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Variation in risk and outcomes of Epstein–Barr virus-associated breast cancer by epidemiologic characteristics and virus detection strategies: an exploratory study

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Abstract

Purpose

A relationship of Epstein–Barr virus (EBV) and breast cancer etiology and outcome may have clinical utility and potential to enhance understanding of tumor biology. Research to date has yielded variable results, likely reflecting differing virus detection assays and unaddressed epidemiologic heterogeneity across studies.

Methods

Applying our novel, five-target assay detection strategy in an exploratory study, we examined demographic, clinical, and tumor characteristics, and overall survival, associated with EBV positivity in breast adenocarcinomas from 59 non-Hispanic white and 68 Hispanic women sampled by age (<50, 50+) and stage (localized, regional/remote) and examined associations based on single assay targets.

Results

EBV was localized only to lymphocytes. Nevertheless, viral prevalence, although low, varied across patient subgroups. Adjusted odds ratios (OR) for EBV positivity were lower for younger Hispanic than white women (p interaction = 0.05), and marginally higher for larger [OR (95% confidence intervals) 1.03 (1.00–1.05) per mm increase] and right-sided [2.8 (0.97–7.8)] tumors. In whites, ORs were marginally higher for larger tumors [1.04 (1.00–1.07)] and marginally lower for age 50+ [0.24 (0.06–1.03)]; in Hispanics, ORs were higher for ER negative [5.6 (1.1–30.5)], and marginally higher for right-sided, tumors [5.8 (0.94–36.2)]. Survival was suggestively poorer for EBV-positive than EBV-negative tumors in older women with localized disease. EBV associations differed across single assay targets, indicating variation in prior findings likely due to assay performance.

Conclusions

The differing EBV associations by age and race/ethnicity suggest a non-random role of EBV in breast cancer and support further study using multi-target assays, relevant epidemiologic design, and a larger study sample.

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References

  1. Huo Q, Zhang N, Yang Q (2012) Epstein–Barr virus infection and sporadic breast cancer risk: a meta-analysis. PLoS One 7:e31656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Joshi D, Buehring GC (2012) Are viruses associated with human breast cancer? Scrutinizing the molecular evidence. Breast Cancer Res Treat 135:1–15

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  4. Glaser SL, Hsu JL, Gulley ML (2004) Epstein–Barr virus and breast cancer: state of the evidence for viral carcinogenesis. Cancer Epidemiol Biomarkers Prev 13:688–697

    CAS  PubMed  Google Scholar 

  5. Zekri AR, Bahnassy AA, Mohamed WS et al (2012) Epstein–Barr virus and breast cancer: epidemiological and molecular study on Egyptian and Iraqi women. J Egypt Natl Canc Inst 24:123–131

    Article  PubMed  Google Scholar 

  6. Rickinson AB (2014) Co-infections, inflammation and oncogenesis: future directions for EBV research. Semin Cancer Biol 26:99–115

    Article  CAS  PubMed  Google Scholar 

  7. Corbex M, Bouzbid S, Traverse-Glehen A et al (2014) Prevalence of papillomaviruses, polyomaviruses, and herpesviruses in triple-negative and inflammatory breast tumors from Algeria compared with other types of breast cancer tumors. PLoS One 9:e114559

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gyu Lee H, Kim H, Jung Kim E et al. (2015) Targeted therapy for Epstein–Barr virus-associated gastric carcinoma using low-dose gemcitabine-induced lytic activation. Oncotarget 6:31018–31029

    Google Scholar 

  9. Stoker S, Novalić Z, Wildeman M et al (2015) Epstein–Barr virus-targeted therapy in nasopharyngeal carcinoma. J Cancer Res Clin Oncol 141:1845–1857

    Article  CAS  PubMed  Google Scholar 

  10. Tse E, Kwong Y-L (2015) Epstein Barr virus-associated lymphoproliferative diseases: the virus as a therapeutic target. Exp Mol Med 47:e136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Murray PG (2006) Epstein–Barr virus in breast cancer: artefact or aetiological agent? J Pathol 209:427–429

    Article  CAS  PubMed  Google Scholar 

  12. Ransohoff DF, Gourlay ML (2010) Sources of bias in specimens for research about molecular markers for cancer. J Clin Oncol 28:698–704

    Article  PubMed  Google Scholar 

  13. Bonnet M, Guinebretiere JM, Kremmer E et al (1999) Detection of Epstein–Barr virus in invasive breast cancers. J Natl Cancer Inst 91:1376–1381

    Article  CAS  PubMed  Google Scholar 

  14. Fina F, Romain S, Ouafik L et al (2001) Frequency and genome load of Epstein–Barr virus in 509 breast cancers from different geographical areas. Br J Cancer 84:783–790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Joshi D, Quadri M, Gangane N, Joshi R, Gangane N (2009) Association of Epstein Barr virus infection (EBV) with breast cancer in rural Indian women. PLoS One 4:e8180

    Article  PubMed  PubMed Central  Google Scholar 

  16. DeSantis C, Ma J, Bryan L, Jemal A (2014) Breast cancer statistics, 2013. CA Cancer J Clin 64:52–62

    Article  PubMed  Google Scholar 

  17. Hung MC, Ekwueme DU, Rim SH, White A (2016) Racial/ethnicity disparities in invasive breast cancer among younger and older women: An analysis using multiple measures of population health. Cancer Epidemiol 45:112–118

    Article  PubMed  Google Scholar 

  18. Glaser SL, Gulley ML, Clarke CA et al (2008) Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations. Int J Cancer 123:1499–1507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vo QN, Geradts J, Gulley ML, Boudreau DA, Bravo JC, Schneider BG (2002) Epstein–Barr virus in gastric adenocarcinomas: association with ethnicity and CDKN2A promoter methylation. J Clin Pathol 55:669–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ryan JL, Fan H, Glaser SL, Schichman SA, Raab-Traub N, Gulley ML (2004) Epstein–Barr virus quantitation by real-time PCR targeting multiple gene segments: a novel approach to screen for the virus in paraffin-embedded tissue and plasma. J Mol Diagn 6:378–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Thorne LB, Ryan JL, Elmore SH, Glaser SL, Gulley ML (2005) Real-time PCR measures Epstein–Barr Virus DNA in archival breast adenocarcinomas. Diagn Mol Pathol 14:29–33

    Article  CAS  PubMed  Google Scholar 

  22. NAACCR Race and Ethnicity Work Group (2011) NAACCR Guideline for Enhancing Hispanic/Latino Identification: Revised NAACCR Hispanic/Latino Identification Algorithm [NHIA v2.2.1]. North American Association of Central Cancer Registries, Springfield, IL

    Google Scholar 

  23. Gomez SL, Glaser SL (2005) Quality of cancer registry birthplace data for Hispanics living in the United States. Cancer Causes Control 16:713–723

    Article  PubMed  Google Scholar 

  24. Keegan TH, John EM, Fish KM, Alfaro-Velcamp T, Clarke CA, Gomez SL (2010) Breast cancer incidence patterns among California Hispanic women: differences by nativity and residence in an enclave. Cancer Epidemiol Biomarkers Prev 19:1208–1218

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ryan J, Shen Y-J, Morgan D et al (2012) Epstein–Barr virus infection is common in inflamed gastrointestinal mucosa. Dig Dis Sci 57:1887–1898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tang W, Fan H, Schroeder J et al (2013) Atypical Epstein–Barr viral genomic structure in lymphoma tissue and lymphoid cell lines. Diagn Mol Pathol 22:91–101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gulley ML, Tang W (2008) Laboratory assays for Epstein–Barr virus-related disease. J Mol Diagn 10:279–292

    Article  PubMed  PubMed Central  Google Scholar 

  28. Mazouni C, Fina F, Romain S, Ouafik LH, Bonnier P, Martin P-M (2015) Outcome of Epstein–Barr virus-associated primary breast cancer. Mol Clin Oncol 3:295–298

    PubMed  Google Scholar 

  29. Hachana M, Amara K, Ziadi S, Romdhane E, Gacem RB, Trimeche M. (2011) Investigation of Epstein–Barr virus in breast carcinomas in Tunisia. Pathol Res Pract 207:695–700.

    Article  PubMed  Google Scholar 

  30. Fawzy S, Sallam M, Mohammad Awad N (2008) Detection of Epstein–Barr virus in breast carcinoma in Egyptian women. Clin Biochem 41:486–492

    Article  CAS  PubMed  Google Scholar 

  31. Mohammadizadeh F, Zarean M, Abbasi M (2014) Association of Epstein–Barr virus with invasive breast carcinoma and its impact on well-known clinicopathologic parameters in Iranian women. Advanced. Biomed Res 3:141

    Google Scholar 

  32. Ryan JL, Morgan DR, Dominguez RL et al (2009) High levels of Epstein–Barr virus DNA in latently infected gastric adenocarcinoma. Lab Invest J Tech Methods Pathol 89:80–90

    Article  CAS  Google Scholar 

  33. Khan G, Philip PS, Al Ashari M, Houcinat Y, Daoud S (2011) Localization of Epstein–Barr virus to infiltrating lymphocytes in breast carcinomas and not malignant cells. Exp Mol Pathol 91:466–470

    Article  CAS  PubMed  Google Scholar 

  34. Khabaz MN (2013) Association of Epstein–Barr virus infection and breast carcinoma. Arch Med Sci 9:745–751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hu H, Luo M-L, Desmedt C et al (2016) Epstein–Barr virus infection of mammary epithelial cells promotes malignant transformation. EBioMedicine 9:148–160

    Article  PubMed  PubMed Central  Google Scholar 

  36. U.S. Department of Commerce Economics and Statistics Administration (2001) The Hispanic Population: Census 2000 Brief. U.S. Census Bureau, Washington, DC

  37. Morales-Sánchez A, Molina-Muñoz T, Martínez-López JLE, et al. (2013) No association between Epstein–Barr virus and mouse mammary tumor virus with breast cancer in Mexican women. Sci Reports 3:2970

  38. Hjalgrim H, Askling J, Rostgaard K et al (2003) Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N Engl J Med 349:1324–1332

    Article  CAS  PubMed  Google Scholar 

  39. Staras SAS, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ (2006) Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clin Infect Dis 43:1143–1151

    Article  PubMed  Google Scholar 

  40. Dowd JB, Palermo T, Brite J, McDade TW, Aiello A (2013) Seroprevalence of Epstein–Barr virus infection in U.S. children ages 6–19, 2003–2010. PLoS One 8:e64921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dowd JB, Zajacova A, Aiello A (2009) Early origins of health disparities: Burden of infection, health, and socioeconomic status in U.S. children. Soc Sci Med 68:699–707

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hsu JL, Glaser SL (2000) Epstein–Barr virus-associated malignancies: epidemiologic patterns and etiologic implications. Crit Rev. Hematol Oncol 34:27–53

    CAS  Google Scholar 

  43. Glaser SL, Clarke CA, Chang ET, Yang J, Gomez SL, Keegan TH (2014) Hodgkin lymphoma incidence in California Hispanics: influence of nativity and tumor Epstein–Barr virus. Cancer Causes Control 25:709–725

    Article  CAS  PubMed  Google Scholar 

  44. Roychoudhuri R, Putcha V, Moller H (2006) Cancer and laterality: a study of the five major paired organs (UK). Cancer Causes Control 17:655–662

    Article  PubMed  Google Scholar 

  45. Sughrue T, Brody JP (2014) Breast tumor laterality in the United States depends upon the country of birth, but not race. PLoS One 9:e103313

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dane S, Erdem T, Gümüştekin K (2001) Cell-mediated immune hypersensitivity is stronger in the left side of the body than the right in healthy young subjects. Percept Mot Skills 93:329–332

    Article  CAS  PubMed  Google Scholar 

  47. Dane Ş (2009) Peripheral asymmetry of cell-mediated immunity. Int J Neurosci 119:611–615

    Article  CAS  PubMed  Google Scholar 

  48. Rickinson AB, Long HM, Palendira U, Münz C, Hislop AD (2014) Cellular immune controls over Epstein–Barr virus infection: new lessons from the clinic and the laboratory. Trends Immunol 35:159–169

    Article  CAS  PubMed  Google Scholar 

  49. Glenn WK, Heng B, Delprado W, Iacopetta B, Whitaker NJ, Lawson JS (2012) Epstein–Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer. PLoS One 7:e48788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Aguayo F, Khan N, Koriyama C et al (2011) Human papillomavirus and Epstein–Barr virus infections in breast cancer from Chile. Infectious Agents Cancer 6:7-

    Article  PubMed  PubMed Central  Google Scholar 

  51. Lorenzetti MA, De Matteo E, Gass H et al (2010) Characterization of Epstein Barr virus latency pattern in Argentine breast carcinoma. PLoS One 5:e13603

    Article  PubMed  PubMed Central  Google Scholar 

  52. Mohammed ZMA, Going JJ, Edwards J, Elsberger B, McMillan DC (2013) The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer. Br J Cancer 109:1676–1684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors acknowledge contributions to this study by the late Sarah Shema, Sandra Elmore, Patricia Weeks, Rita Leung, David O. Nelson, and Meg McKinley. The collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the state-wide cancer-reporting program mandated by California Health and Safety Code, Section 103885; by the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program under contracts N01-PC-35136 awarded to the Cancer Prevention Institute of California, N02-PC-15105 awarded to the Public Health Institute, HHSN261201000140C awarded to the Cancer Prevention Institute of California, HHSN261201000035C awarded to the University of Southern California, and HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreements U55/CCR921930-02 awarded to the Public Health Institute and U58DP003862-01 awarded to the California Department of Public Health. The ideas and opinions expressed herein are those of the authors, and endorsement by the State of California Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred.

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Authors and Affiliations

  1. Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA, 94538, USA

    Sally L. Glaser, Alison J. Canchola, Theresa H. M. Keegan & Christina A. Clarke

  2. Department of Health Research and Policy (Epidemiology), Stanford Medicine, Stanford, CA, 94306, USA

    Sally L. Glaser & Christina A. Clarke

  3. Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, 95817, USA

    Theresa H. M. Keegan

  4. Department of Pathology, Stanford Medicine, Stanford, CA, 94305, USA

    Teri A. Longacre

  5. Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Margaret L. Gulley

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  1. Sally L. Glaser
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  6. Margaret L. Gulley
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Correspondence to Sally L. Glaser.

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Funding

This work was supported in part by the California Breast Cancer Research Program (9WB-0005) (Dr. Glaser), the National Cancer Institute (R03 CA101500) (Dr. Gulley), and the Safeway Foundation (Dr. Glaser).

Conflict of interest

Dr. Clarke has received institutional support for breast cancer research from Genentech and Grail Bio. The other authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

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This article did not involve human participants and informed consent was not required by the Institutional Review Boards reviewing the study.

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Glaser, S.L., Canchola, A.J., Keegan, T.H.M. et al. Variation in risk and outcomes of Epstein–Barr virus-associated breast cancer by epidemiologic characteristics and virus detection strategies: an exploratory study. Cancer Causes Control 28, 273–287 (2017). https://doi.org/10.1007/s10552-017-0865-3

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