Pharmacogenetics of lymphomas

he term lymphoma indicates a heterogeneous group of malignancies derived from lymphoid cells. In Western countries, lymphomas represent the third most frequent cancer, with an incidence that is increasing at the rate of 3% per year. To date, lymphoma represent are the fifth cause of cancer-related death. The clinical course of lymphoma is highly heterogeneous, and is characterized by a wide range of outcomes as documented by a 10-years survival probability ranging from 30% to 90%. Factors affecting the clinical heterogeneity of lymphomas include the pathologic features of the tumor, the extension of the disease and the biological features of the neoplastic clone.

In the last few years, the treatment of lymphoma has been implemented by the introduction of monoclonal antibodies targeting tumor cells and by the development of new molecules targeting the pathways that are deregulated in tumor cells. Although advances in treatment and identification of clinical indicators have led to improved prognosis and have allowed some tailoring of therapy, a significant fraction of lymphoma patients still fail treatment and die of their disease because of refractoriness, relapse or toxic death. This observation prompts investigations aimed at identifying at diagnosis patients that are at high risk of death in order to tailor treatment. Our center has a long standing experience in the field of lymphoma biology and in the identification of biological prognosticators for this disease. Beside the clinical features and the biology of tumor cells, also the genetic background of the host may be relevant for lymphoma prognostication.

Pharmacogenetics investigates the impact of genetic variability of the host on interindividual differences concerning response to drugs. The main aim of pharmacogenetics of the host is to optimize therapy based on the patient's genotype, in order to maximize therapeutic efficacy and, simultaneously, minimize drug side effects.

The center is leading a project aimed at identifying a priori (i.e., at the time of diagnosis) specific polymorphisms or specific combinations of polymorphisms that are predictive of efficacy and of toxicity of chemotherapy in patients affected by lymphoma.

On these general grounds, the project may therefore specifically enable:

i) the identification of novel markers for prognostic stratification and for toxicity prediction in the context of lymphoma therapy;

ii) the construction of a model for dose adjustment of drugs included in chemotherapy regimens in order to maximize therapeutic benefit and minimize treatment toxicity for lymphoma patients;

iii) the design of clinical trials aimed at prospectively tailoring lymphoma therapy.


Project leaders: Gianluca Gaidano, Davide Rossi.

Clinical Centers: Divisione di Ematologia (Ospedale “Maggiore della Carità”, Novara).


Publications

Rossi D, Rasi S, Di Rocco A, Fabbri A, Forconi F, Gloghini A, Bruscaggin A, Franceschetti S, Fangazio M, De Paoli L, Bruna R, Capello D, Chiappella A, Lobetti Bodoni C, Giachelia M, Tisi MC, Pogliani EM, Lauria F, Ladetto M, Hohaus S, Martelli M, Vitolo U, Carbone A, Foà R, Gaidano G. The host genetic background of DNA repair mechanisms is an independent predictor of survival in diffuse large B-cell lymphoma. Blood. 2011 Feb 24;117(8):2405-13.

Rossi D, Rasi S, Franceschetti S, Capello D, Castelli A, De Paoli L, Ramponi A, Chiappella A, Pogliani EM, Vitolo U, Kwee I, Bertoni F, Conconi A, Gaidano G. Analysis of the host pharmacogenetic background for prediction of outcome and toxicity in diffuse large B-cell lymphoma treated with R-CHOP21. Leukemia. 2009;23:1118-26.

Rossi D, Cerri M, Deambrogi C, Sozzi E, Cresta S, Rasi S, De Paoli L, Spina V, Gattei V, Capello D, Forconi F, Lauria F, Gaidano G. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Clin Cancer Res. 2009;15:995-1004.

Aydin S, Rossi D, Bergui L, D'Arena G, Ferrero E, Bonello L, Omedé P, Novero D, Morabito F, Carbone A, Gaidano G, Malavasi F, Deaglio S.CD38 gene polymorphism and chronic lymphocytic leukemia: a role in transformation to Richter syndrome? Blood. 2008;111:5646-53.

Rossi D, Rasi S, Capello D, Gaidano G. Prognostic assessment of BCL2-938C>A polymorphism in chronic lymphocytic leukemia. Blood. 2008;111:466-8.

Rossi D, Zucchetto A, Rossi FM, Capello D, Cerri M, Deambrogi C, Cresta S, Rasi S, De Paoli L, Bodoni CL, Bulian P, Del Poeta G, Ladetto M, Gattei V, Gaidano G. CD49d expression is an independent risk factor of progressive disease in early stage chronic lymphocytic leukemia. Haematologica. 2008;93:1575-9.

Rossi D, Spina V, Cerri M, Rasi S, Deambrogi C, De Paoli L, Laurenti L, Maffei R, Forconi F, Bertoni F, Zucca E, Agostinelli C, Cabras A, Lucioni M, Martini M, Magni M, Deaglio S, Ladetto M, Nomdedeu JF, Besson C, Ramponi A, Canzonieri V, Paulli M, Marasca R, Larocca LM, Carbone A, Pileri SA, Gattei V, Gaidano G. Stereotyped B-Cell Receptor Is an Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter Syndrome. Clin Cancer Res. 2009; doi: 10.1158/1078-0432.CCR-08-3266.

Rossi D, Lobetti Bodoni C, Genuardi E, Monitillo L, Drandi D, Cerri M, Deambrogi C, Ricca I, Rocci A, Ferrero S, Bernocco E, Capello D, De Paoli L, Bergui L, Boi M, Omedè P, Massaia M, Tarella C, Passera R, Boccadoro M, Gaidano G, Ladetto M. Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia. Leukemia. 2009;23:1062-72.

Ferreri AJ, Dell'Oro S, Capello D, Ponzoni M, Iuzzolino P, Rossi D, Pasini F, Ambrosetti A, Orvieto E, Ferrarese F, Arrigoni G, Foppoli M, Reni M, Gaidano G. Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas. Br J Haematol. 2004;126:657-64.

Rossi D, Capello D, Gloghini A, Franceschetti S, Paulli M, Bhatia K, Saglio G, Vitolo U, Pileri SA, Esteller M, Carbone A, Gaidano G. Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia. Haematologica. 2004;89:154-64.

Esteller M, Gaidano G, Goodman SN, Zagonel V, Capello D, Botto B, Rossi D, Gloghini A, Vitolo U, Carbone A, Baylin SB, Herman JG. Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. J Natl Cancer Inst. 2002;94:26-32.