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Grant Details

Grant Number: 5R01CA129539-02 Interpret this number
Primary Investigator: Cerhan, James
Organization: Mayo Clinic Rochester
Project Title: Molecular Epidemiology of Non-Hodgkin Lymphoma Survival
Fiscal Year: 2010
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Abstract

In 2008, over 66,000 people in the US will be diagnosed with Non-Hodgkin lymphoma (NHL), and over 19,000 will die of this cancer. Survival rates have only recently begun to improve, and the current 5-year survival rate is 66%. We have identified a number of candidate host (inherited) immune genes and DNA repair genes that individually and in aggregate predict survival for follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) beyond classic clinical and demographic prognostic factors. We have also found that pre-diagnosis smoking and obesity are associated with poorer overall NHL survival. We propose to replicate and extend these provocative findings. Furthermore, building off these findings, we will evaluate whether the association of host genetics is independent of tumor molecular markers, as well as begin to explore whether there are host–tumor interactions that impact disease progression and survival. The overall goal of this study is to identify host genetic and tumor molecular markers that predict event-free and overall survival in order to improve prognostication, better understand NHL pathophysiology, and ultimately help identify approaches to improve the survival of NHL patients. Our specific aims are: 1) To evaluate the association of polymorphisms in immune and DNA repair genes with event-free and overall survival from FL and DLBCL; 2) To evaluate the association of tumor molecular markers with event-free and overall survival from FL and DLBCL; and 3) To develop multivariate prediction models for FL and DLBCL that integrate standard demographic and clinical characteristics, treatment, host genetic variation (Aim 1) and tumor molecular markers (Aim 2) to predict eventfree and overall survival. In a secondary aim, we will evaluate the role of pre-diagnosis lifestyle factors with event-free and overall survival from NHL. To achieve these aims, we will use the Lymphoma Molecular Epidemiology Resource, an ongoing, prospective prognostic cohort study of newly diagnosed cases from the Mayo Clinic and the University of Iowa initiated in 2002. This resource has several methodologic strengths, including large sample size (>2200cases), central pathology review and classification, availability of tumor tissue, detailed baseline clinical prognostic data, initial and subsequent treatments, and a large patient population treated in the immunochemotherapy (rituximab) era. We have systematically collected detailed outcome data, which will allow us to evaluate both event-free and overall survival. We will also be able to evaluate host genetic and tumor molecular prognostic factors in the context of established demographic and clinical prognostic factors, as well as all treatment(s). Upon completion of these aims, we will have simultaneously evaluated the role of host genetic variation and molecular tumor markers in the prognosis of FL and DLBCL. If host genetic factors are confirmed as robust predictors of outcome, this could lead to a fundamental shift in how patient prognosis is evaluated by incorporating host genotype into prognostic models. Host genetics may also lead to a better understanding of NHL pathophysiology that could lead to new approaches to improve the survival of NHL patients.

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Publications

Host genetic variation in tumor necrosis factor and nuclear factor-κB pathways and overall survival in mantle cell lymphoma: A discovery and replication study.
Authors: Wang Y. , Habermann T.M. , Wang S.S. , Maurer M.J. , Sarangi V. , Link B.K. , Feldman A.L. , Inwards D.J. , Witzig T.E. , Cozen W. , et al. .
Source: American journal of hematology, 2019 Jun; 94(6), p. E153-E155.
EPub date: 2019-03-15.
PMID: 30815899
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Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis.
Authors: Kleinstern G. , Camp N.J. , Goldin L.R. , Vachon C.M. , Vajdic C.M. , de Sanjose S. , Weinberg J.B. , Benavente Y. , Casabonne D. , Liebow M. , et al. .
Source: Blood, 2018-06-07; 131(23), p. 2541-2551.
EPub date: 2018-04-19.
PMID: 29674426
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Cohort Profile: The Lymphoma Specialized Program of Research Excellence (SPORE) Molecular Epidemiology Resource (MER) Cohort Study.
Authors: Cerhan J.R. , Link B.K. , Habermann T.M. , Maurer M.J. , Feldman A.L. , Syrbu S.I. , Thompson C.A. , Farooq U. , Novak A.J. , Slager S.L. , et al. .
Source: International journal of epidemiology, 2017-12-01; 46(6), p. 1753-1754i.
PMID: 29025017
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A susceptibility locus for classical Hodgkin lymphoma at 8q24 near MYC/PVT1 predicts patient outcome in two independent cohorts.
Authors: Ghesquières H. , Larrabee B.R. , Casasnovas O. , Maurer M.J. , McKay J.D. , Ansell S.M. , Montgomery D. , Asmann Y.W. , Farrell K. , Verney A. , et al. .
Source: British journal of haematology, 2018 01; 180(2), p. 286-290.
EPub date: 2016-09-09.
PMID: 27716907
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FCGR3A/2A polymorphisms and diffuse large B-cell lymphoma outcome treated with immunochemotherapy: a meta-analysis on 1134 patients from two prospective cohorts.
Authors: Ghesquières H. , Larrabee B.R. , Haioun C. , Link B.K. , Verney A. , Slager S.L. , Ketterer N. , Ansell S.M. , Delarue R. , Maurer M.J. , et al. .
Source: Hematological oncology, 2017 Dec; 35(4), p. 447-455.
EPub date: 2016-06-10.
PMID: 27282998
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Genome-Wide Association Study of Event-Free Survival in Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy.
Authors: Ghesquieres H. , Slager S.L. , Jardin F. , Veron A.S. , Asmann Y.W. , Maurer M.J. , Fest T. , Habermann T.M. , Bene M.C. , Novak A.J. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015-11-20; 33(33), p. 3930-7.
EPub date: 2015-10-12.
PMID: 26460308
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A genome-wide association study of marginal zone lymphoma shows association to the HLA region.
Authors: Vijai J. , Wang Z. , Berndt S.I. , Skibola C.F. , Slager S.L. , de Sanjose S. , Melbye M. , Glimelius B. , Bracci P.M. , Conde L. , et al. .
Source: Nature communications, 2015-01-08; 6, p. 5751.
EPub date: 2015-01-08.
PMID: 25569183
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Elevated monoclonal and polyclonal serum immunoglobulin free light chain as prognostic factors in B- and T-cell non-Hodgkin lymphoma.
Authors: Witzig T.E. , Maurer M.J. , Habermann T.M. , Link B.K. , Micallef I.N. , Nowakowski G.S. , Ansell S.M. , Colgan J.P. , Inwards D.J. , Porrata L.F. , et al. .
Source: American journal of hematology, 2014 Dec; 89(12), p. 1116-20.
EPub date: 2014-09-26.
PMID: 25228125
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Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma.
Authors: Cerhan J.R. , Berndt S.I. , Vijai J. , Ghesquières H. , McKay J. , Wang S.S. , Wang Z. , Yeager M. , Conde L. , de Bakker P.I. , et al. .
Source: Nature genetics, 2014 Nov; 46(11), p. 1233-8.
EPub date: 2014-09-28.
PMID: 25261932
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Genetic polymorphisms in oxidative stress-related genes are associated with outcomes following treatment for aggressive B-cell non-Hodgkin lymphoma.
Authors: Gustafson H.L. , Yao S. , Goldman B.H. , Lee K. , Spier C.M. , LeBlanc M.L. , Rimsza L.M. , Cerhan J.R. , Habermann T.M. , Link B.K. , et al. .
Source: American journal of hematology, 2014 Jun; 89(6), p. 639-45.
EPub date: 2014-04-12.
PMID: 24633940
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Elevated serum monoclonal and polyclonal free light chains and interferon inducible protein-10 predicts inferior prognosis in untreated diffuse large B-cell lymphoma.
Authors: Witzig T.E. , Maurer M.J. , Stenson M.J. , Allmer C. , Macon W. , Link B. , Katzmann J.A. , Gupta M. .
Source: American journal of hematology, 2014 Apr; 89(4), p. 417-22.
EPub date: 2014-02-10.
PMID: 24382707
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CXCR5 polymorphisms in non-Hodgkin lymphoma risk and prognosis.
Authors: Charbonneau B. , Wang A.H. , Maurer M.J. , Asmann Y.W. , Zent C.S. , Link B.K. , Ansell S.M. , Weiner G.J. , Ozsan N. , Feldman A.L. , et al. .
Source: Cancer immunology, immunotherapy : CII, 2013 Sep; 62(9), p. 1475-84.
EPub date: 2013-06-28.
PMID: 23812490
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia.
Authors: Berndt S.I. , Skibola C.F. , Joseph V. , Camp N.J. , Nieters A. , Wang Z. , Cozen W. , Monnereau A. , Wang S.S. , Kelly R.S. , et al. .
Source: Nature genetics, 2013 Aug; 45(8), p. 868-76.
EPub date: 2013-06-16.
PMID: 23770605
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Germline variation in complement genes and event-free survival in follicular and diffuse large B-cell lymphoma.
Authors: Charbonneau B. , Maurer M.J. , Fredericksen Z.S. , Zent C.S. , Link B.K. , Novak A.J. , Ansell S.M. , Weiner G.J. , Wang A.H. , Witzig T.E. , et al. .
Source: American journal of hematology, 2012 Sep; 87(9), p. 880-5.
EPub date: 2012-06-20.
PMID: 22718493
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LIM domain only 2 protein expression, LMO2 germline genetic variation, and overall survival in diffuse large B-cell lymphoma in the pre-rituximab era.
Authors: Cerhan J.R. , Natkunam Y. , Morton L.M. , Maurer M.J. , Asmann Y. , Habermann T.M. , Vasef M.A. , Cozen W. , Lynch C.F. , Allmer C. , et al. .
Source: Leukemia & lymphoma, 2012 Jun; 53(6), p. 1105-12.
EPub date: 2012-01-03.
PMID: 22066713
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Host genetics in follicular lymphoma.
Authors: Cerhan J.R. .
Source: Best practice & research. Clinical haematology, 2011 Jun; 24(2), p. 121-34.
EPub date: 2011-05-05.
PMID: 21658613
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