of cases but without controls were excluded from the present review, while eight case-control studies of moderate quality were included. Furthermore, the authors of the included studies were not contacted for additional details such as Tumor-Node-Metastasis stage, tumor grade and histopathological diagnosis to increase the possible subgroup analyses.
Conclusions
HPVs seem to be involved in breast tumorigenesis. Future studies with larger sample sizes will shed more light on the role of HPVs in BC, given the burden of this disease to society. If the role of HPVs in BC is established, HPV vaccines could be used for BC prevention and immunotherapy.
Supplementary Material
Supporting Data
Supporting Data
Supporting Data
Supporting Data
Supporting Data
Supporting Data
Acknowledgements
The abstract of the current study has been previously published (https://ijgc.bmj.com/content/33/Suppl_3/A218.1).
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
CK was involved in the conceptualization of the study, methodology used, formal analysis, investigation and preparation of the original draft. SP was involved in the methodology, data validation, writing, reviewing and editing the study, and project supervision/CMS validated the data, carried out investigation, wrote, reviewed and edited the manuscript, and completed project supervision. KD was involved in the conceptualization of the study, data visualization, supervision and project administration. Data authentication is not applicable. CK and SP confirm the authenticity of all the raw data. All authors have read and approved the final version of the manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
BC |
breast cancer |
|
CI |
confidence interval |
|
CMV |
cytomegalovirus |
|
EBV |
Epstein-Barr virus |
|
FFPE |
formalin-fixed paraffin-embedded |
|
HPV |
human papillomavirus |
|
HSV-1 |
herpes simplex virus-1 |
|
IDC |
invasive ductal carcinoma |
|
MMTV |
mouse mammary tumor virus |
|
OR |
odds ratio |
|
PCR |
polymerase chain reaction |
|
PE |
paraffin-embedded |
|
PRISMA |
Preferred Reporting Items for Systematic Reviews and Meta-Analysis |
References
|
Ghaderi L, Montazer M and Naseri AR: Association of two high-risk strains of human papillomavirus (HPV18 and HPV16) with breast cancer in the patients using polymerase chain reaction. J Res Clin Med. 10:122022. View Article : Google Scholar | |
|
Oliveira ES, de Ferreira MVP, Rahal P, Castelo Branco MB and Rabenhorst SHB: High Frequency of Epstein-Barr Virus and Absence of Papillomavirus in Breast Cancer Patients from Brazilian Northeast. Asian Pac J Cancer Prev. 23:2351–2359. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Maldonado-Rodríguez E, Hernández-Barrales M, Reyes-López A, Mendoza-Almanza G and Ayala-Luján JL, Godina-González S, Gallegos-Flores PI, Esparza-Ibarra EL, González-Curiel IE, Aguayo-Rojas J, López-Saucedo A, Mendoza-Almanza G and Ayala-Luján JL: Presence of human papillomavirus DNA in malignant Neoplasia and Non-malignant breast disease. Curr Issues Mol Biol. 44:3648–3665. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Golrokh Mofrad M, Sadigh ZA, Ainechi S and Faghihloo E: Detection of human papillomavirus genotypes, herpes simplex, varicella zoster and cytomegalovirus in breast cancer patients. Virol J. 18:252021. View Article : Google Scholar : PubMed/NCBI | |
|
Sher G, Salman NA, Kulinski M, Fadel RA, Gupta VK, Anand A, Gehani S, Abayazeed S, Al-Yahri O, Shahid F, et al: Prevalence and type distribution of high-risk human papillomavirus (HPV) in breast cancer: A Qatar based study. Cancers (Basel). 12:15282020. View Article : Google Scholar : PubMed/NCBI | |
|
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Alinezhadi M, Makvandi M, Kaydani GA, Jazayeri SN, Charostad J, Talaiezadeh A and Angali KA: Detection of high-risk human papillomavirus DNA in invasive ductal carcinoma specimens. Asian Pac J Cancer Prev. 23:3201–3207. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Gupta I, Ulamec M, Peric-Balja M, Ramic S, Al Moustafa AE, Vranic S and Al-Farsi HF: Presence of high-risk HPVs, EBV, and MMTV in human triple-negative breast cancer. Hum Vaccin Immunother. 17:4457–4466. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Silva RG and Da Silva BB: No evidence for an association of human papillomavirus and breast carcinoma. Breast Cancer Res Treat. 125:261–264. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Herrera-Goepfert R, Khan NA, Koriyama C, Akiba S and Pérez-Sánchez VM: High-risk human papillomavirus in mammary gland carcinomas and non-neoplastic tissues of Mexican women: No evidence supporting a cause and effect relationship. Breast. 20:184–189. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Alibek K, Kakpenova A, Mussabekova A, Sypabekova M and Karatayeva N: Role of viruses in the development of breast cancer. Infect Agent Cancer. 8:322013. View Article : Google Scholar : PubMed/NCBI | |
|
Gebregzabher E, Seifu D, Tigneh W, Bokretsion Y, Bekele A, Abebe M, Lillsunde-Larsson G, Karlsson C and Karlsson MG: Detection of High-And Low-Risk HPV DNA in archived breast carcinoma tissues from Ethiopian women. Int J Breast Cancer. 2021:21401512021. View Article : Google Scholar : PubMed/NCBI | |
|
Aghdam MK, Nadji SA, Alvandimanesh A, Khoddami M and Khademi Y: Absence of human Papillomavirus in benign and malignant breast tissue. Iran J Pathol. 14:279–283. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Corbex M, Bouzbid S, Traverse-Glehen A, Aouras H, McKay-Chopin S, Carreira C, Lankar A, Tommasino M and Gheit T: Prevalence of papillomaviruses, polyomaviruses, and herpesviruses in triple-negative and inflammatory breast tumors from Algeria compared with other types of breast cancer tumors. PLoS One. 9:e1145592014. View Article : Google Scholar : PubMed/NCBI | |
|
Li N, Bi X, Zhang Y, Zhao P, Zheng T and Dai M: Human papillomavirus infection and sporadic breast carcinoma risk: A meta-analysis. Breast Cancer Res Treat. 126:515–520. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Di Lonardo A, Venuti A and Marcante ML: Human papillomavirus in breast cancer. Breast Cancer Res Treat. 21:95–100. 1992. View Article : Google Scholar : PubMed/NCBI | |
|
Mastoraki A, Schizas D, Gkiala A, Ntella V, Hasemaki N, Pentara I, Ntomi V, Kapelouzou A and Liakakos T: Human Papilloma Virus infection and breast cancer development: Challenging theories and controversies with regard to their potential association. J BUON. 25:1295–1301. 2020.PubMed/NCBI | |
|
Mou X, Chen L, Liu F, Shen Y, Wang H, Li Y, Yuan L, Lin J, Lin J, Teng L and Xiang C: Low prevalence of human papillomavirus (HPV) in Chinese patients with breast cancer. J Int Med Res. 39:1636–1644. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Guo H, Idrovo JP, Cao J, Roychoudhury S, Navale P, Auguste LJ, Bhuiya T and Sheikh-Fayyaz S: Human Papillomavirus (HPV) detection by chromogenic in situ hybridization (CISH) and p16 immunohistochemistry (IHC) in breast intraductal papilloma and breast carcinoma. Clin Breast Cancer. 21:e638–e646. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Calderon G, Castaneda CA, Castillo M, Sanchez J, Bernabe L, Suarez N, Tello K, Torres E, Cotrina JM, Dunstan J, et al: Human papillomavirus, cytomegalovirus infection and P16 staining in breast tumors from Peruvian women. Asian Pac J Cancer Prev. 23:1571–1576. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Delgado-García S, Martínez-Escoriza JC, Alba A, Martín-Bayón TA, Ballester-Galiana H, Peiró G, Caballero P and Ponce-Lorenzo J: Presence of human papillomavirus DNA in breast cancer: A Spanish case-control study. BMC Cancer. 17:3202017. View Article : Google Scholar : PubMed/NCBI | |
|
Clark J, Glasziou P, Del Mar C, Bannach-Brown A, Stehlik P and Scott AM: A full systematic review was completed in 2 weeks using automation tools: A case study. J Clin Epidemiol. 121:81–90. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, et al: The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Syst Rev. 10:892021. View Article : Google Scholar : PubMed/NCBI | |
|
Critical Appraisal Skills Programme (CASP), . Case-Control Study Checklist. 2022. | |
|
Cochrane Handbook for Systematic Reviews of Interventions, . Available from. https://training.cochrane.org/handbook/current | |
|
Mostafaei S, Kazemnejad A, Norooznezhad AH, Mahaki B and Moghoofei M: Simultaneous effects of viral factors of human papilloma virus and Epstein-Barr virus on progression of breast and thyroid cancers: Application of structural equation modeling. Asian Pac J Cancer Prev. 21:1431–1439. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Oramas DM, Bell D and Middleton LP: Sinonasal analogue HPV related breast multiphenotypic carcinoma, a report of a case with the first description in the breast. Diagn Pathol. 15:1372020. View Article : Google Scholar : PubMed/NCBI | |
|
Balci FL, Uras C and Feldman SM: Is human papillomavirus associated with breast cancer or papilloma presenting with pathologic nipple discharge? Cancer Treat Res Commun. 19:1001222019. View Article : Google Scholar : PubMed/NCBI | |
|
Baltzell KA, Shen HM, Krishnamurthy S, Sison JD, Nuovo GJ and Buehring GC: Bovine leukemia virus linked to breast cancer but not coinfection with human papillomavirus: Case-control study of women in Texas. Cancer. 124:1342–1349. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Kouloura A, Nicolaidou E, Misitzis I, Panotopoulou E, Theodoraki K, Smyrniotis V, Corso G, Veronesi P and Arkadopoulos N: HPV infection and breast cancer. Results of a microarray approach. Breast. 40:165–169. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Ghaffari H, Nafissi N, Hashemi-Bahremani M, Alebouyeh MR, Tavakoli A, Javanmard D, Bokharaei-Salim F, Mortazavi HS and Monavari SH: Molecular prevalence of human papillomavirus infection among Iranian women with breast cancer. Breast Dis. 37:207–213. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Wang YW, Zhang K, Zhao S, Lv Y, Zhu J, Liu H, Feng J, Liang W, Ma R and Wang J: HPV Status and Its Correlation with BCL2, p21, p53, Rb, and survivin expression in breast cancer in a Chinese Population. Biomed Res Int. 2017:63153922017. View Article : Google Scholar : PubMed/NCBI | |
|
Wang YX, Li YZ, Zhang ZY, Wang JQ, Cui J and Qian XL: HPV16 E6 promotes breast cancer proliferation via upregulation of COX-2 expression. Biomed Res Int. 2017:29484672017. View Article : Google Scholar : PubMed/NCBI | |
|
Rezaei H, Rassi H and Mansur FN: Investigation of Methylenetetrahydrofolate Reductase C677T polymorphism and human papilloma virus genotypes in Iranian breast cancer. Monoclon Antib Immunodiagn Immunother. 36:124–128. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Naushad W, Surriya O and Sadia H: Prevalence of EBV, HPV and MMTV in Pakistani breast cancer patients: A possible etiological role of viruses in breast cancer. Infect Genet Evol. 54:230–237. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Islam S, Dasgupta H, Roychowdhury A, Bhattacharya R, Mukherjee N, Roy A, Mandal GK, Alam N, Biswas J, Mandal S, et al: High-risk human papillomavirus in mammary gland carcinomas and non-neoplastic tissues of Mexican women: No evidence supporting a cause and effect relationship: Study of association and molecular analysis of human papillomavirus in breast cancer of Indian patients: Clinical and prognostic implication. PLoS One. 12:e01727602017. View Article : Google Scholar : PubMed/NCBI | |
|
Atique S, Hsieh CH, Hsiao RT, Iqbal U, Nguyen PAA, Islam MM, Li YJ, Hsu CY, Chuang TW and Syed-Abdul S: Viral warts (Human Papilloma Virus) as a potential risk for breast cancer among younger females. Comput Methods Programs Biomed. 144:203–207. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Tsuboi M, Yamane A, Horiguchi J, Yokobori T, Kawabata-Iwakawa R, Yoshiyama S, Rokudai S, Odawara H, Tokiniwa H, Oyama T, et al: APOBEC3B high expression status is associated with aggressive phenotype in Japanese breast cancers. Breast Cancer. 23:780–788. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Søgaard M, Farkas DK, Ording AG, Sørensen HT and Cronin-Fenton DP: Conisation as a marker of persistent human papilloma virus infection and risk of breast cancer. Br J Cancer. 115:588–591. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Mohtasebi P, Rassi H, Maleki F, Hajimohammadi S, Bagheri Z, Fakhar Miandoab M and Naserbakht M: Detection of human papillomavirus genotypes and major BRCA mutations in familial breast cancer. Monoclon Antib Immunodiagn Immunother. 35:135–140. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Ehsan Ilahi N, Anwar S, Noreen M, Naiyar Hashmi S and Murad S: Detection of human papillomavirus-16 DNA in archived clinical samples of breast and lung cancer patients from North Pakistan. J Cancer Res Clin Oncol. 142:2497–2502. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Wang D, Fu L, Shah W, Zhang J, Yan Y, Ge X, He J, Wang Y and Li X: Presence of high-risk HPV DNA but indolent transcription of E6/E7 oncogenes in invasive ductal carcinoma of breast. Pathol Res Pract. 212:1151–1156. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Yan C, Teng ZP, Chen YX, Shen DH, Li JT and Zeng Y: Viral etiology relationship between human papillomavirus and human breast cancer and target of gene therapy. Biomed Environ Sci. 29:331–339. 2016.PubMed/NCBI | |
|
El-Shinawi M, Mohamed HT, Abdel-Fattah HH, Ibrahim SA, El-Halawany MS, Nouh MA, Schneider RJ and Mohamed MM: Inflammatory and Non-inflammatory Breast Cancer: A potential role for detection of multiple viral DNAs in disease progression. Ann Surg Oncol. 23:494–502. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Fimereli D, Gacquer D, Fumagalli D, Salgado R, Rothé F, Larsimont D, Sotiriou C and Detours V: No significant viral transcription detected in whole breast cancer transcriptomes. BMC Cancer. 15:1472015. View Article : Google Scholar : PubMed/NCBI | |
|
Ali SH, Al-Alwan NA and Al-Alwany SH: Detection and genotyping of human papillomavirus in breast cancer tissues from Iraqi patients. East Mediterr Health J. 20:372–377. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Piana AF, Sotgiu G, Muroni MR, Cossu-Rocca P, Castiglia P and De Miglio MR: HPV infection and triple-negative breast cancers: An Italian case-control study. Virol J. 11:902014. View Article : Google Scholar | |
|
Ohba K, Ichiyama K, Yajima M, Gemma N, Nikaido M, Wu Q, Chong P, Mori S, Yamamoto R, Wong JE and Yamamoto N: In vivo and in vitro studies suggest a possible involvement of HPV infection in the early stage of breast carcinogenesis via APOBEC3B induction. PLoS One. 9:e977872014. View Article : Google Scholar : PubMed/NCBI | |
|
Hong L and Tang S: Does HPV 16/18 infection affect p53 expression in invasive ductal carcinoma? An experimental study. Pak J Med Sci. 30:789–792. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Liang W, Wang J, Wang C, Lv Y, Gao H, Zhang K, Liu H, Feng J, Wang L and Ma R: Detection of high-risk human papillomaviruses in fresh breast cancer samples using the hybrid capture 2 assays. J Med Virol. 85:2087–2092. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Herrera-Goepfert R, Vela-Chávez T, Carrillo-García A, Lizano-Soberón M, Amador-Molina A, Oñate-Ocaña LF and Hallmann RSR: High-risk human papillomavirus (HPV) DNA sequences in metaplastic breast carcinomas of Mexican women. BMC Cancer. 13:4452013. View Article : Google Scholar : PubMed/NCBI | |
|
Pereira Suarez AL, Lorenzetti MA, Gonzalez Lucano R, Cohen M, Gass H, Martinez Vazquez P, Gonzalez P, Preciado MV and Chabay P: Presence of human papilloma virus in a series of breast carcinoma from argentina. PLoS One. 8:e616132013. View Article : Google Scholar : PubMed/NCBI | |
|
Hossein R, Behzad S, Tahar M and Azadeh NA: Prevalence of human papillomavirus genotypes associated with cervical and breast cancers in Iran. Monoclon Antib Immunodiagn Immunother. 32:399–403. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Herrera-Romano L, Fernández-Tamayo N, Gómez-Conde E, Reyes-Cardoso JM, Ortiz-Gutierrez F, Ceballos G, Valdivia A, Piña P and Salcedo M: Absence of human papillomavirus sequences in epithelial breast cancer in a Mexican female population. Med Oncol. 29:1515–1517. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Hansen BT, Nygård M, Falk RS and Hofvind S: Breast cancer and ductal carcinoma in situ among women with prior squamous or glandular precancer in the cervix: A register-based study. Br J Cancer. 107:1451–1453. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Glenn WK, Heng B, Delprado W, Iacopetta B, Whitaker NJ and Lawson JS: Epstein-Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer. PLoS One. 7:e487882012. View Article : Google Scholar : PubMed/NCBI | |
|
Baltzell K, Buehring GC, Krishnamurthy S, Kuerer H, Shen HM and Sison JD: Limited evidence of human papillomavirus on breast tissue using molecular in situ methods. Cancer. 118:1212–1220. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Hedau S, Kumar U, Hussain S, Shukla S, Pande S, Jain N, Tyagi A, Deshpande T, Bhat D, Mir MM, et al: Breast cancer and human papillomavirus infection: No evidence of HPV etiology of breast cancer in Indian women. BMC Cancer. 11:272011. View Article : Google Scholar : PubMed/NCBI | |
|
Khammapirad T, Prueksadee J, Diaz-Arrastia C, Botting SK, Leonard M, Bonoan-Deomampo L and Eltorky MA: Intraductal papilloma of the breast in association with preoncogenic gene of breast cancer. Asian Pac J Trop Biomed. 1:161–163. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Cazzaniga M, Gheit T, Casadio C, Khan N, Macis D, Valenti F, Miller MJ, Sylla BS, Akiba S, Bonanni B, et al: Analysis of the presence of cutaneous and mucosal papillomavirus types in ductal lavage fluid, milk and colostrum to evaluate its role in breast carcinogenesis. Breast Cancer Res Treat. 114:599–605. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Fan CL, Zhou JH and Hu CY: Expression of human papillomavirus in mammary carcinoma and its possible mechanism in carcinogenesis. Virol Sin. 23:226–231. 2008. View Article : Google Scholar | |
|
Akil N, Yasmeen A, Kassab A, Ghabreau L, Darnel AD and Al Moustafa AE: High-risk human papillomavirus infections in breast cancer in Syrian women and their association with Id-1 expression: A tissue microarray study. Br J Cancer. 99:404–407. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Liang W and Tian H: Hypothetic association between human papillomavirus infection and breast carcinoma. Med Hypotheses. 70:305–307. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Duò D, Ghimenti C, Migliora P, Pavanelli MC, Mastracci L and Angeli G: Identification and characterization of human papillomavirus DNA sequences in Italian breast cancer patients by PCR and line probe assay reverse hybridization. Mol Med Rep. 1:673–677. 2008.PubMed/NCBI | |
|
De Cremoux P, Thioux M, Lebigot I, Sigal-Zafrani B, Salmon R and Sastre-Garau X: No evidence of Human papillomavirus DNA sequences in invasive breast carcinoma. Breast Cancer Res Treat. 109:55–58. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Choi YL, Cho EY, Kim JH, Nam SJ, Oh YL, Song SY, Yang JH and Kim DS: Detection of human papillomavirus DNA by DNA chip in breast carcinomas of Korean women. Tumor Biol. 28:327–332. 2007. View Article : Google Scholar | |
|
Yasmeen A, Bismar TA, Dekhil H, Ricciardi R, Kassab A, Gambacorti-Passerini C and Moustafa AE Al: ErbB-2 receptor cooperates with E6/E7 oncoproteins of HPV type 16 in breast tumorigenesis. Cell Cycle. 6:2939–2943. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Yasmeen A, Bismar TA, Kandouz M, Foulkes WD, Desprez PY and Al Moustafa AE: E6/E7 of HPV type 16 promotes cell invasion and metastasisof human breast cancer cells. Cell Cycle. 6:2038–2042. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Lindel K, Forster A, Altermatt HJ, Greiner R and Gruber G: Breast cancer and human papillomavirus (HPV) infection: No evidence of a viral etiology in a group of Swiss women. Breast. 16:172–177. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Kroupis C, Markou A, Vourlidis N, Dionyssiou-Asteriou A and Lianidou ES: Presence of high-risk human papillomavirus sequences in breast cancer tissues and association with histopathological characteristics. Clin Biochem. 39:727–731. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Tsai JH, Tsai CH, Cheng MH, Lin SJ, Xu FL and Yang CC: Association of viral factors with non-familial breast cancer in Taiwan by comparison with non-cancerous, fibroadenoma, and thyroid tumor tissues. J Med Virol. 75:276–281. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
de Villiers E-M, Sandstrom RE, zur Hausen H and Buck CE: Presence of papillomavirus sequences in condylomatous lesions of the mamillae and in invasive carcinoma of the breast. Breast Cancer Res. 7:R1–R11. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Widschwendter A, Brunhuber T, Wiedemair A, Mueller-Holzner E and Marth C: Detection of human papillomavirus DNA in breast cancer of patients with cervical cancer history. J Clin Virol. 31:292–297. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Afshar RM, Balar N, Mollaei HR, Arabzadeh SA and Iranpour M: Low prevalence of human papilloma virus in patients with breast cancer, Kerman; Iran. Asian Pac J Cancer Prev. 19:3039–3044. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Ahangar-Oskouee M, Shahmahmoodi S, Jalilvand S, Mahmoodi M, Ziaee AA, Esmaeili HA, Keshtvarz M, Pishraft-Sabet L, Yousefi M, Mollaei-Kandelous Y, et al: No detection of ‘High-risk’ human papillomaviruses in a group of Iranian women with breast cancer. Asian Pac J Cancer Prev. 15:4061–4065. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Antonsson A, Spurr TP, Chen AC, Francis GD, McMillan NA, Saunders NA, Law M and Bennett IC: High prevalence of human papillomaviruses in fresh frozen breast cancer samples. J Med Virol. 83:2157–2163. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Bakhtiyrizadeh S, Hosseini SY, Yaghobi R, Safaei A and Sarvari J: Almost complete lack of human cytomegalovirus and human papillomaviruses genome in benign and malignant breast lesions in Shiraz, Southwest of Iran. Asian Pac J Cancer Prev. 18:3319–3324. 2017.PubMed/NCBI | |
|
Cavalcante JR, Pinheiro LGP, de Almeida PRC, Ferreira MVP, Cruz GA, Campelo TA, Silva CS, Lima LNGC, Oliveira BMK, Lima LM, et al: Association of breast cancer with human papillomavirus (HPV) infection in northeast brazil: Molecular evidence. Clinics. 73:6–11. 2018. View Article : Google Scholar | |
|
Chang P, Wang T, Yao Q, Lv Y, Zhang J, Guo W, Wang L and Chen J: Absence of human papillomavirus in patients with breast cancer in north-west China. Med Oncol. 29:521–525. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Damin AP, Karam R, Zettler CG, Caleffi M and Alexandre CO: Evidence for an Association of human papillomavirus and breast carcinomas. Breast Cancer Res Treat. 84:131–137. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
de León DC, Montiel DP, Nemcova J, Mykyskova I, Turcios E, Villavicencio V, Cetina L, Coronel A and Hes O: Human papillomavirus (HPV) in breast tumors: prevalence in a group of Mexican patients. BMC Cancer. 9:262009. View Article : Google Scholar : PubMed/NCBI | |
|
Doosti M, Bakhshesh M, Zahir ST, Shayestehpour M and Karimi-Zarchi M: Lack of evidence for a relationship between high risk human papillomaviruses and breast cancer in Iranian patients. Asian Pac J Cancer Prev. 17:4357–4361. 2016.PubMed/NCBI | |
|
ElAmrani A, Gheit T, Benhessou M, McKay-Chopin S, Attaleb M, Sahraoui S, El Mzibri M, Corbex M, Tommasino M and Khyatti M: Prevalence of mucosal and cutaneous human papillomavirus in Moroccan breast cancer. Papillomavirus Res. 5:150–155. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Fu L, Wang D, Shah W, Wang Y, Zhang G and He J: Association of human papillomavirus type 58 with breast cancer in Shaanxi province of China. J Med Virol. 87:1034–1040. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Gannon OM, Antonsson A, Milevskiy M, Brown MA, Saunders NA and Bennett IC: No association between HPV positive breast cancer and expression of human papilloma viral transcripts. Sci Rep. 5:180812015. View Article : Google Scholar : PubMed/NCBI | |
|
Li J, Ding J and Zhai K: Detection of human papillomavirus DNA in patients with breast tumor in China. PLoS One. 10:e01360502015. View Article : Google Scholar : PubMed/NCBI | |
|
Mendizabal-Ruiz AP, Morales JA, Ramírez-Jirano LJ, Padilla-Rosas M, Morán-Moguel MC and Montoya-Fuentes H: Low frequency of human papillomavirus DNA in breast cancer tissue. Breast Cancer Res Treat. 114:189–194. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Salman NA, Davies G, Majidy F, Shakir F, Akinrinade H, Perumal D and Ashrafi GH: Association of high-risk human papillomavirus and breast cancer: A UK based Study. Sci Rep. 7:435912017. View Article : Google Scholar : PubMed/NCBI | |
|
Sigaroodi A, Nadji SA, Naghshvar F, Nategh R, Emami H and Velayati AA: Human papillomavirus is associated with breast cancer in the north part of Iran. ScientificWorldJournal. 2012:8371912012. View Article : Google Scholar : PubMed/NCBI | |
|
Tawfeik AM, Mora A, Osman A, Moneer MM, El-Sheikh N and Elrefaei M: Frequency of CD4+ regulatory T cells, CD8+ T cells, and human papilloma virus infection in Egyptian Women with breast cancer. Int J Immunopathol Pharmacol. 34:20587384209668222020. View Article : Google Scholar : PubMed/NCBI | |
|
Vernet-Tomas M, Mena M, Alemany L, Bravo I, De Sanjosé S, Nicolau P, Bergueiro A, Corominas JM, Serrano S, Carreras R and Lloveras B: Human papillomavirus and breast cancer: No evidence of association in a Spanish set of cases. Anticancer Res. 35:851–856. 2015.PubMed/NCBI | |
|
Wang T, Zeng X, Li W, Zhu H, Wang G, Liu X, Lv Y, Wu J, Zhuang X, Zhang J, et al: Detection and analysis of human papillomavirus (HPV) DNA in breast cancer patients by an effective method of HPV capture. PLoS One. 9:e903432014. View Article : Google Scholar : PubMed/NCBI | |
|
Tufanaru C, Munn Z, Stephenson M and Aromataris E: Fixed or random effects meta-analysis? Common methodological issues in systematic reviews of effectiveness. Int J Evid Based Healthc. 13:196–207. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Gupta I, Jabeen A, Al-Sarraf R, Farghaly H, Vranic S, Sultan AA, Al Moustafa AE and Al-Thawadi H: The co-presence of high-risk human papillomaviruses and Epstein-Barr virus is linked with tumor grade and stage in Qatari women with breast cancer. Hum Vaccin Immunother. 17:982–989. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Nagi K, Gupta I, Jurdi N, Jabeen A, Yasmeen A, Batist G, Vranic S and Al-Moustafa AE: High-risk human papillomaviruses and Epstein-Barr virus in breast cancer in Lebanese women and their association with tumor grade: A molecular and tissue microarray study. Cancer Cell Int. 21:3082021. View Article : Google Scholar : PubMed/NCBI | |
|
Habyarimana T, Attaleb M, Mazarati JB, Bakri Y and El Mzibri M: Detection of human papillomavirus DNA in tumors from Rwandese breast cancer patients. Breast Cancer. 25:127–133. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Bønløkke S, Blaakær J, Steiniche T, Høgdall E, Jensen SG, Hammer A, Balslev E, Strube ML, Knakkergaard H and Lenz S: Evidence of no association between human papillomavirus and breast cancer. Front Oncol. 8:2092018. View Article : Google Scholar : PubMed/NCBI | |
|
Gupta I, Al-Sarraf R, Farghaly H, Vranic S, Sultan AA, Al-Thawadi H, Al Moustafa AE and Al-Farsi HF: Incidence of HPVs, EBV, and MMTV-Like Virus in Breast Cancer in Qatar. Intervirology. 65:188–194. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Favere K, Menon S, Valentine K, Bogers J and Vanden Broeck D: Human papillomavirus prevalence and breast carcinogenesis: A systematic review and meta-analysis of published literature. Eur J Gynaecol Oncol. 39:160–173. 2018. | |
|
Simões PW, Medeiros LR, Simões Pires PD, Edelweiss MI, Rosa DD, Silva FR, Silva BR and Rosa MI: Prevalence of human papillomavirus in breast cancer: A systematic review. Int J Gynecol Cancer. 22:343–347. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Jalilvand S, Shoja Z and Hamkar R: Human papillomavirus burden in different cancers in Iran: A systematic assessment. Asian Pac J Cancer Prev. 15:7029–7035. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Sokal DC, Vach TH, Nanda K, McCann MF, Weiner DH, Drobnes C, Rochanawutanon M, Duc NB and Loan ND: Quinacrine sterilization and gynecologic cancers: A case-control study in northern Vietnam. Epidemiology. 21:164–171. 2010. View Article : Google Scholar : PubMed/NCBI |
