Cervical carcinoma arises from normal cervical epithelium through the progressive development of low grade and high grade cervical intraepithelial lesions CINs , where hrHPV infection plays a major causative role Figure 1.
The hrHPV infection into the cervical epithelium results in host genome alterations, leading to the silencing of various tumor-suppressor factors on one hand, and inducing aberrant functioning of various tumor-promoting factors on the other.
The imbalance and instability caused by various hrHPV-derived oncogenic factors into the host genome of the cervical epithelial cells drive neoplastic progression over the course of years. However, the severity of the outcomes towards CC development depends on the specific subtypes of the HPV.
To date, subtypes of HPV have been identified and categorized as low, medium, and high-risk types [ 19 ]. While the low and medium-risk subtypes bear low potential towards malignant transformation, the high-risk subtypes, particularly type 16 and 18, are the major promoters of neoplastic transformation.
Enhanced telomerase activity is known to be associated with epithelial cell immortalization and tumorigenesis, and hrHPV-E6 is known to activate telomerase activity in the cervical epithelium [ 5 , 21 ]. Thus, the oncogenic E6 and E7 components of the HPV genome have the ability to reprogram the host genome, proteome, and intracellular signaling network in the cervical epithelial niche in order to sustain and promote viral oncogenesis. Cervical cancer development, prevention, and treatment.
Invasive cervical cancer development from normal to progressive cervical intraepithelial neoplasia CIN through high-risk human papilloma virus hrHPV oncogenesis and host genome alterations.
Available interventions in preventing and treating cervical cancer have also been shown. Molecular pathogenesis of HPV-associated cervical cancer. Multiple nuclear and mitochondrial genetic alteration pathways leading to cervical cancer progression and racial health disparities.
E6, E7: oncogenic HPV molecules. To date, several molecular alterations have been documented in CC. On the other hand, the CC suppressor role of miRa, miR, mirp, and mir were also demonstrated [ 29 , 30 , 31 , 32 ]. In addition, this study identified HPV integration breakpoints in In addition to these molecular alterations, chromosomal amplifications in chr. Of note, the 3q26 locus is linked to the telomerase gene, which is more frequently found to be altered in CIN lesions.
In addition, amplifications in closely located PD-L1 9p All of these studies identified various pathways associated with CC progression. However, a connecting link between these alterations and aggressive outcome in CC health disparities is yet to be established. Chromosomal and molecular aberrations driving human papilloma virus-associated cervical cancer initiation, development, and progression.
Inactivation of tumor suppressor genes TSGs , often achieved through promoter hypermethylation epigenetic changes , could initiate preneoplastic and neoplastic changes in cancers including CC through progressive cervical intraepithelial neoplasia development.
Epigenetic alterations are emerging as the critical determinants of cell fate in CC [ 38 , 39 ]. Classically, an epigenetic change will result in an addition of a methyl group on the 5-position of the cytosine 5mC base in a CpG dinucleotide, which will eventually be oxidized into 5-hydroxymethylcytosine 5-hmc , a more stable indicator of methylation state [ 40 ]. Accumulation of these methylation signatures in CpG-rich regions around the transcriptional start site TSS of various genes leads to chromatin organization, which alters transcriptional activity in a locus-specific manner [ 40 ].
Utilizing pyrosequencing and targeted next generation bisulfite sequencing, a recent study of liquid-based cytology specimens identified a three-gene methylation signature including SOX1 , DCC , and EPB41L3 in CC subjects [ 47 ] Figure 3. Employing unbiased genome-wide DNA methylation profiling and comprehensive stepwise verification and validation studies using in vitro and patient-derived samples, another study identified three promising methylation markers, GHSR , SST , and ZIC1 , associated with a chromosome 3q gain for the detection of cervical preneoplasia [ 48 ].
Other than epigenetic alterations, earlier studies have also demonstrated frequent loss of chromosomal regions 2q, 3p, 4p, 5q, 6q, 11q, 13q, and 18q in CC Figure 3 [ 6 , 34 , 35 , 36 ].
Thus, emerging studies have identified various molecular aberrations that could be associated with CC development and progression and may potentially be useful in biomarker and therapeutic development. In addition, their utility in the context of CC health racial disparities should also be tested. Reprogramming of mitochondrial mt dynamics and function are a hallmark of cancer, and alterations in mtDNA and their functional role in promoting tumor growth and metastases have been documented [ 49 , 50 , 51 ].
As opposed to the study described above, this group observed an increased mtDNA copy number in progressive cervical cancer samples compared to the corresponding normal controls [ 53 ]. This study demonstrated a progressive abundance of mtDNA alterations during CC progression from preneoplastic to neoplastic progression.
Genetic polymorphisms in various genes have been linked to the risk of development of various cancers [ 55 ]. In recent studies, polymorphic variants of various human leukocyte antigen HLA molecules have been linked to the development of CC [ 55 ]. Another study suggested a potential association between MBL2 gene exon1 polymorphisms and an increased risk of CC development [ 57 ]. The onset and development of CC is preventable through regular screening strategies using hrHPV, Pap, and colposcopy alone or in combination [ 1 , 5 , 7 , 10 , 11 , 14 , 18 , 58 , 59 , 60 , 61 ].
These tests in combination can simultaneously detect hrHPV integration and associated preneoplastic changes in the normal cervical epithelium at the very early stages.
Two doses for routine HPV vaccination are now recommended for females and males aged 9—14 [ 63 , 64 ]. These vaccines for example, Cervarix are used against hrHPV subtypes 16 and 18 in the majority of cases [ 64 ].
The quadrivalent vaccine against HPV-6, 11, 16, and 18 is Gardasil; the novel nanovalent one is known as Gardasil 9, which targets HPV-6, 11, 16, 18, 31, 33, 45, 52, and 58 [ 64 , 65 , 66 ]. Of note, HPV vaccines do not offer protection for individuals with existing and stable infections.
Moreover, these vaccines cannot protect against all HPV subtypes. Thus, women should be screened periodically for CC detection and follow specific and recommended guidelines. Abnormalities in squamous and glandular cells are considered separately in the BRS. These squamous cells do not appear completely normal, but there is uncertainty about the nature of the cellular changes, which could be related to hrHPV infection or other factors. The second category refers to atypical squamous cells, with a possibility of a high-grade squamous intraepithelial lesion ASC-H.
On the other hand, cells harboring mild dysplastic changes in the cervical epithelium caused due to HPV integration are regarded as low-grade squamous intraepithelial lesions LGSILs. In addition to cervical biopsies, endocervical curettages are also performed in certain clinical situations, including an unsatisfactory colposcopy following low-grade intraepithelial lesion, colposcopy evaluation of high-grade squamous intraepithelial lesion, and evaluation of all subcategories of atypical glandular cell cytology.
Women diagnosed with CIN-2 or more advanced lesions would receive further treatment depending on age, pregnancy status, and fertility situation. The treatment options include loop electrosurgical excision procedure LEEP , cryotherapy low grade CINs , laser therapy, and conization Figure 1 [ 9 , 10 , 17 , 58 , 68 ]. If not screened periodically followed by preventive treatment in the pre-cancer stages, cervical cancer may develop eventually.
In early stages of CC, surgery is the treatment choice. The standard of care in most progressive CC involves systemic platinum-based chemotherapy and radiotherapy in combination Figure 1 [ 2 , 5 , 21 , 33 , 69 ]. Immunomodulatory vaccination is another choice for effectively treating hrHPV-integrated CC subjects, which can be used alone or in combination with chemoradiation therapy.
It is generated in a gram-positive bacterium Listeria monocytogenes and engineered to express HPVE7 and has shown promising therapeutic efficacy [ 70 ] Figure 1. GN is another therapeutic vaccine harboring Mycobacterium bovis heat shock protein Hsp65 covalently linked to an entire HPVE7 sequence [ 71 , 72 ]. This vaccine has elicited anti-tumor response and also demonstrated activity against CIN lesions. The incidence of CC and associated mortality has been reduced appreciably with the implementation of hrHPV and Pap test-based screening strategies.
This socioeconomic stress factor puts these women at higher risk for CC development in their life time. Adequate measures and initiatives should be taken in a timely manner to screen these underserved women to prevent CC onset.
Numerous studies as described above and depicted in Figure 2 and Figure 3 have identified different types of nuclear and mitochondrial genetic alterations in CC in general.
However, the identification and characterization of the molecular biological pathways distinctively driving aggressive outcomes in racially disparate populations and leading to higher mortality have yet to be established. Future studies in these directions are warranted to develop clinically applicable preventive and therapeutic strategies for better CC management as are being developed for various other cancers in this era of precision medicine [ 80 , 81 , 82 ].
Among them, the most notorious are smoking, immunodeficiency, long term use of oral contraceptives, promiscuous behavior and having more than two pregnancies. A family history of CC and other descriptive characteristics, obesity and poor diet are also associated with CC [ 19 , 20 , 21 , 22 ]. Although in Serbia there is an organized CC screening program and the HPV vaccine is recommended and available for purchase, CC still remains one of the most prevalent malignancies.
According to data from the last available national registry in , it was the fourth most common cancer among women in Central Serbia [ 23 ]. In , it was assessed that it causes about new cases and deaths annually. In addition, Serbia has the highest age-standardized CC mortality rates when compared with other Southeast European countries [ 2 ].
The idea was to identify potential target groups for the implementation of customized health promotion programs. The study was designed as a cross-sectional survey conducted between December and March All subjects were informed that participation in the study was voluntary and that by completing the questionnaire the consent for publication was given.
It was made clear that the data collected would remain anonymous. A total of questionnaires were distributed and fully completed, valid questionnaires were included in the study. Data were collected using a semi-structured questionnaire specially created for this investigation.
It was a self-administered questionnaire with three distinct sections Supplement File 1. In addition, participants were asked if they ever had sexual intercourse and, if yes, how many sexual partners they had had. CC knowledge was evaluated by a composite score estimated using a total of 18 items regarding risk and protective factors, preventive measures and the outcome of CC. Participants had three possible response options regarding proposed factors protective factor, risk factor and do not know and correct answers were coded with either one or two points, deepening factor significance.
The maximum number of points was All questions were based on data from the relevant literature and information provided by the American Cancer Society [ 14 , 15 , 16 ]. The remaining three items were related to HPV vaccination. Subjects were asked to indicate if they have heard about the HPV vaccine.
If the answer was positive, they then answered when the best time to get the HPV vaccine is and if the HPV vaccine is available in Serbia. Thirteen multiple choice answers, from three categories of source personal contact, organized health education OHE and media were offered. The opportunity to declare not having any knowledge was also given. Data are presented as the mean and standard deviation SD or as frequencies and proportions. Comparison of the mean values between two groups was done using t -tests or Mann—Whitney tests depending on data distribution, while the mean values between the three groups were compared using either ANOVA or Kruskal—Wallis tests.
The chi-squared test was used for the comparison of categorical variables. All statistical analyses were performed using R software, version 3. Overall, participants completed the whole questionnaire, meaning that the response rate was The average age of the study population was Their other socio-demographic characteristics are presented in Table 1. As described in the methodology, the knowledge about CC was evaluated using a composite score. It was established that the average score in our students was Likewise, having a father with high education meant having higher score Table 2.
Thus, participants with high and middle incomes demonstrated higher scores Table 2. Hohd On the other hand, no significant difference was proven between women that had sexual experience and those who did not Table 2. It is correct. The total number of participants that had heard of HPV infection was When it comes to HPV vaccine, the overall awareness was quite low The other two questions about HPV vaccination were correctly answered by only a small number of subjects.
Of those who declared that they were aware of HPV and the vaccine, only 37 knew when the best time to get the HPV vaccine is and 48 knew that it is available in Serbia. No difference between distinct demographic groups was established Table 3. The media was listed as the dominant source of information about the investigated topics by of the examined students. The other two categories, organized health education OHE and personal contact, were reported as sources by and students, respectively.
Two hundred and fifty-five subjects declared having no knowledge about the investigated topics. The knowledge score was significantly higher in subjects that received information from any of the three source categories compared to subjects who denied receiving information from those particular categories Table 4. A similar relationship is noted between information sources and HPV awareness. Among the students who knew about HPV, significantly more reported acquiring information through each of the source categories vs.
Prevention is especially important in oncology, since cancer is one of the biggest public health issues in the modern world. Paradoxically, despite being highly suitable for thriving preventive programs, CC still represents the most common gynecological cancer worldwide [ 1 ].
Therefore, public education is needed for a better understanding of CC, its risk factors and for better disease prevention. Such education programs are only efficient when planned with carefully selected target groups.
Aiming to define possible groups for these education programs in Serbia, in this article, we analyzed the knowledge and awareness of first-year female students about CC and HPV. Our students demonstrated decent knowledge about CC, with the mean score being more than half of the total possible score. This discrepancy can be explained by differences in the study population, since our research included only college students, the future intellectual elite of the state.
Furthermore, a good share of our participants had affiliation with the medical profession, which greatly contributed to a higher CC knowledge level. In that manner, we proved that subjects involved in medical studies or those that attended medical high school had the highest knowledge about CC.
Other authors also confirmed that medical students are highly educated on this matter [ 27 , 28 ], which is understandable and very commendable, as they represent the leaders of further education of the general public about CC. In accordance with the previous interpretation, the results of another Serbian study showed that both students of a secondary medical school and midwives who had finished at that same school had significantly better knowledge than patients [ 29 ].
Apart from education, we also identified good financial status, living in urban areas and having parents with higher education as factors that contribute to better knowledge about CC. This means that higher socio-economic status is associated with a better health standard and can explain the fact that the highest prevalence of CC is seen in underdeveloped countries [ 1 ].
However, data from relevant studies are inconsistent regarding this matter, occasionally showing low knowledge about CC even in people from developed countries.
In Romania, even though the majority of interviewed women had heard of HPV, the level of knowledge was low, especially about risk factors for infection [ 30 ]. Likewise, Greek adolescents were also insufficiently informed about risk factors and protection methods against CC [ 31 ].
A similar situation is also recorded in Hungary and Slovenia [ 32 , 33 ]. The inconsistency of the results from different studies was also noted regarding the association between relationship status and knowledge about CC. While in our study, students in relationship had a higher CC-KS, there are other studies in which being single was associated with knowledge about CC screening [ 34 ].
Despite relatively good knowledge about CC in the investigated population, HPV awareness was quite low. Research performed in Slovenia [ 33 ] that included women of a wide range of ages and research that included adolescents from Greece [ 31 ] also noted low awareness of HPV.
On the other hand, studies in the UK [ 35 ] and in neighboring Romania [ 30 ] showed that between two thirds and three quarters of questioned women had heard about HPV. Advances in radiotherapy technology, such as intensity-modulated radiotherapy, have resulted in less treatment-related toxicity for women with locally-advanced disease. For women with metastatic or recurrent disease, the overall prognosis remains poor; nevertheless, the incorporation of the anti-VEGF agent bevacizumab has been able to extend overall survival beyond 12 months.
Preliminary results of novel immunotherapeutic approaches, similarly to other solid tumours, have shown promising results so far. The L1 major capsid protein of human papillomavirus type 11 recombinant virus-like particles interacts with heparin and cell-surface glycosaminoglycans on human keratinocytes.
Kim, K. Blatt, and M. The effects of interferon on the expression of human papillomavirus oncogenes. Kim, J. Wright, and S. Cost-effectiveness of alternative triage strategies for atypical squamous cells of undetermined significance. Kiviat, N. Specific human papillomavirus types as the causal agents of most cervical intraepithelial neoplasia: implications for current views and treatment.
Kleter, B. Schrauwen, A. Molijn, S. Sastrowijoto, J. TerSchegget, J. Lindeman, B. Ter Harmsel, M. Burger, and W. Development and clinical evaluation of a highly sensitive PCR-reverse hybridization line probe assay for detection and identification of anogenital human papillomavirus.
Koopmanschap, M. Habbema, and K. Cervical cancer screening: attendance and cost-effectiveness. Int J. Cancer 45 : Kurman, R. Henson, A. Herbst, K. Noeller, and M. Interim guidelines for management of abnormal cervical cytology.
The National Cancer Workshop. Lee, J. Wilhelm, L. Kuan, D. Ellison, X. Lei, S. Oh, and S. AutoPap system performance is screening for low prevalence and small cell abnormalities. Lee, K. Ashfaq, G. Birdsong, M. Corkill, K. McIntosh, and S. Comparison of conventional Papanicolaou smears and a fluid-based, thin-layer system for cervical cancer screening.
Lizard, G, M. Roignot, and P. Lonquet, M. Beaudenon, and G. Lorincz, A. Lancaster, and G. Cloning and characterization of the DNA of a new human papillomavirus from a woman with dysplasia of the uterine cervix. Quinn, W. A new type of papillomavirus associated with cancer of the uterine cervix. Temple, R. Kurman, A. Jenson, and W. Oncogenic association of specific human papillomavirus types with cervical neoplasia. JNCI 79 : Quinn, M.
Goldsborough, P. McAllister, and G. Human papillomavirus type a new virus detected in cervical cancers. Goldsborough, B. Schmidt, and G. Cloning and partial DNA sequencing of two new human papillomavirus types associated with condylomas and low-grade cervical neoplasia. Association of human papillomavirus with gynecological cancer.
Reid, A. Jenson, M. Greenberg, W. Lancaster, and R. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Magnusson, P. Lichtenstein, and U. Heritability of cervical tumors. Cancer 88 : Mandelblatt, J. Lawrence, S. Womack, D. Jacobson, B. Yi, Y. Hwang, K. Gold, J. Barter, and K. Benefits and costs of using HPV testing to screen for cervical cancer.
Manos, M. Kinney, L. Hurley, M. Sherman, J. Shieh-Ngai, R. Ramsey, B. Fetterman, J. Hartinger, K. McIntosh, G. Pawlik, and R. Identifying women with cervical neoplasia: Using human papillomavirus DNA testing for equivocal Papanicolaou results. Matsukura, T. Molecular cloning of a novel human papillomavirus type 58 from an invasive cervical carcinoma.
Meyers, C. Frattini, J. Biosynthesis of human papillomavirus from a continuous cell line upon epithelial differentiation. Science : Moscicki, A. Palefsky, G. Smith, S. Siboshski, and G.
Variability of human papillomavirus DNA testing in a longitudinal cohort of young women. Munoz, N. Bosch, K. Shah, and A. The epidemiology of cervical cancer and human papillomavirus. Scientific Publication Naghashfar, Z. Rosenshein, A. Lorincz, J. Buscema, and K. Characterization of human papillomavirus type 45, a new type related virus of the genital tract. Nobbenhuis, M. Meijer, A. Rozendaal, F. Voorhoost, E. Risse, R. Verheijen, and T. Addition of high-risk HPV testing improves the current guidelines on follow-up after treatment for cervical intraepithelial neoplasia.
Cancer 84 : Nuovo, G. Crum, E. Levine, and S. Isolation of a novel human papillomavirus type 51 from a cervical condyloma. Jablonska, and G. HPV-associated intraepithelial neoplasia of external genitalia. Okamoto, A. Woodworth, K. Yen, J. Chung, S. Isonishi, T. Nikaido, T. Kiyokawa, H. Seo, Y. Kitahara, K. Ochiai, and T. Combination therapy with podophyllin and vidarabine for human papillomavirus positive cervical intraepithelial neoplasia.
Ostor, A. Natural history of cervical intraepithelial neoplasia: a critical review. Papanicolaou, G. A survey of actualities and potentialities of exfoliative cytology in cancer diagnosis. Philips, D. Smoking-related DNA adducts in human cervical biopsies. IARC Sci. Quint, W. Scholte, L. Van Doorn, B. Kleeter, P. Smits, and J. Razzaque, A. Williams, J. Wang, and J. Reid, R.
Greenberg, A. Husain, J. Willett, Y. Daoud, G. Temple, C. Stanhope, A. Sherman, G. Phibbs, and A. Sexually transmitted papillomavirus infections. The anatomic distribution and pathogenic grade of neoplastic lesions associated with different viral types. Rho, J.
Roy-Burman, H. Kim, E. Matsukura, and J. Nucleotide sequence and phylogenetic classification of human papillomavirus type Richart, R. Cervical intraepithelial neoplasia. Ries, L.
Eisner, C. Hankey, B. Miller, L. Glegg, and B. SEER cancer statistics review National Cancer Institute, Bethesda, Md. Roden, R. Lowy, and J. Papillomavirus is resistant to dessication. Romano, N. Romano, E. Viviano, F. Vitale, M. Viaalfrate, A. Perna, and F. Rare association of human herpesvirus 6 DNA with human papillomavirus DNA in cervical smears of women with normal and abnormal cytologies. Ronnett, B. Manos, J.
Ransley, B. Fetterman, W. Hurley, J. Ngai, R. Kurman, and M. Atypical glandular cells of undetermined significance AGUS : cytopathologic features, histopathologic results, and human papillomavirus DNA detection.
Ryan, M. Stastny, R. Remmers, M. Pedigo, L. Cahill, and W. PapNet-directed rescreening of cervicovaginal smears: a study of cases of atypical squamous cells of undetermined significance. Sapp, M. Volpers, M.
Muller, and R. Organization of the major and minor capsid proteins in human papillomavirus type 33 virus-like particles. Sawaya, G. Kerlikowske, G. Gildengorin, and A.
Incidence of Pap test abnormalities within 3 years of a normal Pap test—United States, Schiffman, M. Hildesheim, M. Sherman, M. Bratti, S. Wacholder, M. Alfaro, M. Hutcinson, J. Morales, M. Greenberg, and A. Results from women in a high-risk province of Costa Rica. Sheets, E. Constantine, S. Sinisco, B. Dean, and E. Colposcopically-directed biopsies provide a basis for comparing the accuracy of ThinPrep and Papanicoloau smears. Shen, C. Ho, S. Chang, M. Yen, H.
Ng, E. Huang, and C. High rate of concurrent genital infections with human cytomegalovirus and human papillomaviruses in cervical cancer patients. Mango, D. Kelly, G. Paull, V. Ludin, C. Copeland, D. Solomon, and M. PapNet analysis of reportedly negative smears preceeding the diagnosis of a high grade squamous intraepithelial lesion or carcinoma. Schiffman, A. Lorincz, M. Manos, D. Scott, R. Kurman, N.
Kiviat, M. Stoler, A. Glass, and B. Toward objective quality assurance in cervical cytopathology: correlation of cytopathologic diagnoses with detection of high-risk human papillomavirus types.
Shimoda, K.
0コメント