The role of ABCB1 polymorphism as a prognostic marker for primary central nervous system lymphoma
To investigate the possible role of functional single nucleotide polymorphism (SNP) in circadian genes as prognostic markers of primary central nervous system lymphoma (PCNSL). We conducted a prospective study using data from Huashan Hospital 2006–2015 and followed up 91 PCNSL patients until June 30, 2016. The survival of patients with different prognostic factors was compared by log-rank test. Univariate and multivariate analyses were performed by Cox regression. During a long-term follow-up (6–110 months), overall survival (OS) was 32 months (95% CI, 13.3–91.1) and progression-free survival (PFS) was 23 months (95% CI, 9.0–41.0) for the entire cohort. Age (P = 0.046, P = 0.001) and performance status (PS) score (P = 0.013, P = 0.003) showed differences in OS and PFS. ABCB1 rs1045642 variant showed significant difference in PFS between patients with CC genotype and those with CT/TT genotypes (P = 0.020). In multivariate analysis, age (HR = 2.3; 95% CI, 1.2–4.2, P = 0.008), PS (HR = 2.4; 95% CI, 1.3–4.4, P = 0.007), and ABCB1 rs1045642 (HR = 1.9; 95% CI, 1.0–3.3, P = 0.036) were the independent risk factors for PFS. In our results, the most important prognostic factors associated with higher risk of progression were ABCB1 rs1045642 CC genotype, PS > 2, and older age.
KeywordsABCB1 gene Primary central nervous system lymphoma Single nucleotide polymorphism Prognostic factors
primary central nervous system lymphoma
diffuse large B cell lymphomas
single nucleotide polymorphism
18F-2-fluoro-2-deoxy-d-glucose positron emission tomography
magnetic resonance imaging
acute lymphoblastic leukemia
Bobin Chen, Hui Kang, and Xiaoping Xu designed the research. Hui Kang, Dongxiao Zhuang, and Dina Suolitiken collected the clinical data. Ting Wu, Hui Kang, Yan Ma, and Zhiguang Lin performed the research. Ting Wu analyzed the data and wrote the manuscript. All authors read and approved the final manuscript.
This research was supported/funded by the Chinese Medicine Scientific Research Foundation of Shanghai Municipal Commission of Health and Family Planning (Grant No. 2014JP003A), the Science and Technology Development Fund of Bao Shan District (Grant No. 13-E-34), and the Shanghai Hospital Development Center (Grant No.16CR2043B).
Compliance with ethical standards
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Huashan Hospital. Written informed consent was obtained from the patients.
Consent for publication
The authors declare that they have no competing interests.
- 2.Camilleri-Broet S, Criniere E, Broet P, Delwail V, Mokhtari K, Moreau A, Kujas M, Raphael M, Iraqi W, Sautes-Fridman C, Colombat P, Hoang-Xuan K, Martin A (2006) A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 107(1):190–196. https://doi.org/10.1182/blood-2005-03-1024 CrossRefGoogle Scholar
- 3.Carbone A, Gloghini A, Larocca LM, Capello D, Pierconti F, Canzonieri V, Tirelli U, Dalla-Favera R, Gaidano G (2001) Expression profile of MUM1/IRF4, BCL-6, and CD138/syndecan-1 defines novel histogenetic subsets of human immunodeficiency virus-related lymphomas. Blood 97(3):744–751CrossRefGoogle Scholar
- 5.Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, Calderoni A, Rossi A, Vavassori V, Conconi A, Devizzi L, Berger F, Ponzoni M, Borisch B, Tinguely M, Cerati M, Milani M, Orvieto E, Sanchez J, Chevreau C, Dell’Oro S, Zucca E, Cavalli F (2003) Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol 21(2):266–272CrossRefGoogle Scholar
- 6.Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W, Schultz C, Leibel S, Nelson D, Mehta M, DeAngelis LM (2006) Primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 24(36):5711–5715. https://doi.org/10.1200/jco.2006.08.2941 CrossRefGoogle Scholar
- 7.Roth P, Keller A, Hoheisel JD, Codo P, Bauer AS, Backes C, Leidinger P, Meese E, Thiel E, Korfel A, Weller M (2015) Differentially regulated miRNAs as prognostic biomarkers in the blood of primary CNS lymphoma patients. Eur J Cancer 51(3):382–390. https://doi.org/10.1016/j.ejca.2014.10.028 CrossRefGoogle Scholar
- 10.Lee KM, Lan Q, Kricker A, Purdue MP, Grulich AE, Vajdic CM, Turner J, Whitby D, Kang D, Chanock S, Rothman N, Armstrong BK (2007) One-carbon metabolism gene polymorphisms and risk of non-Hodgkin lymphoma in Australia. Hum Genet 122(5):525–533. https://doi.org/10.1007/s00439-007-0431-2 CrossRefGoogle Scholar
- 11.Wang SS, Maurer MJ, Morton LM, Habermann TM, Davis S, Cozen W, Lynch CF, Severson RK, Rothman N, Chanock SJ, Hartge P, Cerhan JR (2009) Polymorphisms in DNA repair and one-carbon metabolism genes and overall survival in diffuse large B-cell lymphoma and follicular lymphoma. Leukemia 23(3):596–602. https://doi.org/10.1038/leu.2008.240 CrossRefGoogle Scholar
- 12.Al-Dayel F, Al-Rasheed M, Ibrahim M, Bu R, Bavi P, Abubaker J, Al-Jomah N, Mohamed GH, Moorji A, Uddin S, Siraj AK, Al-Kuraya K (2008) Polymorphisms of drug-metabolizing enzymes CYP1A1, GSTT and GSTP contribute to the development of diffuse large B-cell lymphoma risk in the Saudi Arabian population. Leuk Lymphoma 49(1):122–129. https://doi.org/10.1080/10428190701704605 CrossRefGoogle Scholar
- 13.Gra OA, Glotov AS, Nikitin EA, Glotov OS, Kuznetsova VE, Chudinov AV, Sudarikov AB, Nasedkina TV (2008) Polymorphisms in xenobiotic-metabolizing genes and the risk of chronic lymphocytic leukemia and non-Hodgkin’s lymphoma in adult Russian patients. Am J Hematol 83(4):279–287. https://doi.org/10.1002/ajh.21113 CrossRefGoogle Scholar
- 14.Morton LM, Schenk M, Hein DW, Davis S, Zahm SH, Cozen W, Cerhan JR, Hartge P, Welch R, Chanock SJ, Rothman N, Wang SS (2006) Genetic variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2) and risk of non-Hodgkin lymphoma. Pharmacogenet Genomics 16(8):537–545. https://doi.org/10.1097/01.fpc.0000215071.59836.29 CrossRefGoogle Scholar
- 15.Cerhan JR, Habermann TM, Maurer MJ, Wooldridge JE, Ansell SM, Nowakowski GS, Micallef IN, Thompson CA, Wang AH, Macon WR, Syrbu SI, Slager SL, Witzig TE, Link B (2010) Genetic polymorphisms in genes involved in R-CHOP metabolism and event-free and overall survival in diffuse large B-cell lymphoma. Blood 116(21):439–439Google Scholar
- 16.Chen BB, Xu XP, Shen L, Han TJ, Lin ZG, Chen Z, Kang H, Huang B, Lin GW (2013) Prognostic value of clinical characteristics and immunophenotypic biomarkers in 115 patients with primary central nervous system lymphoma. Chin Med J 126(3):482–487Google Scholar
- 17.Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science (New York, NY) 323(5922):1718–1722. https://doi.org/10.1126/science.1168750 CrossRefGoogle Scholar
- 20.Vinolas N, Provencio M, Reguart N, Cardenal F, Alberola V, Sanchez-Torres JM, Baron FJ, Cobo M, Maestu I, Moreno I, Mesia C, Izquierdo A, Felip E, Lopez-Brea M, Marquez A, Sanchez-Ronco M, Taron M, Santarpia MC, Rosell R (2011) Single nucleotide polymorphisms in MDR1 gen correlates with outcome in advanced non-small-cell lung cancer patients treated with cisplatin plus vinorelbine. Lung Cancer (Amsterdam, Netherlands) 71(2):191–198. https://doi.org/10.1016/j.lungcan.2010.05.005 CrossRefGoogle Scholar
- 22.Li Y, Yan PW, Huang XE, Li CG (2011) MDR1 gene C3435T polymorphism is associated with clinical outcomes in gastric cancer patients treated with postoperative adjuvant chemotherapy. Asian Pac J Cancer Prev 12(9):2405–2409Google Scholar
- 25.Gregers J, Green H, Christensen IJ, Dalhoff K, Schroeder H, Carlsen N, Rosthoej S, Lausen B, Schmiegelow K, Peterson C (2015) Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. Pharmacogenomics J 15(4):372–379. https://doi.org/10.1038/tpj.2014.81 CrossRefGoogle Scholar
- 26.Yang YL, Lin DT, Chang SK, Lin SR, Lin SW, Chiou RJ, Yen CT, Lin KH, Jou ST, Lu MY, Chang HH, Chang WH, Lin KS, Hu CY (2010) Pharmacogenomic variations in treatment protocols for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 54(2):206–211. https://doi.org/10.1002/pbc.22292 Google Scholar
- 27.Rao DN, Anuradha C, Vishnupriya S, Sailaja K, Surekha D, Raghunadharao D, Rajappa S (2010) Association of an MDR1 gene (C3435T) polymorphism with acute leukemia in India. Asian Pac J Cancer Prev 11(4):1063–1066Google Scholar
- 28.Jamroziak K, Mlynarski W, Balcerczak E, Mistygacz M, Trelinska J, Mirowski M, Bodalski J, Robak T (2004) Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol 72(5):314–321. https://doi.org/10.1111/j.1600-0609.2004.00228.x CrossRefGoogle Scholar
- 30.Suthandiram S, Gan GG, Zain SM, Bee PC, Lian LH, Chang KM, Ong TC, Mohamed Z (2014) Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies. Pharmacogenomics 15(11):1479–1494. https://doi.org/10.2217/pgs.14.97 CrossRefGoogle Scholar
- 32.Organista-Nava J, Gomez-Gomez Y, Saavedra-Herrera MV, Rivera-Ramirez AB, Teran-Porcayo MA, Alarcon-Romero Ldel C, Illades-Aguiar B, Leyva-Vazquez MA (2010) Polymorphisms of the gamma-glutamyl hydrolase gene and risk of relapse to acute lymphoblastic leukemia in Mexico. Leuk Res 34(6):728–732. https://doi.org/10.1016/j.leukres.2009.11.027 CrossRefGoogle Scholar