TP53 polymorphism in plasma cell myeloma
Abstract
Introduction. Significant and accessible predictive factors for bortezomib treatment in plasma cell myeloma (PCM) are still lacking. TP53 codon 72 polymorphism (P72R) results in proline (P) or arginine (R) at 72 amino acid position, which causes synthesis of proteins with distinct functions. The aims of our study were to: 1) analyze whether this polymorphism is associated with an increased risk of PCM; 2) study whether the P72R polymorphism affects overall survival (OS) among PCM patients; 3) assess the possible association of the P72R polymorphism with sensitivity to bortezomib in cell cultures derived from PCM patients.
Material and methods. Genomic DNA from newly diagnosed 59 patients (without IgVH gene rearrangements and TP53 deletions) and 50 healthy blood donors were analyzed by RFLP-PCR to identify TP53 polymorphism. Chromosomal aberrations were detected by use of cIg-FISH. The lymphocyte cell cultures from a subgroup of 40 PCM patients were treated with bortezomib (1, 2 and 4 nM).
Results. The P allele of the P72R polymorphism was more common than the R allele in PMC patients compared to controls (39% vs. 24%), and the difference was significant (p = 0.02). The PP and PR genotypes (in combination) were more frequent among cases than in controls (65% vs. 42%, OR = 2.32, p = 0.04). At the cell culture level and 2 nM bortezomib concentration the PP genotype was associated with higher necrosis rates (10.5%) compared to the PR genotype (5.7%, p = 0.006) or the RR genotype (6.3%, p = 0.02); however, no effect of genotypes was observed at bortezomib concentrations of 1 and 4 nM. The shortest OS (12 months) was observed in patients with the PP genotype compared to patients with the PR or RR genotypes (20 months) (p = 0.04).
Conclusions. The results suggest that P72R polymorphisms may be associated with an increased PCM risk and may affect OS of PCM patients. However, we saw no consistent results of the polymorphism effect on apoptosis and necrosis in cell cultures derived from PCM patients. Further studies are need in this regard.
Keywords: TP53 genepolymorphismplasma cell myelomabortezomibapoptosisnecrosis
References
- Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011; 364(11): 1046–1060.
- Rajkumar S, Dimopoulos M, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The Lancet Oncology. 2014; 15(12): e538–e548.
- Bergsagel PL, Mateos MV, Gutierrez NC, et al. Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood. 2013; 121(6): 884–892.
- Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice. Blood Cancer J. 2015; 5: e365.
- Kumar SK, Mikhael JR, Buadi FK, et al. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009; 84(12): 1095–1110.
- Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002; 2(3): 175–187.
- Braggio E, Fonseca R, Fonseca R, et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood. 2002; 100(4): 1417–1424.
- Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004; 64(4): 1546–1558.
- Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23(12): 2210–2221.
- Boyd KD, Ross FM, Chiecchio L, et al. NCRI Haematology Oncology Studies Group. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial. Leukemia. 2012; 26(2): 349–355.
- Neben K, Jauch A, Bertsch U, et al. Combining information regarding chromosomal aberrations t(4;14) and del(17p13) with the International Staging System classification allows stratification of myeloma patients undergoing autologous stem cell transplantation. Haematologica. 2010; 95(7): 1150–1157.
- Kern SE, Kinzler KW, Bruskin A, et al. Identification of p53 as a sequence-specific DNA-binding protein. Science. 1991; 252(5013): 1708–1711.
- Hollstein M. Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucl Acids Res. 1996; 24(1): 141–146.
- Kang HJ, Feng Z, Sun Y, et al. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci USA. 2009; 106(24): 9761–9766.
- Frebourg T, Friend SH. The importance of p53 gene alterations in human cancer: is there more than circumstantial evidence? J Natl Cancer Inst. 1993; 85(19): 1554–1557.
- Dumont P, Leu JIJ, Della Pietra AC, et al. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet. 2003; 33(3): 357–365.
- Siddique M, Sabapathy K. Trp53-dependent DNA-repair is affected by the codon 72 polymorphism. Oncogene. 2006; 25(25): 3489–3500.
- Greenblatt MS, Bennett WP, Hollstein M, et al. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994; 54(18): 4855–4878.
- Bilous NI, Abramenko IV, Chumak AA, et al. TP53 codon 72 single nucleotide polymorphism in chronic lymphocytic leukemia. Exp Oncol. 2014; 36(4): 258–261.
- Dunna NR, Vure S, Sailaja K, et al. TP53 codon 72 polymorphism and risk of acute leukemia. Asian Pac J Cancer Prev. 2012; 13(1): 347–350.
- Hattori Y, Ikeda Y, Suzuki Y, et al. Codon 72 polymorphism of TP53 gene is a novel prognostic marker for therapy in multiple myeloma. Br J Haematol. 2014; 165(5): 728–731.
- Liu YC, Hsiao HH, Yang WC, et al. MDM2 promoter polymorphism and p53 codon 72 polymorphism in chronic myeloid leukemia: the association between MDM2 promoter genotype and disease susceptibility, age of onset, and blast-free survival in chronic phase patients receiving imatinib. Mol Carcinog. 2014; 53(12): 951–959.
- Ortega MM, Honma HN, Zambon L, et al. GSTM1 and codon 72 P53 polymorphism in multiple myeloma. Ann Hematol. 2007; 86(11): 815–819.
- Xiong X, Wang M, Wang L, et al. Risk of MDM2 SNP309 alone or in combination with the p53 codon 72 polymorphism in acute myeloid leukemia. Leuk Res. 2009; 33(11): 1454–1458.
- Papadakis ED, Soulitzis N, Spandidos DA. Association of p53 codon 72 polymorphism with advanced lung cancer: the Arg allele is preferentially retained in tumours arising in Arg/Pro germline heterozygotes. Br J Cancer. 2002; 87(9): 1013–1018.
- Miller DP, Liu G, De Vivo I, et al. Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. Cancer Res. 2002; 62(10): 2819–2823.
- Jung T, Catalgol B, Grune T. The proteasomal system. Mol Aspects Med. 2009; 30(4): 191–196.
- Rajkumar SV, Richardson PG, Hideshima T, et al. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol. 2005; 23(3): 630–639.
- Jänen SB, Chaachouay H, Richter-Landsberg C. Autophagy is activated by proteasomal inhibition and involved in aggresome clearance in cultured astrocytes. Glia. 2010; 58(14): 1766–1774.
- Ding WX, Ni HM, Gao W, et al. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol. 2007; 171(2): 513–524.
- Ross FM, Avet-Loiseau H, Ameye G, et al. European Myeloma Network. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica. 2012; 97(8): 1272–1277.
- Ahmann GJ, Jalal SM, Juneau AL, et al. A novel three-color, clone-specific fluorescence in situ hybridization procedure for monoclonal gammopathies. Cancer Genet Cytogenet. 1998; 101(1): 7–11.
- Dmoszynska A, Chocholska S. Molecular biology methods in the diagnosis of multiple myeloma. In: Witt M, Dawidowska M, Szczepanski T. ed. Molecular aspects of hematologic malignancies: diagnostic tools and clinical applications. Springer-Verlag, Berlin-Heidelberg 2012: 443–449.
- Carter A, Hocherman I, Linn S, et al. Prognostic significance of plasma cell morphology in multiple myeloma. Cancer. 1987; 60(5): 1060–1065, doi: 10.1002/1097-0142(19870901)60:5<1060::aid-cncr2820600522>3.0.co;2-3..
- Monneret Cl, Buisson JP, Magdelenat H. [A new therapy with bortezomib, an oncologic medicinal product of the year 2004]. Ann Pharm Fr. 2005; 63(5): 343–349.
- Lane DP, Cheok CF, Lain S. p53-based cancer therapy. Cold Spring Harb Perspect Biol. 2010; 2(9): a001222.
- Eischen CM, Lozano G. The Mdm network and its regulation of p53 activities: a rheostat of cancer risk. Hum Mutat. 2014; 35(6): 728–737.
- Gottlieb E, Oren M. p53 facilitates pRb cleavage in IL-3-deprived cells: novel pro-apoptotic activity of p53. EMBO J. 1998; 17(13): 3587–3596.
- Wang YC, Lee HS, Chen SK, et al. Prognostic significance of p53 codon 72 polymorphism in lung carcinomas. Eur J Cancer. 1999; 35(2): 226–230.
- Matta H, Chaudhary PM. The proteasome inhibitor bortezomib (PS-341) inhibits growth and induces apoptosis in primary effusion lymphoma cells. Cancer Biol Ther. 2005; 4(1): 77–82.
- Ercetin AP, Ozcan MA, Aktas S, et al. Ex vivo evaluation of the effect of regulatory T cells on the anti-tumor activity of bortezomib in multiple myeloma. Exp Hematol. 2016; 44(4): 223–230.
- Marin MC, Jost CA, Brooks LA, et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet. 2000; 25(1): 47–54.
- Krętowski R, Stypułkowska A, Cechowska-Pasko M. Efficient apoptosis and necrosis induction by proteasome inhibitor: bortezomib in the DLD-1 human colon cancer cell line. Mol Cell Biochem. 2015; 398(1-2): 165–173.
- Mihou D, Katodritou E, Zervas K. Multiple myeloma staging based on the combination of beta-2-microglobulin and albumin: the role of albumin in the model. Hematology. 2007; 12(6): 527–531.
- Chng WJ, Price-Troska T, Gonzalez-Paz N, et al. Clinical significance of TP53 mutation in myeloma. Leukemia. 2007; 21(3): 582–584.
- Lodé L, Eveillard M, Trichet V, et al. Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma. Haematologica. 2010; 95(11): 1973–1976.
- Chen MH, Qi CXY, Saha MN, et al. p53 nuclear expression correlates with hemizygous TP53 deletion and predicts an adverse outcome for patients with relapsed/refractory multiple myeloma treated with lenalidomide. Am J Clin Pathol. 2012; 137(2): 208–212.
- Chou T. Multiple myeloma: recent progress in diagnosis and treatment. J Clin Exp Hematop. 2012; 52(3): 149–159.
- Elnenaei MO, Gruszka-Westwood AM, A'Hernt R, et al. Gene abnormalities in multiple myeloma; the relevance of TP53, MDM2, and CDKN2A. Haematologica. 2003; 88(5): 529–537.
