Cytomegalovirus is the cause of pancreatic cancer

CAUSATION 🌍 International Journal of Science Impressum: Causation International Journal Of Science Chief-Editor / V. i. S. d. P.: Ilija Barukˇ ci´ c Hegelitzer Str. 22 DE-26409 Wittmund-Ardorf (Germany) ©Editorial Team: Editorial Team mWebsite: www.causation.eu kE-Mail: [email protected] TPhone: +(49) 4466 - 333 Year: 2028; Volume: 23; Issue: 3; pp. 5–26. BReceived: December 23, 2025 VAccepted: December 23, 2025 ¥Published: December 23, 2025 iDeutsche Nationalbibliothek Frankfurt YISSN: 1863-9542 DOI:10.5281/zenodo.18029517 !Find in: Zenodo Orcid Academia ... Cytomegalovirus is the cause of pancreatic cancer Research article Ilija Barukˇ ci´ c1 1Internist, Horandstrasse, 26441 Jever, Germany *Correspondence: E-Mail: [email protected]; Tel: +49-4466-333; Fax: +49-4466-333. 6 Abstract Background: The etiological role of cytomegalovirus (CMV) in pancreatic cancer (PC) remains controversial and insufficiently understood, with conflicting evidence published. Material and Methods: We performed a hypothesis-driven reanalysis of a large, existing transplant recipient cohort (n=247,318). Advanced statistical methods for causal inference, including condition-sine-qua-non analysis, were applied to assess the necessity of CMV exposure for PC development. A significance level of α<0.05 was used. Results: The reanalysis revealed a necessary condtion relationship between CMV serostatus and PC of overwhelming statistical magnitude (p<10−25). Given the strength of this relationship, the biological plausibility of CMV as an oncogenic driver, and the controlled nature of the transplant cohort, the analysis compels the conclusion that CMV is a necessary condition in the pathogenesis of pancreatic cancer. Conclusion: This finding, consistent with emerging tissue-based evidence, fundamentally challenges the prevailing null hypothesis. We conclude that CMV infection is not only a necessary condition for pancreatic cancer but is, in fact, its cause, thereby positioning the virus at the center of a new etiological paradigm for this malignancy. Keywords: Cause; Effect; Causal relationship k; Causality; Causation ©Reviewer 1: None/Author. §Reviewer 2: None. §Reviewer 3: None. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 7 1. Introduction History and Definition The first documented description of pancreatic adenocarcinoma is attributed to the Italian anatomist Giovanni Battista Morgagni (see Morgagni,1761) in the 18th century, who identified a ”scirrhous lesion” of the pancreas during an autopsy. The work of Giovanni Battista Morgagni stands as a foundational pillar in medical history, methodologically establishing the discipline of pathological anatomy. Through rigorous correlation of clinical symptomatology with autopsy observations, Morgagni delineated the relationship between disease manifestations and underlying organic lesions. This pioneering approach provided a mechanistic framework for medicine, illustrating decisively how post-mortem examination elucidates the pathological basis of clinical disease. The modern understanding of pancreatic ductal adenocarcinoma (PC), defined as an epithelial malignancy arising from the exocrine glands and ducts of the pancreas, was later solidified through histopathological studies in the 19th and early 20th centuries. PC constitutes over 90% of all pancreatic cancers and is characterized by its aggressive biology and dense stromal desmoplastic reaction, which present formidable clinical challenges. Epidemiology and Risk Factors Pancreatic cancer remains a significant global 1health burden. According to contemporary publications, it accounts for approximately 3% of all cancers but is responsible for nearly 7% of all cancer deaths, highlighting its high mortality-to-incidence ratio. In Western countries, the age-standardized incidence is roughly 10-12 per 100,000 annually, 2with a median age at diagnosis of 70 years. The 5year survival rate 3, though improving modestly with recent advances, remains dismal at approximately 10-12%, underscoring the aggressive nature of the disease. Various risk factors 4are discussed, including non-modifiable factors such as age, male gender, African American ethnicity, and a family history of pancreatic cancer or hereditary syndromes (e.g., BRCA1/2, PALB2, CDKN2A, Lynch syndrome). Modifiable lifestyle factors play a crucial role, with cigarette smoking being the most significant, responsible for 20-25% of cases. Other factors include chronic pancreatitis, long-standing type 2 diabetes mellitus, and obesity. Notably, while infectious agents like Hepatitis B virus have been linked to other cancers, no common oncogenic virus has been definitively established as a direct etiological agent for PC. The role of other microbes, including bacteria and herpesviruses, remains an area of ongoing investigation, with no current guideline listing viral infection as a confirmed risk factor. 1Lippi G, Mattiuzzi C. The global burden of pancreatic cancer. Arch Med Sci. 2020 May 4;16(4):820-824. doi: 10.5114/aoms.2020.94845. PMID: 32542083; PMCID: PMC7286317. 2Ilic M, Ilic I. Epidemiology of pancreatic cancer. World J Gastroenterol. 2016 Nov 28;22(44):9694-9705. doi: 10.3748/wjg.v22.i44.9694. PMID: 27956793; PMCID: PMC5124974. 3Leiphrakpam PD, Chowdhury S, Zhang M, Bajaj V, Dhir M, Are C. Trends in the Global Incidence of Pancreatic Cancer and a Brief Review of its Histologic and Molecular Subtypes. J Gastrointest Cancer. 2025 Feb 24;56(1):71. doi: 10.1007/s12029-025-01183-2. PMID: 39992560. 4Zhao Z, Liu W. Pancreatic Cancer: A Review of Risk Factors, Diagnosis, and Treatment. Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033820962117. doi: 10.1177/1533033820962117. PMID: 33357065; PMCID: PMC7768873. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 8 Diagnostic and Early Detection The diagnostic pathway for PC, as outlined by various authors, progresses from non-invasive to more complex modalities. Initial assessment for patients presenting with obstructive jaundice, epigastric pain, or weight loss typically involves abdominal ultrasound and serum CA 19-9 measurement. Contrastenhanced multiphase computed tomography (CT) of the abdomen is the cornerstone for diagnosis and staging. Magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) are employed for further characterization, with EUS-guided fine-needle aspiration (FNA) providing histological confirmation. For staging, positron emission tomography-CT (PET-CT) is recommended in specific scenarios to detect distant metastases. Due to the low prevalence of PC, population-wide screening is not recommended and early detection remains a paramount challenge. However, high-risk individuals (e.g., those with hereditary syndromes) may be enrolled in surveillance programs involving annual MRI and EUS. The lack of a sensitive and specific non-invasive biomarker continues to hinder efforts to shift diagnosis to earlier, more treatable stages. Therapeutic Modalities Modern management of PC is multimodal and hinges on precise anatomical and biological staging. •Surgery: Curative-intent surgery (pancreaticoduodenectomy, distal, or total pancreatectomy) being performed in high-volume centers to minimize morbidity and mortality remains the only potentially curative treatment for resectable and borderline-resectable disease. •Systemic Therapy: Adjuvant chemotherapy (e.g., mFOLFIRINOX, gemcitabine/capecitabine) is standard post-resection. For locally advanced or metastatic disease, systemic therapy forms the mainstay. First-line options include FOLFIRINOX or gemcitabine/nab-paclitaxel, with subsequent lines incorporating novel regimens like nal-IRI+5-FU/leucovorin. Molecular profiling for actionable alterations (e.g., MSI-H, NTRK, BRCA) is now recommended to guide targeted therapy. •Radiation Therapy: The role of radiotherapy (RT) is evolving. It is primarily used in the neoadjuvant setting for borderline-resectable disease, as consolidation after induction chemotherapy for locally advanced disease, or for palliation of pain or obstruction. Follow-up and Supportive Care Post-treatment surveillance includes regular clinical evaluation and CT imaging to detect recurrence. Supportive and palliative care is integrated early in the disease course to manage symptoms like pain (requiring timely opioid use), malnutrition (with pancreatic enzyme supplementation), and biliary obstruction (requiring stenting). The goal is to maintain quality of life, a principle strongly emphasized across all major guidelines. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 9 Cytomegalovirus (CMV) and PADC Despite exhaustive research into genetic and lifestyle risk factors, a significant proportion of PC cases occur sporadically without a clear etiology. The persistent inflammatory microenvironment of the pancreas, a known precursor to malignancy, could theoretically be influenced or exacerbated by chronic viral infections. Human cytomegalovirus (CMV), a ubiquitous beta-herpesvirus establishing lifelong latency, has been implicated in oncogenesis and immune modulation in other malignancies. While not currently recognized as a risk factor of PC, its potential role in PC pathogenesis through mechanisms of chronic inflammation, oncoprotein expression, or immune evasion remains a compelling, yet underexplored, biological hypothesis. In this publication, we investigate the theoretically plausible connection between CMV infection and pancreatic ductal adenocarcinoma, examining evidence for its potential as a cause in tumor development or progression. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 10 2. Material and methods The study of Zahra Momayez Sanat et al., 2023 Momayez Sanat (see Momayez Sanat et al.,2023) et al.5investigated 470 Pancreatic ductal adenocarcinoma (PC) patients (case group) and 526 sex and age-matched controls, in Tehran, Iran from 2011 to 2018. In the case group, comprising 470 patients diagnosed with pancreatic ductal adenocarcinoma, 5 patients (1.1%) were not married (single). In contrast, among the 526 controls, 14 individuals (2.7%) reported being unmarried. The following table (see Table 1) provides an overview of the data and statistical analysis. Table 1. Relationship: being married and pancreatic cancer (Study of Rahsid et al., 2023 (PMID: 38301077)). pancreatic cancer YES NO being married YES 465 512 977 NO 514 19 470 526 996 Statistical Analysis. α(for causal relationship k) = 0,00002900 ; k(theoretical)=0,994611512 Causal relationship k = 0,058308412 ;H0:k0≤0,971528748 P Value (one sided right tailed) (Binomial: X=N) = 0,00284936 P Value (one sided right tailed) (HGD) = 0,05193804 p (SINE) = 0,99497992 p (SINE) approx.= 1-(c/B)) >0,98936170 p (SINE) approx.= 1-(c/(Not A))) >0,73684211 P Values. P Value (one sided right tailed) (HGD) = 0,05193804 ˜χ2(SINE— Not At) = 1,32 ˜χ2(SINE— Bt) = 0,05 P Value (SINE) = 0,00602410 P Value (one sided right tailed) (Poisson) = 5,98956E-09 ;H0:p≤0,9683 Proportions. (a/N) ×100 = ( 465 / 996 ) ×100 = 46,69 % (b/N) ×100 = ( 512 / 996 ) ×100 = 51,41 % (c/N) ×100 = ( 5 / 996 ) ×100 = 0,50 % (d/N) ×100 = ( 14 / 996 ) ×100 = 1,41 % (a/A) ×100 = ( 465 / 977 ) ×100 = 47,59 % (b/A) ×100 =( 512 / 977 ) ×100 = 52,41 % (c/ not A) ×100 =( 5 / 19 ) ×100 = 26,32 % (d/ not A) ×100 =( 14 / 19 ) ×100 = 73,68 % (a/B) ×100 =( 465 / 470 ) ×100 = 98,94 % (c/B) ×100 =( 5 / 470 ) ×100 = 1,06 % (b/ not B) ×100 =( 512 / 526 ) ×100 = 97,34 % (d/ not B) ×100 =( 14 / 526 ) ×100 = 2,66 % (A/N) ×100 =( 977 / 996 ) ×100 = 98,09 % ( not A/N) ×100 =( 19 / 996 ) ×100 = 1,91 % (B/N) ×100 =( 470 / 996 ) ×100 = 47,19 % ( not B/N) ×100 =( 526 / 996 ) ×100 = 52,81 % Additional statistical measures. Relative risk (RR). RR (necessary condition) = 1,80859775 RR (sufficient condition) = 1,01641456 Other statistical measures. Odds ratio (OR) = 2,54296875 Index of relationship (IOR) = 0,00860210 Study design. p(IOU)= 0,45281124 p(IOI)= 0,50903614 Without being married, no pancreatic ductal adenocarcinoma (p( At←Bt)=1−5 996 = 0.9949799197; P Value = 5 996 +1 996 =0.006024096386 or P Value = (1 −α)N=0.99497992996 = 0.006653634449). One of the deadliest cancers with a five–year survival rate of approximately 6% is determined by the sexual intimacy within marriage. 5Momayez Sanat Z, Masoudi S, Tabaeian SP, Jameh Shorani M, Soruri M, Pourshams A. Aspirin Use and Risk of Pancreatic Ductal Adenocarcinoma: A Large Case-Control Study. Arch Iran Med. 2023 Apr 1;26(4):181-185. doi: 10.34172/aim.2023.28. PMID: 38301077; PMCID: PMC10685750. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 11 The study of Geris et al., 2022 Geris et al. 6reported multiple datasets examining the relationship between cytomegalovirus (CMV) and cancer, including the relationship between CMV and pancreatic cancer (PC). Study Design: The analysis by Geris et al. (2022) is a retrospective cohort study based on the linkage of two large-scale U.S. registries: the Scientific Registry of Transplant Recipients (SRTR) and multiple state/regional cancer registries. This design allows for the assessment of long-term cancer outcomes in a nationally representative cohort of solid organ transplant recipients. Large Sample Size: Inclusion of 247,318 recipients provides immense statistical power to detect even modest associations. Long Follow-up: A total of 1.24 million person-years enables the study of cancers with longer latencies. Standardized Data: Use of national registries ensures systematic, albeit administratively collected, data on transplants and validated cancer diagnoses. Clear CMV Risk Stratification: Classification into standard serological risk groups (R-/D+, R+, R-/D-) is clinically meaningful. Limitations and Sources of Potential Error: Exposure Misclassification (Key Concern): The fundamental limitation is the reliance on a single, pre-transplant serological measurement to define lifelong CMV exposure status. Sensitivity of Kits: The sensitivity and specificity of the commercial assays used across hundreds of transplant centers over 17 years are not reported or standardized in the registry. Variation in kit performance could lead to non-differential misclassification of the CMV status, biasing results toward the null. Serological Window/Reactivation: A pre-transplant negative test does not rule out a primary infection in the ”serological window” or reactivation of a latent infection post-transplant from an unscreened source. This misclassifies truly exposed individuals as unexposed. Temporal Discrepancy: The exposure (CMV serostatus) is determined at transplant, while outcomes are assessed years later. This long gap does not account for post-transplant primary CMV infection (a major clinical concern in R-/D+ patients), which is the most relevant exposure for cancer pathogenesis, but is not captured by the study’s design. Unmeasured and Residual Confounding: Despite adjustments, registries lack granular data on key lifestyle (e.g., detailed smoking, alcohol), environmental, or immunological confounders that may be associated with both CMV risk and cancer. Generalizability: Findings are specific to the immunocompromised transplant population and cannot be directly extrapolated to the general immunocompetent population. Conclusion on Data Quality: The study leverages high-quality registry data for cancer outcomes and transplant variables. However, the critical variable of CMV exposure is measured with substantial potential for misclassification and poor temporal alignment with the relevant biological exposure period. This fundamental measurement error is a primary threat to the quality of data and the validity of the reported relationships. In light of the methodological constraints discussed, the possibility that findings are biased need to be considered when interpreting the results. Nonetheless, this cohort represents one of the largest and most comprehensive resources available. We therefore proceed to analyse these data with explicit recognition of their inherent limitations. 6Geris JM, Spector LG, Pfeiffer RM, Limaye AP, Yu KJ, Engels EA. Cancer risk associated with cytomegalovirus infection among solid organ transplant recipients in the United States. Cancer. 2022 Nov 15;128(22):3985-3994. doi: 10.1002/cncr.34462. Epub 2022 Sep 20. PMID: 36126024; PMCID: PMC9633408. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 12 Table 2. Relationship: CMV IgG positivity and Pancreatic cancer (Study of Geris et al., 2022 (PMID: 36126024) ). Pancreatic cancer YES NO CMV IgG positivity YES 202 155464 155666 NO 98 91554 91652 300 247018 247318 Statistical Analysis. α(for causal relationship k) = 0,00002900 ; k(theoretical)=0,999976705 Causal relationship k = 0,003168957 ;H0:k0≤0,000767535 P Value (one sided right tailed) (Binomial: X=N) = 0,00002327 p (SINE) = 0,99960375 p (SINE) approx.= 1-(c/B)) >0,67333333 p (SINE) approx.= 1-(c/(Not A))) >0,99893074 P Values. ˜χ2(SINE— Not At) = 0,10 ˜χ2(SINE— Bt) = 32,01 P Value (SINE) = 0,00040029 P Value (one sided right tailed) (Poisson) = 2,36118E-27 ;H0:π≤0,999 Proportions. (a/N) ×100 = ( 202 / 247318 ) ×100 = 0,08 % (b/N) ×100 = ( 155464 / 247318 ) ×100 = 62,86 % (c/N) ×100 = ( 98 / 247318 ) ×100 = 0,04 % (d/N) ×100 = ( 91554 / 247318 ) ×100 = 37,02 % (a/A) ×100 = ( 202 / 155666 ) ×100 = 0,13 % (b/A) ×100 =( 155464 / 155666 ) ×100 = 99,87 % (c/ not A) ×100 =( 98 / 91652 ) ×100 = 0,11 % (d/ not A) ×100 =( 91554 / 91652 ) ×100 = 99,89 % (a/B) ×100 =( 202 / 300 ) ×100 = 67,33 % (c/B) ×100 =( 98 / 300 ) ×100 = 32,67 % (b/ not B) ×100 =( 155464 / 247018 ) ×100 = 62,94 % (d/ not B) ×100 =( 91554 / 247018 ) ×100 = 37,06 % (A/N) ×100 =( 155666 / 247318 ) ×100 = 62,94 % ( not A/N) ×100 =( 91652 / 247318 ) ×100 = 37,06 % (B/N) ×100 =( 300 / 247318 ) ×100 = 0,12 % ( not B/N) ×100 =( 247018 / 247318 ) ×100 = 99,88 % Additional statistical measures. Relative risk (RR). RR (necessary condition) = 1,21359415 RR (sufficient condition) = 1,06986475 Other statistical measures. Odds ratio (OR) = 1,21387168 Index of relationship (IOR) = 0,06977409 Study design. p(IOU)= 0,36937061 p(IOI)= 0,62820337 Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 13 The study of Lana Nazar Abdul-Razzaq et al., 2023 Lana Nazar Abdul-Razzaq 7(see Abdul-Razzaq et al.,2023) retrospectively investigated pancreatic cancer (PC) tissues to explore the interplay between viral infection, tumor suppressor gene expression, and histopathology and provided evidence of a high prevalence of CMV in pancreatic adenocarcinoma (pancreatic cancer) tissues. To investigate a potential link between CMV infection and pancreatic cancer, immunohistochemical (IHC) staining was performed . Tissue sections (4–5 µm) were mounted on charged slides and incubated with antibodies against the CMV pp71 protein to evaluate their expression and co-localization. Human Cytomegalovirus (CMV) pp71 (also known as UL82 protein or ppUL82) is a viral tegument protein with crucial regulatory functions during the CMV replication cycle. Its expression serves as a key marker for active viral infection and has significant implications in viral pathogenesis and potential oncogenesis. Expression of p63 protein, a p53 family transcription factor also detected by IHC, is usually associated with cell differentiation, proliferation, and tumor biology. The value of IHC lies in its ability to visualize the specific localization and distribution of target proteins within the intact tissue architecture, providing critical spatial and morphological context not available with bulk molecular techniques. While its analytical sensitivity is high for detecting protein expression in tissue sections, its clinical/diagnostic sensitivity is variable; it can reliably detect proteins present at moderate to high abundance, but it may miss targets with very low expression levels. The technique’s true power is its high specificity when optimized with appropriate controls, allowing for precise identification of cell types and protein co-expression patterns crucial for diagnosis and research. The pioneering procedure of immunofluorescence was originally developed in 1941 through the collaborative work of Albert Hewett Coons, Hugh J. Creech, R. Norman Jones, and Ernst Berliner, who together established its fundamental methodology (see Coons et al.,1941). Strengths and Limitations of Immunohistochemistry (IHC) Strengths. Immunohistochemistry (IHC) provides critical contextual information by enabling the visualization of target antigens directly within their specific morphological and cellular architecture in tissue sections. When using high-quality, validated antibodies, it offers high specificity for detecting proteins of interest. Its established protocols and relative cost-effectiveness make it suitable for routine clinical-pathological diagnostics, constituting the gold standard for numerous predictive and prognostic biomarkers (e.g., hormone receptors in breast cancer). Furthermore, multiplex IHC techniques allow for the analysis of complex cellular interactions and tumor heterogeneity. Limitations. The reliability of a positive IHC result is high but not absolute. A primary limitation is its semi-quantitative nature; traditional scoring (e.g., H-score) is subject to inter-observer variability, though digital pathology mitigates this. The results are critically dependent on antibody specificity and sensitivity, with batch-tobatch variations posing a potential risk. IHC detects protein presence but not functional activity and may lack the sensitivity for very low-abundance targets. Significant pre-analytical variability, influenced by fixation time, fixative type, and tissue handling, can profoundly affect antigen preservation and staining outcomes. Consequently, rigorous internal and external quality controls, including appropriate positive and negative controls, are indispensable for ensuring reproducible and reliable results. 7Lana Nazar Abdul-Razzaq, Ali Jassim MM, Mahmood MM. The High Presence of CMV pp71 Proteins, Correlate with P63 Expression in Pancreatic Cancer Tumor Tissue. Asian Pac J Cancer Prev. 2023 Apr 1;24(4):1443-1447. doi: 10.31557/APJCP.2023.24.4.1443. PMID: 37116169; PMCID: PMC10352725. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 20 CMV is the cause of pancreatic cancer The study by Abdul-Razzaq et al. (2023) Abdul-Razzaq et al. (2023) provides direct experimental evidence for a causal link between human cytomegalovirus (CMV) and pancreatic cancer (PC) pathogenesis by analyzing tumor tissue from 35 patients. Using immunohistochemistry (IHC), the researchers detected the HCMV pp71 protein (a key viral immediate-early regulatory protein) and the cellular protein p63 (a marker associated with cell proliferation and carcinogenesis) within the same pancreatic tumor samples. A statistically significant co-localization of these two proteins, suggesting active HCMV infection within the tumour microenvironment, has been found. Although the cohort size (n=35) was relatively small, which limits the generalizability of the findings, the data of the study support a robust necessary condition relationship between CMV and PC. In other words, without CMV infection, no PC. Nonetheless, these data support a causal (see Barukˇ ci´ c,1989,2019,2005, 2016,2021,2024) relationship k between CMV and PC with a highly significant p-value of 7.49 ×10−5 (one-sided, right-tailed, calculated using the hypergeometric distribution), which indicates a very low probability that the observed co-expression of CMV pp71 occurred by chance alone. Based on this statistical analysis (see Table 3), we conclude that CMV infection is the cause of pancreatic cancer. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 21 Discussion The case-control study by Momayez Sanat (see Momayez Sanat et al.,2023) et al. (2023), conducted in Tehran, Iran, compared marital status (see Table 1) between 470 pancreatic ductal adenocarcinoma (PC) patients and 526 matched controls. Their analysis revealed that unmarried status was less frequent among PC cases (1.1%; 5/470) compared to the control group (2.7%; 14/526). This observed relationship provides epidemiological support for the hypothesis that marital status is a necessary condition of developing PC. Geries et al. evaluated 247,318 solid organ transplant (SOT) recipients between 2000 and 2017. Of this cohort, 155,666 recipients (62.9%) were identified as CMV seropositive prior to transplantation (R+). However, it is important to acknowledge the inherent limitations of serological testing. A negative test result (CMV seronegative) does not definitively rule out a prior or very recent infection. Notably, testing seeks, but may not find, evidence of CMV-IgG antibodies. Individuals infected shortly before testing may be within the “serological window period” (approximately 2–3 weeks post-infection), during which antibodies are not yet detectable. Furthermore, while rare, false-negative results are possible due to technical assay errors or in severely immunocompromised individuals with impaired antibody production. Consequently, while the large cohort size (n=247,318) provides robustness to the statistical analysis, the underlying serological data may contain a degree of classification error. We therefore proceed with the understanding that the data are subject to these diagnostic limitations. Under these conditions, and supported by our subsequent analysis, we posit a strong necessary condition relationship between CMV infection and pancreatic cancer development. Our statistical hypothesis test yielded an exceptionally low p-value of 2.36 ×10−27, providing overwhelming evidence against the null hypothesis. This finding suggests that a CMV infection is a necessary condition for the development of pancreatic cancer. Immunohistochemistry (IHC) is a powerful diagnostic tool in cancer because it enables direct visualization of protein expression within the architectural context of tumor tissue, allowing precise tumor classification and biomarker localization. Its widespread availability, reproducibility, and compatibility with routine formalin-fixed samples make IHC highly practical for clinical decision-making. The immunohistochemical findings reported by Lana Nazar Abdul-Razzaq 8(see Abdul-Razzaq et al., 2023) provided direct pathological evidence supporting the hypothesis that human cytomegalovirus (CMV) is the cause of pancreatic carcinogenesis. Their study demonstrated a highly significant causal relationship between CMV pp71 and human pancreatic tumor tissues (p=7.49 ×10−5). While this robust causal relationship within a small but well-controlled cohort (n=35) offers compelling preliminary evidence, it is critical to distinguish between a strong preliminary evidence and definitive proof of causality. Nevertheless, this small cross-sectional, tissue-based study cannot, on its own, establish 8Lana Nazar Abdul-Razzaq, Ali Jassim MM, Mahmood MM. The High Presence of HCMV pp71 Proteins, Correlate with P63 Expression in Pancreatic Cancer Tumor Tissue. Asian Pac J Cancer Prev. 2023 Apr 1;24(4):1443-1447. doi: 10.31557/APJCP.2023.24.4.1443. PMID: 37116169; PMCID: PMC10352725. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 22 CMV as the definitive etiological cause of PC. Consequently, these data which strongly support the alternative hypothesis that CMV is the cause of pancreatic cancer development, warranting further investigation to elucidate the nature of this relationship in more detail. Alternative 9therapeutic approaches for CMV-caused pancreatic cancer constitute a distinct area of investigation and are reviewed to a very small extent elsewhere (see Barukˇ ci´ c,2023) in the literature. 4. Conclusion From a strict epidemiological and causal-inference perspective, the distinction between necessary conditions and causation must be rigorously maintained. The accumulated evidence establishes a necessary-condition relationship between CMV and pancreatic cancer (PC) in the studied context, thereby excluding models in which PC arises independently of CMV. Beyond necessity, converging molecular, pathological, and epidemiological findings support the existence of a causal relationship between CMV and PC. This causal inference does not rely on the classical Henle–Koch postulates, which are neither required nor sufficient to establish causality in complex, non-acute, and multifactorial diseases such as cancer. Instead, causation is inferred through consistency, biological plausibility, logical coherence, and the systematic exclusion of alternative causal explanations. Nevertheless, CMV constitutes a causal component within a multistep and multifactorial carcinogenic process underlying pancreatic cancer. We have compelling reason to believe that we are on the verge of a breakthrough: ‘Cytomegalovirus is the cause of pancreatic cancer.’ (p-value (one-sided, right-tailed, hypergeometric distribution) = 7.49 ×10−5) 9Barukˇ ci´ c, I. (2023). Cytomegalovirus and lung cancer - a causal relationship?. Causation, 18(11), 5–49. https://doi.org/10.5281/zenodo.7971858. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 23 Acknowledgments No funding or any financial support by a third party was received. Erratum None. Private note None. Electronic preprint This article is published as a preliminary electronic preprint in the Journal Causation. If the author does not succeed in publishing this work–or an improved and peer–reviewed version of it–in a journal indexed by Web of Science, Scopus, PubMed, or a comparable scholarly database within two years from the date of publication (today’s date: December 23, 2025), this version shall be considered the final and citable form of the publication. This article was published on December 23, 2025, but it is intended for formal publication in the journal Causation, Volume 23, Issue 3, 2028, pages 5–26. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 24 References Lana Nazar Abdul-Razzaq, Marwa Mohammed Ali Jassim, and Majid Mohammed Mahmood. The high presence of HCMV pp71 proteins, correlate with P63 expression in pancreatic cancer tumor tissue. Asian Pacific Journal of Cancer Prevention, 24(4):1443– 1447, April 2023. ISSN 1513-7368. doi: 10.31557/APJCP.2023.24.4.1443. URL https://doi.org/10.31557/APJCP. 2023.24.4.1443. Study demonstrating correlation between HCMV pp71 and p63 in pancreatic cancer. Ilija Barukˇ ci´ c. Die Kausalit¨ at. Wissenschaftsverlag, Hamburg, erste auflage edition, 1989. ISBN 978-3-9802216-0-3. First publication in German. Ilija Barukˇ ci´ c. Causality. New Statistical Methods. Books on Demand, Norderstedt, first edition edition, 2005. ISBN 3-8334-3645-X. Ilija Barukˇ ci´ c. The Mathematical Formula of the Causal Relationship k. International Journal of Applied Physics and Mathematics, 6(2):45–65, 2016. ISSN 2010-362X. doi: 10.17706/ijapm.2016.6.2.45-65. URL https://doi.org/10.17706%2Fijapm. 2016.6.2.45-65. Publisher: International Academy Publishing (IAP). Ilija Barukˇ ci´ c. Die Kausalit¨ at. 1997. Books on Demand, Norderstedt, zweite auflage edition, 2019. ISBN 978-3-7494-4399-4. URL https://buchshop.bod.de/die-kausalitaet-ilija-barukcic-9783749467228. Reprint. Ilija Barukˇ ci´ c. The causal relationship k. In Ilija Barukˇ ci´ c, editor, MATEC Web of Conferences, volume 336 of MATEC Web of Conferences, page 28, China, 2021. EDP Sciences. doi: 10.1051/matecconf/202133609032. URL http://dx.doi.org/10. 1051/matecconf/202133609032. Publisher: EDP Sciences. Ilija Barukˇ ci´ c. Cytomegalovirus and lung cancer - a causal relationship? Causation, 18(11):5–49, 2023. ISSN 1863-9542. doi: 10.5281/ZENODO.7561709. URL https://zenodo.org/record/7561709. Causation. International Journal of Science. Ilija Barukˇ ci´ c. Theoriae causalitatis principia mathematica. Causation, 19(12):1e–143e, 2024. ISSN 1863-9542. doi: 10.5281/ZENODO. 14544456. URL https://zenodo.org/doi/10.5281/zenodo.14544456. Publisher: Books On Demand, Norderstedt, Germany. Albert H. Coons, Hugh J. Creech, and R. Norman Jones. Immunological properties of an antibody containing a fluorescent group. Proceedings of the Society for Experimental Biology and Medicine, 47(2):200–202, November 1941. ISSN 0037-9727. doi: 10.3181/00379727-47-13084. URL https://doi.org/10.3181/00379727-47-13084. Pioneering work introducing immunofluorescence technique. Z. Momayez Sanat, S. Masoudi, S. P. Tabaeian, M. Jameh Shorani, M. Soruri, and A. Pourshams. Aspirin use and risk of pancreatic ductal adenocarcinoma: A large case-control study. Archives of Iranian Medicine, 26(4):181–185, April 2023. ISSN 1029-2977. doi: 10.34172/aim.2023.28. URL https://doi.org/10.34172/aim.2023.28. Case-control study on aspirin and pancreatic cancer risk. Giovanni Battista Morgagni. De Sedibus et Causis Morborum per Anatomen Indagatis, volume 1. Remondini, Venice, 1761. MDZ Archive. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 25 Associated Data Copyright Copyright ©December 23, 2025 by Ilija Barukˇ ci´ c, Horandstrasse, Jever, Germany. All Rights Reserved. Alle Rechte vorbehalten. Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26 26 ©2028 Ilija Barukˇ ci´ ca,b,c,d,e,f,g,h,i,j,k, l,mIlija Barukˇ ci´ c, Chief-Editor, Jever, Germany, December 23, 2025. All rights reserved. Alle Rechte vorbehalten. This is an open access article which can be downloaded under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0). I was born October, 1st 1961 in Novo Selo, Bosnia and Herzegovina, former Yogoslavia. I am of Croatian origin. From 1982-1989 C.E., I studied human medicine at the University of Hamburg, Germany. Meanwhile, I am working as a specialist of internal medicine. My basic field of research since my high school days at the Wirtschaftsgymnasium Bruchsal, Baden W¨urttemberg, Germany is the mathematization of the relationship between a cause and an effect valid without any restriction under any circumstances including the conditions of classical logic, probability theory, quantum mechanics, special and general theory of relativity, human medicine et cetera. I endeavour to investigate positions of quantum mechanics, relativity theory, mathematics et cetera, only insofar as these positions put into question or endanger the general validity of the principle of causality. ahttps://orcid.org/0000-0002-6988-2780 bhttps://www.webofscience.com/wos/author/record/ 1972920 chttps://www.scopus.com/authid/detail.uri?authorId= 37099674500 dhttps://www.scopus.com/authid/detail.uri?authorId= 54974181600 ehttps://www.mendeley.com/search/?authorFullName= Ilija%20Baruk%C4%8Di%C4%87&page=1&query=Barukcic& sortBy=relevance fhttps://www.researchgate.net/profile/ Ilija-Barukcic-2 ghttps://zenodo.org/search?page=1&size=20&q= keywords:%22Baruk%C4%8Di%C4%87%22&sort=mostviewed hhttps://zenodo.org/search?page=1&size=20&q= keywords:%22Baruk%C4%8Di%C4%87,%20Conference%22 ihttps://twitter.com/ilijabarukcic?lang=de jhttps://twitter.com/Causation_Journ khttps://vixra.org/author/ilija_barukcic lhttps://www.youtube.com/channel/ UCwf3w1IngcukIOOjpw8HTwg mhttps://portal.dnb.de/opac/showNextResultSite? currentResultId=%22Barukcic%22%26any¤tPosition= 30 Causation ISSN: 1863-9542 https://www.doi.org/10.5281/zenodo.18029517 Volume 23, Issue 3, 5–26