From Infection to Malignancy: Viral Infections as Hidden Drivers of Cancer-A Systematic Review and Meta-analysis

Materials and Methods

Search Strategy

We performed a comprehensive search of published literature from three [3] major bibliographic databases (PubMed [RRID: SCR_004846], Scopus, and Web of Science), using each of the databases’ keyword search engines, covering the period January 1, 2000, to October 31, 2025 (approximately 25 years). In addition to searching with the combination of keywords “oncogenic virus” AND “cancer”, we also used the keyword combinations “HPV” OR “EBV” OR “HBV” OR “HCV”/ “KSHV” OR “HTLV-1” OR “viral infection” OR “malignancy”. In addition to these sources, a comprehensive review was performed of each citation reference list for all studies included in our initial review to further identify any relevant studies.

Inclusion and Exclusion Criteria

Inclusion Criteria

a) Human studies that described viral dissemination to tumoral tissues or evaluated the likelihood of developing cancer as a result of viral infection
b) Studies using observational (cohort, case-control, crosssectional) and interventional methods
c) Studies providing enough information to calculate the effect of viral infection on cancer risk (OR, RR).

Exclusion Criteria

a) Non-human or In Vitro studies.
b) Case reports, editorials, conference abstract, or reviews without primary data.
c) Studies lacking outcome measures or full text.

Data Extraction

The authors screened all studies meeting eligibility criteria. The authors extracted relevant information from these studies according to an established data extraction framework. The authors extracted the following data: name of first author; date of publication; type of research design; country/region(s) studied; number of subjects enrolled in each study; type(s) of virus(es) studied; method(s) used to identify virus(es); type(s) of cancer studied; and effects (e.g., Odds Ratios [ORs]; Relative Risk [RR]).

To avoid mistakes in data extraction, the author rechecked all extracted data on three separate occasions.

Quality Assessment

The authors used the Newcastle-Ottawa Scale (NOS) to evaluate the methodological quality of observational studies. Studies that had a NOS score of 7 or more were judged to be high quality. The author evaluated the risk of bias for each of the three domains: selection, comparability, and outcome/exposure.

Statistical Analysis

The author’s meta-analysis, which employs random effects models, utilized this methodology in its analysis, as well as a review of the output after the original analysis using R to confirm consistent results through RevMan v.5. Overall odds ratios (ORs) are presented with a 95% Confidence Interval (CI). The measure of statistical heterogeneity was calculated using the I² statistic, which was classified as moderate to high heterogeneity (when greater than 50%) and was assessed for potential bias using Egger’s Test of Regression and funnel plots.

Additional Comments on the Rigour of this Study: As a systematic review and meta-analysis, power analyses were not applicable. Statistical codes used in R can be provided upon request.

Protocol: No formal protocol was registered prospectively. This is acknowledged as limitations (Figure 1).

Results

Study Characteristics

In total, this systematic review and meta-analysis encompassed 152 studies that included 34 different countries, with a total of 78,463 patients involved in these studies. The available literature from these studies was distributed throughout multiple geographic areas, allowing for an increased ability to generalize the results from this review. The breakdown of studies by viral group is as follows:

Figure 1:Presents the PRISMA flow diagram of study selection. Initial search yield 3524 records, after duplicates screening, 152 studies met inclusion criteria.

a) HPV (Human Papillomavirus): 64 studies with 32,150 patient participants
b) EBV (Epstein-Barr Virus): 34 studies with 15,820 patient participants
c) HBV (Hepatitis B Virus): 22 studies with 10,645 patient participants
d) HCV (Hepatitis C Virus): 19 studies with 8,723 patient participants
e) KSHV (Kaposi’s Sarcoma-Associated Herpesvirus): 8 studies with 5,125 patient participants
f) HTLV-1 (Human T-Lymphotropic Virus Type 1): 5 studies with 6,000 patient participants

For all included studies, both PCR-based assays were the most commonly used method for viral detection (72%), followed by serological assays (18%) with ISH methods (10%). Well-controlled PCR assays have greater sensitivity and specificity for the detection of the viral DNA or RNA in cancer tissues than other methods, which may explain their widespread use in our studies (Table 1) (Figure 2).

Viral Prevalence and Cancer Association

Human Papilloma Virus (HPV): There is a significant positive association between Human Papillomavirus (HPV) and cervical cancer as shown by the strong and consistent relationship through the robust odds ratio (OR) of 8.75 (95% CI: 7.20-10.63), but there is some moderate heterogeneity (I² = 48%) present. Cervical cancer has been found to be associated with the pathways involving HPV E6 / E7. Additionally, the association between HPV and oropharyngeal cancer was given a pooled OR of 4.12 (95% CI: 3.20-5.31) in this cohort.

Figure 2:PRISMA flow diagram.

Table 1:Summarizes the characteristics of included studies highlighting the distribution of study count, patient number, cancer types and diagnostic modalities across virus group.

Epstein-Barr Virus (EBV): EBV was significantly associated with Nasopharyngeal Carcinoma (NPC) with an overall Odds Ratio (OR) of 6.18 (95% CI: 4.55-8.39), with a moderate to high level of heterogeneity (I²=52%). EBV was also found to be significantly associated with Burkitt lymphoma (OR=3.95; 95% CI=2.80-5.57).

Hepatitis B virus (HBV) and Hepatitis C viruse (HCV): There is a strong correlation between hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma (HCC). When compared to the uninfected population, the odds of developing (HCC) in those infected with HBV are 7.34 times greater (95% confidence interval (5.88-9.16)) with moderate heterogeneity (I² = 60%). With moderate heterogeneity (I² = 55%), the odds of developing HCC are roughly 4.89 (95% CI 3.95–6.05) times higher in the HCV-infected population.

Kaposi’s Sarcoma associated Herpesvirus (KSHV): KSHV had the largest association magnitude for any virus/cancer pair examined, with a pooled odds ratio of 9.15 (95% confidence interval: 6.78 to 12.34) for Kaposi’s Sarcoma (KS) and low heterogeneity (I² = 35%).

Human T- lymphotropic Virus Type 1 (HTLV-1): HTLV-1 was strongly associated with ATLL, with a pooled odds ratio of 6.42 (95% confidence interval: 4.10 to 10.05) and moderate heterogeneity (I² = 40%) (Table 2) (Figure 3).

Table 2:Meta-analysis pooled odds ratios.

Figure 3:Forest Plot of HPV – cervical cancer meta- analysis.

Figure 4:Global Prevalence Map of Oncogenic Viruses.

Discussion

The body of evidence received from this systematic review and meta-analysis demonstrates the interplay between different types of viruses and human cancers, demonstrating the complex interplay between HPV, EBV, HBV, HCV, KSHV and HTLV-1. Approximately 15– 20% of all worldwide cancers can be attributed to these viruses, either in terms of their ubiquity or in relation to their strong ability to cause cancerous changes [15]. As a result, using data collected from this systematic review and meta-analysis, we have provided a comprehensive view of how viruses play a role in causing cancer and what it means for the prevention, detection and treatment of cancers.

HPV and Cervical / Anogenital Cancer

The highest volume of investigations on an oncogenic virus has been performed on HPV, and amongst the 15 identified highrisk genotypes, 16 and 18 account for the largest number of cases of cervical cancer in the world. The most recent meta-analysis on the subject determined a pooled OR of 8.75 (95% CI: 7.20 - 10.63), confirming a robust causal relationship between HPV and cervical cancer. HPV has also been linked to oropharyngeal, anal, and penile cancers; for each malignancy, the pooled odds ratios range from 3.5 to 4.5, reflecting high risk. The primary method through which HPV causes cancers is through the actions of E6 and E7 proteins that inactivate the p53 and Rb tumor suppressor proteins, leading to genetic instability, disruption of cell cycle checkpoints and inhibition of programmed cell death. Additionally, HPV down-modulates the host immune response through altering the interferon signaling pathway and down-regulating antigen presentation, leading to persistent infection and malignant progression. There has been overwhelming evidence supporting the effectiveness of preventive measures, namely HPV vaccination, at decreasing the prevalence of HPV infection and precancerous lesions.

In countries with a high rate of vaccination coverage, populationbased studies have shown a decrease of >70% in high-grade cervical lesions, indicating that targeted types of HPV may be eradicated within a couple of decades [16]. Although the vast majority of the world is experiencing benefits from HPV vaccination, many lowand middle-income countries are encountering challenges related to limited access to vaccines, cultural and/or social barriers and insufficient screening programs. A concerted effort to broaden vaccination programs, as well as the integration of HPV testing into existing community health screening programs, is likely to make a significant contribution towards reducing the burden of HPVrelated cancers worldwide.

EBV and Nasopharyngeal / B-cell Malignancies

Infectious mononucleosis (mono), a disease caused by the Epstein-Barr virus (EBV), has been suggested to be indirectly associated with Burkitt lymphoma and Hodgkin lymphoma as well. One way of assessing the strength of this association is by examining “Odds Ratios” (OR) generated from population-based studies through a technique known as “Meta-Analysis” (MA). The pooled OR for NPC was reported as 6.18 (95% CI: 4.55-8.39), while the OR for Burkitt lymphoma was reported as 3.95 (95% CI: 2.80-5.57) [7,8]. Comparison of each of the individual contributing studies within the MA highlights that several studies utilized pediatric populations (under 18 years old) for assessing the association of EBV with the development of the malignancies, with these studies reporting statistically significant and large ORs. Also, nearly half of the studies included were from Southeast Asia and Northern Africa, while the remainder were from Europe/Eastern Russia and the United States.

Collectively, this indicates a clear and likely multifactorial relationship between genetic susceptibility, geographic dietary characteristics, and exposure patterns to EBV.As the study of EBV progresses and further identifies risk factors for malignancies, so will advances to help prevent the effect of EBV on people’s health through the development of vaccines targeted to preventing EBV from becoming established within a person’s body (through vaccination of infants and children) and through the use of alternative immune-based therapies whose target is either to treat or help individuals who have developed malignancies as a result of EBV [7,8]. Ongoing studies will further enhance the use of checkpoint inhibitors and EBV-specific cytotoxic T lymphocytes as potential treatments for managing individuals who develop EBVassociated malignancies.

HBV / HCV and Hepatocellular Carcinoma

Hepatotropic Viruses (HBV, HCV) are recognised as the leading cause of Hepatocellular Carcinoma (HCC). Of the meta-analysis, the two pooled ODs were 7.34 (95% CI 5.88-9.16) for HBV and 4.89 (95% CI: 3.95-6.05) for HCV. HBV can integrate its genetic information into the host’s chromosome, thereby causing insertional mutagenesis, chromosomal instability, and oncogene dysregulation while also down-regulating tumour suppressor genes. In addition to this, HBV’s HBx protein enhances proliferation of the hepatocyte and also decreases DNA repair mechanisms. HCV, unlike HBV, does not directly integrate into the chromosomal DNA; however, HCV can still contribute to HCC by creating a microenvironment that encourages malignant transformation through chronic inflammatory pathways, oxidative stress, and hepatic fibrosis.In endemic areas, vaccination against HBV has led to a marked decrease in the incidence of both HBV infection and HCC. In addition, antiviral treatments that target HBV and direct-acting anti-HCV drugs have proven to be effective at resolving HBV and HCV while significantly decreasing the risk for developing HCC. However, even after successfully treating HBV or HCV in individuals with UID cirrhosis or chronic HBV or HCV infection, there remains a residual risk for HCC, which necessitates frequent monitoring and improved early detection methodologies.

KSHV and Kaposi’s Sarcoma

Human Herpesvirus 8 (HHV8), also known as KSHV (Kaposi’s Sarcoma-associated herpes virus), has been implicated in KS (Kaposi’s Sarcoma) and PEL (primary effusion lymphoma). A metaanalysis showed that HHV8 infection is statistically significantly associated with developing KS among HIV+ patients (OR 9.15 [95% CI 6.78 - 12.34]). KSHV encodes a variety of proteins, including vIL-6 and vGPCR, that function as human cytokines, chemokines, and angiogenic products; these proteins help to promote the formation of new blood vessels and the proliferation of endothelial cells. The immunosuppressive effects of HIV compromise the host’s ability to mount an effective immune response against KS. Methods for decreasing KS risk are available through HIV treatment (Antiretroviral Therapy, ART) to restore immune system function and by identifying individuals at risk for KS earlier in the disease process.

HTLV -1 and Adult T- cell Leukemia / Lymphoma

HTLV-1 is a viral infection found predominantly in Japan, the Caribbean, and certain regions in Africa. Associated with the development of Adult T-cell Leukemia/Lymphoma (ATLL), the virus has a pooled odds ratio of 6.42 (95% confidence interval: 4.10-10.05). The effect of viral proteins Tax and HBZ on host cell cycle regulation results in increased reproduction and decreased immune system recognition of infected cells. There are few effective treatments for ATLL, and the disease generally has a poor prognosis. To avoid transmitting this virus, methods of prevention include screening blood products, providing public health information about HTLV-1, and detecting carriers of the virus early on (Figure 4).

Mechanistic insights

Several key molecular and cellular mechanisms were consistently found to be essential to virus-induced oncogenesis in all of the included studies:

Inactivation of Tumor Suppressor Patways

a) Dysregulation of p53 and Rb occurs as a result of E6 and E7 protein expression by HPV.
b) The initiation of NF-kB by LMP1 inhibits apoptosis during the resting phase of EBV.

Chronic Inflammation

Hepatitis B and hepatitis C result in chronic inflammation, increased DNA damage and fibrosis.

Immune Evasion

The ability of viruses to impede the presentation of antigens to the host, to inhibit the interferon signaling system, and to induce immune tolerance assists in creating environments conducive to continuous proliferation of infected cells.

Epigenetic Modulation

The activity of viral proteins on the host cell interferes with DNA methylation and histone modification and ultimately alters the normal patterns of gene expression of the host; thus, the host cell is driven toward oncogenesis. The aforementioned pathways provide insight into the multistep progression toward development of virus-induced cancers through latent periods of time, cumulative cytotoxicity, and aberrant immune function.

Limitations

A considerable degree of variation among the studies was seen, mainly attributed to differences in viral detection techniques employed, study designs utilized, sample sizes examined, and regional distributions of HIV prevalence. Additionally, there may be a potential for publication bias, along with a lack of data from low-income countries to influence the application of these findings to these areas. Therefore, prospective cohort studies using standardized methods need to be conducted. Lack of PROSPERO registration - Publication bias (Egger’s test) - Underrepresentation of low-income countries,

Future Directions

a) In the future, researchers have much to work on related to:
b) Creating a vaccine for EBV, KSHV, and HTLV-1.
c) Combining antiviral therapies with conventional cancer treatment.
d) Identifying virus-associated cancers by early detection using biomarkers.
e) Establishing means for monitoring and identifying highrisk populations via global surveillance programmes.
f) Researching how co-infection and other environmental factors affect a person’s health.

Conclusion

The global cancer problem has received little attention compared to other diseases. Cancer is caused by a variety of factors, including chronic infection with certain human viruses: viruses cause 15% of all cancers worldwide. This systematic review/metaanalysis provides conclusive evidence of an association between six viruses (Human Papillomavirus (HPV), Epstein-Barr Virus (EBV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Kaposi’s Sarcoma Virus (KSHV), and Human T-cell Lymphotropic Virus type I (HTLV-1)) and multiple site-specific malignancies: HPV/cervical cancer; EBV/nasopharyngeal cancer; HBV/HCC; HCV; KSHV/ Kaposi’s sarcoma; and HTLV-1/adult T-cell leukemia/lymphoma. The various mechanisms of how viral oncoproteins, chronic inflammation, immune escape, and epigenetic modifications lead to malignancy demonstrate that viruses are an important target for both preventive and therapeutic interventions.

Vaccination against HPV and immunization against HBV have already resulted in significant decreases in the incidence of malignancies associated with those viruses among vaccinated groups. Vaccination development against EBV/KSHV/HTLV-1 remains a priority in research. Antiviral treatment of HBV and HCV reduces the incidence of cancer significantly when treated early; therefore, early diagnosis combined with treatment is important for controlling the overall impact of these viruses on human health. In conjunction with the integration of these approaches into existing public health efforts, screening programs and educational programs may be necessary in areas where these viruses are prevalent and access to medical services is limited. We have improved our understanding of the mechanisms of viral-induced cancers by learning more about the mechanisms of viral action in general. Our greater understanding of how viruses enter human cells, produce their genetic material and replicate will help develop new therapies for viral-induced cancers. The clinical applications of this knowledge include therapies like CTLs that are activated against EBV, multiple types of immune therapies such as checkpoint inhibitors, and also new therapies being developed against the epigenetic effects of viral infection. Additional developments, such as methods for monitoring at-risk populations for developing viral-induced cancers and the identification of biomarkers for early detection of viral-induced cancers, will help decrease the morbidity and mortality rates associated with cancers caused by the contagious nature of viral infection.

In summary, this article demonstrates how complicated the linking of viral infections to human cancer really is and illustrates the significance of the complete prevention, detection and treatment of these cancers through multidisciplinary synergy and cooperation. The only way to rid the world of these viral-induced cancers and improve health outcomes for people affected by these cancers is through the combined efforts of vaccination for all populations, antiviral medicines for all people who may be asymptomatic, the development of future immunotherapies, and the allocation of research and development funds, as well as a complete and uniform approach to managing cancers caused by virus infection.

Acknowledgements

We would like to express our sincere gratitude to the Faculty of Veterinary Medicine and Animal Science, Habiganj Agricultural University, Habiganj-3300, Bangladesh, for their institutional postdoc support and providing access to applicable academic resources. In addition, we would like to acknowledge the contributions of the original investigators whose published studies provided the basis for this systematic review and meta-analysis. There has been no financial support provided to the authors from any funding agency (governmental or private or non-profit) for this work.

Declaration

Fundings

There was no financial assistance available to this author in the form of a grant from either a government, business, or charitable source to conduct this research. The research, therefore was entirely funded by the researcher and undertaken for the advancement of knowledge.

Conflict of interest / Competing of interest

The author declares that there is no competing interest.

Ethics Approval

The current study used established and publicly available data sources and was not conducted with human or animal participants, so ethical approval is not applicable.

Consent to participate

Not applicable, as the study didn’t involve human participant.

Consent to Publisher

The authors have granted full approval for this article to be published.

Data Availability

In addition, all data used for analysis were obtained from publicly available published literature, with any other derived data or material available to any reasonable request for additional confirmation of the results of the analyses.

Authorship Contribution

a) Conceptualization: M.N. H, M.S.U
b) Literature Review and Analyses: M.N. H, T.N
c) Original Draft Preparation: M.N.H
d) Review and Editing: M.S.U, M.N.H
e) Visualization (Figures/Tables): M.N.H, T.N
f) Supervision: M.S.U
g) Project Administration: M.N.H, T.N

All authors have read and approved the final version of the manuscript.