AbstractHuman papillomavirus HPV is associated withcancer of the cer - PDF document

AbstractHuman papillomavirus (HPV) is associated withcancer of the cervix uteri, penis, vulva, vagina, anus andoropharynx. However, the role of HPV infection in urologicaltumors is not yet clarified. HPV appears not to play a majorcausative role in renal and testicular carcinogenesis.However, HPV infection should be kept in mind regardingcasesofprostate cancer, as well as in a sub-group of patients 2513 Correspondence to: Renate Pichler, MD, FEBU, Medical UniversityInnsbruck, Department of Urology, Anichstreet 35, A-6020 Innsbruck,Austria. Tel: +43 (0)51250482156, Fax:+43 (0)51250428365, e-mail: ReviewThe Role of Human Papilloma Virus in Urological Malignancies, WEGENE BORENAandRENATE PICHLER 0250-7005/2015 $2.00+.40 HPV in Penile Cancercancers in men (13). Emerging evidence suggests that penilecancer follows two etiological pathways: those related to HPVinfection and those related to other factors, including phimosis,chronic inflammation, and lichen sclerosus (13). The findingsbased on a large number of studies evaluating the impact ofHPV incidence and penile cancer. In summary, HPV DNA hasbeen detected in 14%-100% of invasive penile carcinomas penile carcinomas()versus ISH], as well as on the type of tumor tissue storageversusparaffin-embedded tissue). A quantitative reviewof studies using PCR methods for HPV DNA detection foundHPV presence in 45.4% of invasive penile tumors afteradjusting for PCR primer, histological subtype, and year andwarty and 80% of basaloid tumors, but in only about one-thirdof keratinizing and verrucous tumors (15). Heideman detected HPV DNA in 55% of penile cancer (16), whileanother work from Chaux PCR in 35% of cases (17). However, a small study including31 patients measured HPV DNA in more than 80% of penilepositivity in patients with penile cancer (19).A meta-analysis (of 31 studies) examining the prevalenceof HPV subtypes in invasive penile tumors found that HPV-16 was the most common HPV type (60.2%), followed byHPV-18 (13.3%) and HPV types 6/11 (8.13%) (20).infection in penile cancer. Data from Bjorge the concept that HPV seropositivity is associated with higherrisk of developing penile cancer (21).In summary, most studies found a significant number ofpenile cancer cases to be associated with HPV infection. Acarcinogenesis might help planning intervention strategiessuch as vaccination against HPV infection.HPV in Prostate CancerSeveral serological- and tissue-based studies wereundertaken to elucidate differences in HPV presence inresults. Briefly, most studies found no difference in HPV . High-risk oncoproteins E6 and E7 interact with the cell cycle thereby inhibiting the progress from G1 to S phase. AbbreviatioGap 0, G 1=Gap 1, S= Synthesis, G 2=Gap 2, M= Mitosis, E6= HPV oncoprotein E6, p53= Protein 53, p21=Protein 21, CDK= Cyclin depkinases, E7= HPV oncoprotein E7, pRB= Retinoblastoma protein. HeideggerReview . Condyloma acuminatum 2, human papillomavirus (×10) (own data). Arrow, episomal pattern. . Episomal and integrative pattern of (×20) of the preputial epithelium in an asymptomatic man (own data). Thin arrow, integrative pattern.Thick arrow, episomal pattern. expression patterns between cancerous and non-cancerousprostate (reviewed in (23)). Tache

zy for exampledetected HPV DNA in 2% of both prostate adenoma andprostate cancer, moreover no difference in the seroprevalencecancer and non-cancerous prostate was found in this studysignificant role of HPV infection in prostatic disease inIranian patients (25). The Prostate Cancer Prevention Trialconducted a large prospective investigation of HPV types 16,18, and 31 in relation to risk of prostate cancer, including1232 patients. In line with previous studies, no associationswere observed for weak or strong HPV-16, HPV-18 or HPV-31 seropositivity and risk of prostate cancer (26).However, there also exist several studies that found adifferences in HPV expression between prostate cancer andbenign prostate: Already 15 years ago Serth significantly higher (0.02) copy numbers of HPV-16-E6indicating that oncogenic HPV-16 might contribute to thedevelopment of a subset of prostate tumors (27). In line withthis finding, Dillner also revealed a positive correlationbetween HPV seropositivity and prostate cancer risk (28). Inin 41% of prostate tumor biopsies and 20% of benignprostate tissue samples (29). Moreover, they showed that asignificant proportion of HPV-infected (74%) cases had aAnother recent study investigated the prevalence of HPVinfection and the prognostic impact for overall survival in aThereby, they found that overall survival was significantlyassociated with the nuclear expression of E7 protein andother clinicopathological factors, such as age greater than 72years, high nuclear grade, capsule infiltration, and highGleason score at diagnosis; on multivariate analysis, allexcept capsule infiltration were significantly independentprognostic factors for worse survival of patients with primaryIn summary, the HPV link to prostate cancer is stillHPV in Renal Cell Carcinoma Renal cell cancer is a very rare neoplasm, thus only fewstudies evaluated the pathogenetic role of HPV on renal cellcarcinogenesis. Different studies have shown thathigh risk for infection with virus HPV-related de novourogenital malignancies (31, 32). However, there is stillcontroversy regarding the exact prevalence of HPV in kidneycancer. Again, depending on the method used for HPVversusfor example interrogated data from 3,775 malignantneoplasms in the Cancer Genome Atlas database for thepresence of viral sequences using RNA-Seq analysis. One ofthe main findings in this study was the absence of transcribedDNA viral transcripts in some of the most prevalent humancancer types, including kidney cancer (34). Grce found no HPV DNA positivity in analyses of 28 renal cellcarcinomas by PCR using, two sets of consensus primers andspecific primer pairs for HPV types 16, 18, and 33 (35). Inaddition, no positive staining for HPV DNA was found in anynine papillary, and three chromophobe renal cell carcinomas,the renal pelvis and seven oncocytomas), supporting thedevelopment of benign and malignant renal tumors. In thisstudy, signal-amplified colorimetric ISH was performed onmicroarray sections using biotinylated probes for HPVIn contrast to these findings, Salehipoor confirmedhigh-risk HPV DNA positivity (types 16 and 18) ininvestigated 56 renal cell carcinomas for the presenceof HPV DNA (subtypes 6, 11, 16, 18, 31 and 33) andconclude

d that the presence of HPV DNA in these tumorsimplicated HPV viral infection in the etiology of kidneycancer as HPV positivity was found in 52% (38).The results regarding HPV incidence in renal cellcarcinoma remain controversial possibly depending on theHPV DNA detection method used.HPV in Testicular CancerTesticular cancer is a common neoplasm in men of youngerage. In 1984, Newell suggested for the first time thattesticular cancer might have a viral etiology since it exhibitssimilar characteristics to Hodgkin's lymphoma, arguing thatthe similar geographical distribution of both cancer typeswould point to viral etiology as the causative agent fortesticular cancer (39, 40). The viral theory was supported bycertain characteristics of testicular cancer itself, includingyoung age, as well as the increase in overexpression of wild-type p53 in many cases (41). In a large epidemiological study,only 6% of patients with testicular cancer tested positive forHPV type 16 (42). To investigate the transforming activity ofin vivo, Kondoh experiment with transgenic mice carrying HPV-16 E6 and E7open reading frames; they obtained five transgenic foundersand established three transgenic lineages, confirming testicular tumors of germ cell origin in mice of all three lineages. Theseresults suggest that E6 and E7 of HPV-16 have transformingactivity in vivoand preferential effects on germ cells in thetestis (43). In contrast to these findings, HPV genotype 16 andMeyts et al (44). Using real-time PCR employing GP5+/GP6+consensus HPV primers to examine the presence of HPV(n=23), none of the specimens displayed the presence of HPVDNA (45). A recent study confirmed that 155 patients withtesticular cancer had a high prevalence of semen infection withHPV (using fluorescence ISH) that worsened afterradiotherapy and chemotherapy, probably through theirimmunosuppressive action and the effect of a higherfurther.HPV in Urothelial Cancerhuman papilloma virus is still poorly understood. Theprevalence of high-risk HPV in bladder cancer ranges, for example, noticedthat HPV prevalence varies by region, by type of HPV DNAspecimen, as well as by PCR primers used (53). The highestprevalence of HPV positivity was found in Moroccanpatients, with an incidence of 52.4% (HPV-16 in 95.5% ofcancer samples) (54). Although HPV DNA presence appearsnot to play a major causative role in bladder cancer in thegeneral population, HPV infection should be kept in mind incarcinomas with squamous differentiation, neurogenicbladder, urothelial inverted papilloma or inverted papilloma55). In these cases, HPV serology may pave the way forbetter management and follow-up of patients and for optimalevaluation of HPV vaccination (56). However, howvaccination may induce the regression of bladder tumors atsuch mucosal sites has not been sufficiently examined.Interestingly, Domingos-Pereira orthotopic model expressing HPV-16 antigen E7 as a modelusing an adjuvant E7 polypeptide. Subcutaneous andintravaginal vaccination induced a high number of intravesicalT-cells, with confirmed tumor regression (57). In contrast to these findings, urothelial carcinomafollowing renal transplantation does not seem to beCurrently, only one Japanese study showed that patients w

ithHPV DNA positivity/p53 antibody had a significant worsesurvival rate, indicating a poor prognosis (59). Additionally,the data of a pilot study suggested a positive trend in theDNA (48). No recent trial proved any relationship betweenUsing urine samples for HPV detection by highly sensitivewas similar to the control group (3.6%) (60). No positivesignals for high-risk HPV (types 16 and 18) were confirmedby different studies n method using ISH for HPV detection(61-63). Alexander investigated 42 cases of squamoussquamous differentiation. HPV DNA and protein were notdetected in any case of bladder cancer by ISH at the DNAlevel and immunohistochemistry at the protein level (64).In summary, although many trials demonstrated a possibleconvincing evidence regarding bladder carcinogenesis is stilllacking. Additional studies to investigate the carcinogenicSummaryHPV is a recognized risk factor in penile cancer that has beendemonstrated in a large number of studies. Concerning otherurological malignancies, the role of HPV is not yet clear,however, in most studies HPV does not appear to benumbers, unicentric or retrospective study characteristics maypartly explain the differences in HPV detection rates amongthe studies. Moreover, the detection method used for HPVwas recently shown for the first time that the HPV epigeneticsignature is a better predictor of survival than HPV statusalone (65). Thus, further studies with larger patient collectivesConflicts of InterestThe Authors have no conflict of interest regarding this articleReferences 1de Villiers EM and Gunst K: Characterization of seven novelhuman papillomavirus types isolated from cutaneous tissue, butalso present in mucosal lesions. J Gen Virol 2Moscicki AB, Schiffman M, Kjaer S, and Villa LL: Chapter 5:Updating the natural history of HPV and anogenital cancer.Vaccine 24 3Doorbar J: Molecular biology of human papillomavirus infectionand cervical cancer. Clin Sci (Lond) 4Stanley MA: Epithelial cell responses to infection with humanpapillomavirus. Clin Microbiol Rev 5Hebner CM and Laimins LA: Human papillomaviruses: basicmechanisms of pathogenesis and oncogenicity. Rev Med VirolHeideggerReview 6Scheurer ME, Tortolero-Luna G, and Adler-Storthz K: Humanpapillomavirus infection: biology, epidemiology, and prevention.7Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR,and Stanley MA: The biology and life-cycle of humanpapillomaviruses. Vaccine 30 8Duensing S and Munger K: Mechanisms of genomic instabilitypapillomavirus oncoproteins. Int J Cancer 9Lacey CJ, Lowndes CM, and Shah KV: Chapter 4: Burden andmanagement of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine 24 10Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G,Mayrand MH, Dillner J, and Meijer CJ: Overview of humanpapillomavirus-based and other novel options for cervical cancerscreening in developed and developing countries. Vaccine 2611Heidegger I, Pichler R, Muller B, Klocker H, Oswald D, HaidB, Zelger B, Horninger W, and Oswald J: Is real-time PCR thecorrect method to evaluate the incidence of humanpapillomavirus in prepuces of asymptomatic boys and men?World J Urol 12Klinglmair G, Pichler R, Zelger B, Dogan HS, Becker T,Esterbauer J, Riccabona M, Loidl W, Hornin

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