The results of complex analysis of TP53 gene status in patients with diffuse large cell lymphoma
https://doi.org/10.18821/0234-5730-2016-61-3-138-143
Abstract
Analysis of the literature shows that there is no comprehensive description of the variability of TP53 gene in diffuse large B-cell lymphoma (DLBCL). The frequency, spectrum and functional significance of mutations in the TP53 gene were investigated at 74 DLBCL patients. The localization of mutations “hot spots” in the studied sample of patients with DLBCL was shown to be differed from the data presented in IARC TP53 mutation database. The occurrence of DLBCL with pathogenetic intron and synonymous replacements was revealed. The frequency of TP53 promoter methylation in the study group was 5.8%. The loss of heterozygosity in the gene was observed in 25% of cases and only in a subset of patients with modified (mutation or promoter methylation) status of the TP53 gene. The results indicate to the selection of functionally significant mutations in the TP53 DNA-binding region in DLBCL. The lack of function of the gene in DLBCL was shown to be possibly formed on the two-hit principle.
Keywords
gene TP53,
diffuse large B-cell lymphoma,
promoter methylation,
loss of heterozygosity,
mutations,
sequencing
Supporting agencies: The study was executed with the financial support of the Grant of the President of Russian Federation for the State support of leading scientific schools (рroject No 10240.2016.7).
About the Authors
E. N. Voropaeva
Institute of Internal and Preventive Medicine
Russian Federation
Russian Federation
Voropaeva Elena N., MD, PhD, Senior Researcher of the Laboratory of molecular genetic studies of therapeutic diseases
Novosibirsk, 630089
T. I. Pospelova
Novosibirsk State Medical University
Russian Federation
Novosibirsk, 630091
Russian Federation
Novosibirsk, 630091
M. I. Voevoda
Institute of Internal and Preventive Medicine
Russian Federation
Novosibirsk, 630089
Russian Federation
Novosibirsk, 630089
V. N. Maksimov
Institute of Internal and Preventive Medicine
Russian Federation
Novosibirsk, 630089
Russian Federation
Novosibirsk, 630089
References
1. Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stain H., et al. WHO Classification of Tumors of Haematopoetic and Lymphoid Tissues. Lyon; 2008.
2. Niroula R., Butera J. Genetics and diffuse large B-cell lymphoma. R. I. Med. J. 2015; 98(11): 23–6.
3. Skibola C.F., Curry J.D., Nieters A. Genetic susceptibility to lymphoma. Haematologica. 2007; 92(7): 960–9.
4. Xu-Monette Z.Y., Medeiros L.J., Li Y., Orlowski R.Z., Andreeff M., BuesoRamos C.E., et al. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies.Blood. 2012; 119(16): 3668–83. doi: 10.1182/blood-2011-11-366062.
5. Hollstein M., Hainaut P. Massively regulated genes: the example of TP53. J. Pathol. 2010; 220(2): 164–17. doi: 10.1002/path.2637.
6. Cheung K.J., Horsman D.E., Gascoyne R.D. The significance of TP53 in lymphoid malignancies: mutation prevalence, regulation, prognostic impact and potential as a therapeutic target. Br. J. Haematol. 2009; 146(3): 257–69. doi: 10.1111/j.1365-2141.2009.07739.x.
7. Gudkov A.V., Komarova E.A. The role of p53 in determining sensitivity to radiotherapy. Nat. Rev. Cancer. 2003; 3(2): 117–29.
8. Peller S., Rotter V. TP53 in hematological cancer: low incidence of mutations with significant clinical relevance. Hum. Mutat. 2003; 21(3): 277–84.
9. Kopnin B.P., Kopnin P.B., Khromova N.V., Agapova L.S. Multifaced p53: variety of forms, functions, tumor-supressive and oncogenic activities. Clinical Oncohematology. Basic Research and Clinical Practice. Russian Journal (Klinicheskaya onkogematologiya). 2008; 1(1): 2–9. (in Engl.)
10. Kitts A., Phan L., Ward M., Holmes J.B. The Database of Short Genetic Variation (dbSNP). The NCBI Handbook. 2nd ed. Bethesda: National Center for Biotechnology Information (US); 2013. (Last Update: April 3, 2014). http://www.ncbi.nlm.nih.gov/books/NBK174586/
11. http://www.ncbi.nlm.nih.gov/snp/?term=TP53
12. Whibley C., Pharoah P.D., Hollstein M. P53 polymorphisms: cancer implications. Nature Rev. Cancer. 2009; 9(2): 95–107.
13. Voropaeva E.N., Voevoda M.I., Pospelova T.I., Maksimov V.N. Linkage disequilibrium and haplotypes of rs1042522, rs1625895 and rs17878362 gene TP53 markers in patients with diffuse large B-cell lymphoma. Mol. Biol. (Mosk). 2014; 48(5): 663–70.
14. Voropaeva E.N., Voevoda M.I., Pospelova T.I., Maksimov V.N. Prognostic impact of the TP53 rs1625895 polymorphism in DLBCL patients. Br. J. Haematol. 2015; 169(1): 32–5.
15. Lu J.T., Cen L., Zhou M. Prognostic value of P53 aberrations in diffuse large B-cell lymphoma. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2012; 20(1): 100–2.
16. Sun G.X., Cao X.S., Li Q., Wang Z.L. Correlation of BCL-6, MYC and p53 gene abnormalities with immunological subtypes andprognosis of diffuse large B-cell lymphoma. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2012; 29(5): 576–81.
17. Gao P., Li Q., Wang Z., Yan F., Lu C., Cao X. Significance of BCL-6, MYC, P53 genes abnormalities for the prognosis of diffuse large B-cell lymphoma. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2014; 31(5): 628–31. doi: 10.3760/cma.j.issn.1003-9406.2014.01.020.
18. Stefancikova L., Moulis M., Fabian P., Vasova I., Zedek F., Ravcukova B., et al. Prognostic impact of p53 aberrations for R-CHOP-treated patients with diffuse large B-cell lymphoma. Int. J. Oncol. 2011; 39(6): 1413–20.
19. Stocklein H., Smardova J., Macak J., Katzenberger T., Holler S., Wessendorf S., et al. Detailed mapping of chromosome 17p deletions reveals HIC1 as a novel tumor suppressor gene candidate telomeric to TP53 in difuse large B-cell lymphoma. Oncogene. 2008; 27(18): 2613–25.
20. Tamimi Y., Al-Harthy S., Al-Haddabi I., Al-Kindi M., Babiker H., Al-Moundhri M., Burney I. The p53 mutation/deletion profle in a small cohort of the Omani population with diffuse large B-cell lymphoma.Sultan Qaboos Univ. Med. J. 2014; 14(1): e50–8.
21. Simonitsch-Klupp I., Hauser I., Ott G., Drach J., Ackermann J., Kaufmann J., et al. Diffuse large B-cell lymphomas with plasmablastic/ plasmacytoid features are associated with TP53 deletions and poor clinical outcome. Leukemia. 2004; 18(1): 146–55.
22. Xu-Monette Z.Y., Wu L., Visco C., Tai Y.C., Tzankov A., Liu W.M., et al. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study. Blood. 2012; 120(19): 3986–96.
23. Young K.H., Leroy K., Møller M.B., Colleoni G.W., Sánchez-Beato M., Kerbauy F.R., Haioun C., et al. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood. 2008; 112(8): 3088–98.
24. Edlund K., Larsson O., Ameur A., Bunikis I., Gyllensten U., Leroy B., et al. Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors. Proc. Natl. Acad. Sci. USA. 2012; 109(24): 9551–6.
25. http://p53.iarc.fr/DownloadDataset.aspx
26. Frebourg T., Barbier N., Kassel J., Ng Y.S., Romero P., Friend S.H. A functional screen for germ line p53 mutations based on transcriptional activation. Сancer Res. 1992; 52(24): 6976–8.
27. Tennis M., Krishnan S., Bonner M., Ambrosone C.B., Vena J.E., Moysich K., et al. p53 mutation analysis in breast tumors by a DNA microarray method. Cancer Epidemiol. Biomarkers Prev. 2006; 15(1): 80–5.
28. Glick B.R., Pasternak J.J., eds. Moleculer biotechnology. Principles and applications of Recombinant DNA. 2nd ed. Washington: ASM Press; 1994.
29. Lehman T.A., Haffty B.G., Carbone C.J., Bishop L.R., Gumbs A.A., Krishnan S. et al. Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer. Cancer Res. 2000; 60(4): 1062–9.
30. Agirre X., Novo F.J., Calasanz M.J., Larrayoz M.J., Lahortiga I., Valganon M., et al. TP53 is frequently altered by methylation, mutation, and/or deletion in acute lymphoblastic leukaemia. Mol. Carcinog. 2003; 38(4): 201–8.
31. Pogribny I.P., James S.J. Reduction of p53 gene expression in human primary hepatocellular carcinoma is associated with promoter region methylation without coding region mutation. Cancer Lett. 2002; 176(2): 169–74.
32. Kang J.H., Kim S.J., Noh D.Y., Park I.A., Choe K.J., Yoo O.J., Kang H.S. Methylation in the p53 promoter is a supplementary route to breast carcinogenesis: correlation between CpG methylation in the p53 promoter and the mutation of the p53 gene in the progression from ductal carcinoma in situ to invasive ductal carcinoma. Lab. Invest. 2001; 81(4): 573–9.
33. Garcia-Delgado M., Larrayoz M.J., Novo F.J. Methylation of CpG dinucleotides and/or CCWGG motifs at the promoter of TP53 correlates with decreased gene expression in a subset of acute lymphoblastic leukemia patients. Oncogene. 2003; 22(7): 1070–2.
34. Amara K., Trimeche M., Ziadi S., Laatiri A., Hachana M., Sriha B., et al. Presence of simian virus 40 DNA sequences in diffuse large B-cell lymphomas in Tunisia correlates with aberrant promoter hypermethylation of multiple tumor suppressor genes. Int. J. Cancer. 2007; 121(12): 2693–702.
35. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N. Engl. J. Med. 1993; 329(14): 987–94.
36. http://p53.iarc.fr/download/tp53_directsequencing_iarc.pdf
37. Petitjean A., Mathe E., Kato S., Ishioka C., Tavtigian S. V., Hainaut P., et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum. Mutat. 2007; 28(6): 622–9.
38. Adzhubei I., Jordan D.M., Sunyaev S.R. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013; Ch.7: Unit 7.20. doi: 10.1002/0471142905.hg0720s76.
39. Almeida L.O., Custódio A.C., Pinto G.R., Santos M.J., Almeida J.R., Clara C.A. et al. Polymorphisms and DNA methylation of gene TP53 associated with extra-axial brain tumors. Genet. Mol. Res. 2009; 8(1): 8–18.
40. Grebe S.K., McIver B., Hay I.D., Wu P.S., Maciel L.M., Drabkin H.A., et al. Frequent loss of heterozygosity on chromosomes 3p and 17p without VHL or p53 mutations suggests involvement of unidentified tumor suppressor genes in follicular thyroid carcinoma. J. Clin. Endocrinol. Metab. 1997; 82(11): 3684–91.
41. Shiraishi K., Kato S., Han S.Y., Liu W., Otsuka K., Sakayori M., et al. Isolation of temperature-sensitive p53 mutations from a comprehensive missense mutation library. J. Biol. Chem. 2004; 279(1): 348–55.
42. Monti P., Campomenosi P., Ciribilli Y., Iannone R., Inga A., Abbondandolo A., et al. Tumour p53 mutations exhibit promoter selective dominance over wild type p53. Oncogene. 2002; 21(11): 1641–8.
43. Campomenosi P., Monti P., Aprile A., Abbondandolo A., Frebourg T., Gold B., et al. Р53 mutants can often transactivate promoters containin gap21 but not Bax or PIG3 responsive elements. Oncogene. 2001; 20(27): 3573–9.
44. Kakudo Y., Shibata H., Otsuka K., Kato S., Ishioka C. Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s. Cancer Res. 2005; 65(6): 2108–14.
45. Monti P., Campomenosi P., Ciribilli Y., Iannone R., Aprile A., Inga A., et al. Characterization of the p53 mutants ability to inhibit p73 beta transactivation using a yeast-based functional assay. Oncogene. 2003; 22(34): 5252–60.
46. Dearth L.R., Qian H., Wang T., Baroni T.E., Zeng J., Chen S.W., et al. Inactive full-leng thеp53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers. Carcinogenesis. 2007; 28(2): 289–98.
47. Leroy B., Fournier J.L., Ishioka C., Monti P., Inga A., Fronza G., Soussi T. The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis. Nucleic Acids Res. 2013; 41 (Database issue): D962–9. doi: 10.1093/nar/gks1033.
48. Lehman T.A., Haffty B.G., Carbone C.J., Bishop L.R., Gumbs A.A., Krishnan S., et al. Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer. Cancer Res. 2000; 60(4): 1062–9.
49. Bourdon J.C., Fernandes K., Murray-Zmijewski F., Liu G., Diot A., Xirodimas D.P., et al. p53 isoforms can regulate p53 transcriptional activity. Genes Dev. 2005; 19(18): 2122–37.
50. Dekairelle A.F., Tombal B., Cosyns J.P., Gala J.L. Аssessment of the transcriptional activity of p53 improves the prediction of recurrence in superficial transitional cell carcinoma of the bladder. Clin Cancer Res. 2005; 11(13): 4724–32.
51. Young K.H., Weisenburger D.D., Dave B.J., Smith L., Sanger W., Iqbal J., et al. Mutations in the DNA-binding codons of TP53, which are associated with decreased expression of TRAIL receptor-2, predict for poor survival in diffuse large B-cell lymphoma. Blood. 2007; 110(13): 4396–405.
52. Stefancikova L., Moulis M., Fabian P., Vasova I., Zedek F., Ravcukova B., et al. Prognostic impact of p53 aberrations for R-CHOP-treated patients with diffuse large B-cell lymphoma. Int. J. Oncol. 2011; 39(6): 1413–20.
53. Zenz T., Eichhorst B., Busch R., Denzel T., Habe S., Winkler D., et al. TP53 mutation and survival in chronic lymphocytic leukemia. J. Clin. Oncol. 2010; 28(29): 4473–9.
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For citations:
Voropaeva E.N., Pospelova T.I., Voevoda M.I., Maksimov V.N. The results of complex analysis of TP53 gene status in patients with diffuse large cell lymphoma. Russian journal of hematology and transfusiology. 2016;61(3):138-143. (In Russ.) https://doi.org/10.18821/0234-5730-2016-61-3-138-143
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