Use of Molecular Testing to Identify a Cluster of Patients with Polycythemia Vera in Eastern Pennsylvania Vincent Seaman, 1 Aisha Jumaan, 1 Emad Yanni, 1 Brian Lewis, 1 Jonathan Neyer, 1 Paul Roda, 2 Mingjiang Xu, 3,4 and Ronald Hoffman 3,4 1 Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention, Atlanta, Georgia; 2 Geisinger/HazletonCancerCenter,Hazleton,Pennsylvania; 3 Hematology/OncologySection,UniversityofIllinois CollegeofMedicine,Chicago,Illinois;and 4 Hematology/OncologySection,TischCancerInstitute,and DepartmentofMedicine,MountSinaiSchoolofMedicine,NewYork,NewYork Abstract Background: The role of the environment in the origin of polycythemia vera has not been well documented. Recently, molecular diagnostic tools have been devel- oped to facilitate the diagnosis of polycythemia vera. A cluster of patients with polycythemia vera was sus- pected in three countries in eastern Pennsylvania where there have long been a concern about environ- ment hazards. Methods: Rigorous clinical criteria and JAK2 617V>F testing were used to confirm the diagnosis of polycy- themia vera in patients in this area. Participants included cases of polycythemia vera from the 2001 to 2005 state cancer registry as well as self- and physician- referred cases. Finding: A diagnosis of polycythemia vera was con- firmed in 53% of 62 participants using WHO criteria, which includes JAK2 617V>F testing. A statistically significant cluster of cases (P < 0.001) was identified where the incidence of polycythemia vera was 4.3 times that of the rest of the study area. The area of the cluster contained numerous sources of hazardous material including waste-coal power plants and U.S. Environ- mental Protection Agency Superfund sites. Interpretation: The diagnosis of polycythemia vera based solely on clinical criteria is frequently erroneous, suggesting that our prior knowledge of the epide- miology of this disease might be inaccurate. The JAK2 617V>F mutational analysis provides diagnostic clarity and permitted the confirmation of a cluster of polycythemia vera cases not identified by traditional clinical and pathologic diagnostic criteria. The close proximity of this cluster to known areas of hazardous material exposure raises concern that such environ- mental factors might play a role in the origin of polycythemia vera. (Cancer Epidemiol Biomarkers Prev2009;18(2):534–40) Introduction Polycythemia vera is a chronic hematologic malignancy characterized by erythrocytosis, not infrequently leuko- cytosis and thrombocytosis, splenomegaly, and marrow hypercellularity. Patients exhibit a predisposition to develop vascular thrombosis and undergo evolution to myelofibrosisandacuteleukemia(1,2).Lessthan10%of patients develop polycythemia vera-related myelofibro- sis, a marrow failure state that may lead to transforma- tion to acute leukemia in a small number of patients (<2%overall;refs.1-3).Polycythemiaveraisamemberof a group of hematologic malignancies termed myelopro- liferative disorders (MPD), which also include chronic myeloid leukemia, essential thrombocythemia, and pri- mary myelofibrosis. These disorders are clonal in origin andareassociatedwithhematopoieticprogenitorhyper- sensitivity to cytokines (4). Greater insight into the pathology of the MPD has occurred over the past 3 years with the discovery of an acquiredpointmutationinanintracellularkinase,JAK2, which plays a pivotal role in the cytokine regulation of hematopoiesis. The recurrent mutation in JAK2, consist- ing of a valine-to-phenylalanine change at position 617 (JAK2 617V>F) in the JH2 pseudokinase domain, occurs in >90% of patients with polycythemia vera and 50% of other MPD patients (either essential thrombocythemia or primary myelofibrosis; refs. 5-7). The implementation ofmolecularteststodetectJAK2617V>Fhasrevolution- ized the manner by which physicians pursue the diagnosis of a MPD. The widespread availability of JAK2 617V>F testing has led to a revision of the diagnostic criteria for the MPD. This revision, which Cancer Epidemiol Biomarkers Prev 2009;18(2). February 2009 Received9/30/08;revised10/21/08;accepted11/3/08;publishedOnlineFirst2/3/09. Grant support: AgencyforToxicSubstancesandDiseaseRegistry,CentersforDisease Control and Prevention; Myeloproliferative Disorders Foundation; and National Cancer Institute grant P01-CA108671. V.SeamanandR.Hoffmanhadfullaccesstoallthedatainthestudyandtake responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design: V. Seaman, Ph.D.; A. Jumaan, Ph.D.; E. Yanni, M.D.; and R. Hoffman,M.D.Acquisitionofdata:V.Seaman,Ph.D.;J.Neyer,M.D.;E.Yanni,M.D.; P.Roda,M.D.;M.Xu,M.D.,Ph.D.;andR.Hoffman,M.D.Statisticalanalysis:B.Lewis; J. Neyer, M.D.; and E. Yanni, M.D. Analysis and interpretation of data: V. Seaman, Ph.D., and R. Hoffman, M.D. Critical revision of the article for important intellectual content:V.Seaman,Ph.D.;A.Jumaan,Ph.D.;B.Lewis;J.Neyer,M.D.;P.Roda,M.D.; E. Yanni, M.D.; M. Xu, M.D., Ph.D.; and R. Hoffman, M.D. Obtained funding: R. Hoffman, M.D. Study supervision: V. Seaman, Ph.D. Expert panel: Rueben Mesa, M.D. (Mayo Clinic School of Medicine), Josef T. Prchal, M.D. (University of Utah SchoolofMedicine),andP.Roda,M.D.(Geisinger/HazletonCancerCenter)provided consultation on cases where the diagnosis was made without sufficient evidence to clearly satisfy the case definition. Geospatial statistical consult: Carol Gotway- Crawford, Ph.D., and Owen Devine, Ph.D. (Centers for Disease Control and Prevention) provided expertise and recommendations for the geospatial cluster analysis. Field investigation support/case interviews: Lora Werner, M.P.H. and Ana Pomales, M.S. (Agency for Toxic Substances and Disease Registry Region 3); Kim Warren, M.P.H. (PADOH Northeast Region). Requests for reprints: Ronald Hoffman, Hematology/Oncology Section, Tisch Cancer Institute, and Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1079, New York, NY 10029. Phone: 212-241-2297; Fax: 212-876-5276. E-mail: Ronald.hoffman@mssm.edu Copyright D 2009 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-08-0922 534 Research. on October 2, 2021. © 2009 American Association for Cancer cebp.aacrjournals.org Downloaded from