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Cytomegalovirus and cancer-related mortality in the national health and nutritional examination survey

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Abstract

Purpose

Cytomegalovirus (HCMV) is a common viral infection that shapes lifelong immunity. A history of infection with HCMV has been associated with many chronic diseases, including cancer. In addition, prospective cohort studies have established that HCMV is associated with all-cause mortality. However, there are limited data regarding HCMV and cancer mortality.

Methods

Data were obtained from the National Health and Nutrition Examination Survey (NHANES) III study (1988–1994): subjects aged 18 to 98, who had HCMV serology results, did not report having cancer at baseline, and were eligible for mortality follow-up (n = 14,498). Mortality was ascertained until December 2011 using National Death Index (NDI) linkage.

Results

The unadjusted risk of all-cancer mortality was higher in HCMV seropositive individuals (HR 2.74, 95% CI 2.05–3.64). This association was attenuated after adjusting for age (HR 1.39, 95% CI 1.02–1.92), and other covariates (age, sex, race/ethnicity, smoking status, BMI, education, and C-reactive protein (CRP); HR 1.21, 95% CI 0.91–1.81). There was a statistically significant interaction between HCMV and sex (p = 0.01): HCMV seropositivity was associated with increased cancer mortality in men (HR 1.65, 95% CI 0.99–2.73) but not in women (HR 0.95, 95% CI 0.59–1.54).

Conclusion(s)

Consistent with prior reports, HCMV seropositivity may be associated with an increased risk of cancer-related mortality but the association is partially driven by socioeconomic status and other risk factors. Future research is needed to determine whether HCMV is a risk factor for cancer, as well as identify the specific cancer types where HCMV increases mortality.

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Data availability

The data that support the findings of this study are openly available in “https://wwwn.cdc.gov/nchs/nhanes/nhanes3/default.aspx”.

Data citation

Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, [1988–1994] [https://wwwn.cdc.gov/nchs/nhanes/nhanes3/default.aspx].

References

  1. Cannon MJ, Schmid DS, Hyde TB (2010) Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol 20:202–213

    PubMed  Google Scholar 

  2. Michaelis M, Doerr HW, Cinatl J (2009) The story of human cytomegalovirus and cancer: increasing evidence and open questions. Neoplasia 11:1–9

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Jackson SE, Mason GM, Wills MR (2011) Human cytomegalovirus immunity and immune evasion. Virus Res 157:151–160

    CAS  PubMed  Google Scholar 

  4. van de Berg PJ, Yong SL, Remmerswaal EB et al (2012) Cytomegalovirus-induced effector T cells cause endothelial cell damage. Clin Vaccine Immunol 19:772–779

    PubMed  PubMed Central  Google Scholar 

  5. Nazmi A, Diez-Roux AV, Jenny NS et al (2010) The influence of persistent pathogens on circulating levels of inflammatory markers: a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis. BMC Public Health 10:706

    PubMed  PubMed Central  Google Scholar 

  6. Söderberg-Nauclér C (2008) HCMV microinfections in inflammatory diseases and cancer. J Clin Virol 41:218–223

    PubMed  Google Scholar 

  7. Simanek AM, Dowd JB, Pawelec G et al (2011) Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS ONE 6:e16103

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Gkrania-Klotsas E, Langenberg C, Sharp SJ et al (2013) Seropositivity and higher immunoglobulin g antibody levels against cytomegalovirus are associated with mortality in the population-based European prospective investigation of Cancer-Norfolk cohort. Clin Infect Dis 56:1421–1427

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Sutcliffe S, Till C, Gaydos CA et al (2012) Prospective study of cytomegalovirus serostatus and prostate cancer risk in the Prostate Cancer Prevention Trial. Cancer Causes Control 23:1511–1518

    PubMed  PubMed Central  Google Scholar 

  10. Richardson AK, Currie MJ, Robinson BA et al (2015) Cytomegalovirus and Epstein-Barr virus in breast cancer. PLoS ONE 10:e0118989

    PubMed  PubMed Central  Google Scholar 

  11. Cox B, Richardson A, Graham P et al (2010) Breast cancer, cytomegalovirus and Epstein-Barr virus: a nested case-control study. Br J Cancer 102:1665–1669

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Rådestad AF, Estekizadeh A, Cui HL et al (2018) Impact of human cytomegalovirus infection and its immune response on survival of patients with ovarian cancer. Transl Oncol 11:1292–1300

    PubMed  PubMed Central  Google Scholar 

  13. Pawelec G, Akbar A, Beverley P et al (2010) Immunosenescence and Cytomegalovirus: where do we stand after a decade? Immun Ageing 7:13

    PubMed  PubMed Central  Google Scholar 

  14. Soderberg-Naucler C, Johnsen JI (2015) Cytomegalovirus in human brain tumors: Role in pathogenesis and potential treatment options. World J Exp Med 5:1–10

    PubMed  PubMed Central  Google Scholar 

  15. Blaheta RA, Beecken W-D, Engl T (2004) Human cytomegalovirus infection of tumor cells downregulates NCAM (CD56): a novel mechanism for virus-induced tumor invasiveness. Neoplasia 6:323–331

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cinatl J, Scholz M, Kotchetkov R et al (2004) Molecular mechanisms of the modulatory effects of HCMV infection in tumor cell biology. Trends Mol Med 10:19–23

    CAS  PubMed  Google Scholar 

  17. Samanta M, Harkins L, Klemm K et al (2003) High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma. J Urol 170:998–1002

    PubMed  Google Scholar 

  18. Soroceanu L, Cobbs CS (2011) Is HCMV a tumor promoter? Virus Res 157:193–203

    CAS  PubMed  Google Scholar 

  19. El-Shinawi M, Mohamed HT, El-Ghonaimy EA et al (2013) Human cytomegalovirus infection enhances NF-κB/p65 signaling in inflammatory breast cancer patients. PLoS ONE 8:e55755

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Taher C, de Boniface J, Mohammad AA et al (2013) High prevalence of human cytomegalovirus proteins and nucleic acids in primary breast cancer and metastatic sentinel lymph nodes. PLoS ONE 8:e56795

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wolmer-Solberg N, Baryawno N, Rahbar A et al (2013) Frequent detection of human cytomegalovirus in neuroblastoma: a novel therapeutic target? Int J Cancer 133:2351–2361

    CAS  PubMed  Google Scholar 

  22. Bai B, Wang X, Chen E, Zhu H (2016) Human cytomegalovirus infection and colorectal cancer risk: a meta-analysis. Oncotarget 7:76735–76742

    PubMed  PubMed Central  Google Scholar 

  23. Chen H-P, Jiang J-K, Chen C-Y et al (2016) Identification of human cytomegalovirus in tumour tissues of colorectal cancer and its association with the outcome of non-elderly patients. J Gen Virol 97:2411–2420

    CAS  PubMed  Google Scholar 

  24. Carlson JW, Radestad AF, Soderberg-Naucler C, Rahbar A (2018) Human cytomegalovirus in high grade serous ovarian cancer possible implications for patients survival. Medicine (Baltimore) 97:e9685

    CAS  Google Scholar 

  25. Han S, Wang PF, Xing YX et al (2018) Human Cytomegalovirus (HCMV) infection was not correlated with overall survival in glioblastomas. Neoplasma 65:431–435

    CAS  PubMed  Google Scholar 

  26. Sehic D, Forslund O, Sandén E et al (2013) Absence of Epstein-Barr and cytomegalovirus infection in neuroblastoma cells by standard detection methodologies. Pediatr Blood Cancer 60:E91–E93

    PubMed  Google Scholar 

  27. Yamashita Y, Ito Y, Isomura H et al (2014) Lack of presence of the human cytomegalovirus in human glioblastoma. Mod Pathol 27:922–929

    CAS  PubMed  Google Scholar 

  28. Cinatl J Jr, Vogel JU, Kotchetkov R, Wilhelm Doerr H (2004) Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression. FEMS Microbiol Rev 28:59–77

    CAS  PubMed  Google Scholar 

  29. NHANES - About the National Health and Nutrition Examination Survey. https://www.cdc.gov/nchs/nhanes/about_nhanes.htm. Accessed 22 Dec 2019

  30. Plan and operation of the Third National Health and Nutrition Examination Survey, 1988–94. Series 1: programs and collection procedures (1994) Vital Health Stat 1. 32: 1–407. https://www.ncbi.nlm.nih.gov/pubmed/7975354. Accessed 22 Dec 2019

  31. Prince HE, Lape-Nixon M, Novak-Weekley SM (2014) Performance of a cytomegalovirus IgG enzyme immunoassay kit modified to measure avidity. Clin Vaccine Immunol 21:808–812

    PubMed  PubMed Central  Google Scholar 

  32. National Center for Health Statistics. Office of Analysis and Epidemiology, National Health and Nutrition Examination Survey (NHANES) 1999–2004 Linked Mortality Files, Mortality follow-up through 2006: Matching Methodology May 2009.Hyattsville, Maryland. https://www.cdc.gov/nchs/data/datalinkage/matching_methodology_nhanes3_final.pdf. Accessed 22 Dec 2019

  33. Bate SL, Dollard SC, Cannon MJ (2010) Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988–2004. Clin Infect Dis 50:1439–1447

    PubMed  Google Scholar 

  34. Staras SAS, Dollard SC, Radford KW et al (2006) Seroprevalence of Cytomegalovirus Infection in the United States, 1988–1994. Clin Infect Dis 43:1143–1151

    PubMed  Google Scholar 

  35. Dowd JB, Aiello AE, Alley DE (2009) Socioeconomic disparities in the seroprevalence of cytomegalovirus infection in the US population: NHANES III. Epidemiol Infect 137:58–65

    CAS  PubMed  Google Scholar 

  36. Dollard SC, Staras SA, Amin MM et al (2011) National prevalence estimates for cytomegalovirus IgM and IgG avidity and association between high IgM antibody titer and low IgG avidity. Clin Vaccine Immunol 18:1895–1899

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Tarter KD, Simanek AM, Dowd JB, Aiello AE (2014) Persistent viral pathogens and cognitive impairment across the life course in the third national health and nutrition examination survey. J Infect Dis 209:837–844

    PubMed  Google Scholar 

  38. Delaney AS, Thomas W, Balfour HH Jr (2015) Coprevalence of Epstein-Barr virus, cytomegalovirus, and herpes simplex virus type-1 antibodies among United States children and Factors Associated With Their Acquisition. J Pediatr Infect Dis Soc 4:323–329

    Google Scholar 

  39. Lanzieri TM, Kruszon-Moran D, Amin MM et al (2015) Seroprevalence of cytomegalovirus among children 1 to 5 years of age in the United States from the National Health and Nutrition Examination Survey of 2011 to 2012. Clin Vaccine Immunol 22:245–247

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang C, Dollard SC, Amin MM, Bialek SR (2016) Cytomegalovirus IgM Sseroprevalence among women of reproductive age in the United States. PLoS ONE 11:e0151996

    PubMed  PubMed Central  Google Scholar 

  41. Fleck-Derderian S, McClellan W, Wojcicki JM (2017) The association between cytomegalovirus infection, obesity, and metabolic syndrome in U.S. adult females. Obesity (Silver Spring) 25:626–633

    Google Scholar 

  42. Mendy A, Gasana J, Vieira ER, Diallo H (2014) Prospective study of cytomegalovirus seropositivity and risk of mortality from diabetes. Acta Diabetol 51:723–729

    PubMed  Google Scholar 

  43. Feinstein L, Douglas CE, Stebbins RC et al (2016) Does cytomegalovirus infection contribute to socioeconomic disparities in all-cause mortality? Mech Ageing Dev 158:53–61

    PubMed  PubMed Central  Google Scholar 

  44. Taher C, Frisk G, Fuentes S et al (2014) High prevalence of human cytomegalovirus in brain metastases of patients with primary breast and colorectal cancers. Transl Oncol 7:732–740

    PubMed  PubMed Central  Google Scholar 

  45. Hellstrand K, Martner A, Bergstrom T (2013) Valganciclovir in patients with glioblastoma. N Engl J Med 369:2066–2067

    CAS  PubMed  Google Scholar 

  46. Capone I, Marchetti P, Ascierto PA et al (2018) Sexual dimorphism of immune responses: a new perspective in cancer immunotherapy. Front Immunol 9:552

    PubMed  PubMed Central  Google Scholar 

  47. Taneja V (2018) Sex hormones determine immune response. Front Immunol 9:1931

    PubMed  PubMed Central  Google Scholar 

  48. Fischer J, Jung N, Robinson N, Lehmann C (2015) Sex differences in immune responses to infectious diseases. Infection 43:399–403

    CAS  PubMed  Google Scholar 

  49. Nunn CL, Lindenfors P, Pursall ER, Rolff J (2009) On sexual dimorphism in immune function. Philos Trans R Soci B 364:61–69

    Google Scholar 

  50. McCombe PA, Greer JM (2014) Sexual dimorphism in the immune system. Academic Press, New York, pp 319–328

    Google Scholar 

  51. van der Heiden M, van Zelm MC, Bartol SJW et al (2016) Differential effects of Cytomegalovirus carriage on the immune phenotype of middle-aged males and females. Sci Rep 6:26892

    PubMed  PubMed Central  Google Scholar 

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for profit sectors.

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Authors and Affiliations

  1. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA

    Olasunmbo O. Okedele, Heather H. Nelson, Mosun L. Oyenuga & Anna Prizment

  2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Heather H. Nelson, Bharat Thyagarajan & Anna Prizment

  3. Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA

    Bharat Thyagarajan

  4. Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Phillips Wangensteen Building, 516 Delaware Street SE, Minneapolis, MN, 55455, USA

    Anna Prizment

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  1. Olasunmbo O. Okedele
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Correspondence to Anna Prizment.

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Okedele, O.O., Nelson, H.H., Oyenuga, M.L. et al. Cytomegalovirus and cancer-related mortality in the national health and nutritional examination survey. Cancer Causes Control 31, 541–547 (2020). https://doi.org/10.1007/s10552-020-01296-y

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  • DOI: https://doi.org/10.1007/s10552-020-01296-y

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