Abstract
A comparative analysis of oncogene mutations shows that variations in their frequency, spectrum, and hot-spot locations depends on the type of tumor and the ethnic origin of the population studied. The current version of the IARC TP53 Mutation Database lacks information about the frequency and spectrum of TP53 mutations in patients with DLBCL in Russia. The aim of this study was to assess the frequency and functional significance of TP53 mutations in patients with DLBCL in Novosibirsk. The TP53 coding sequence and the adjacent intron regions were analyzed by direct sequencing in the tumor material from 74 patients with DLBCL. Mutations of the TP53 coding sequence were found in 18 (24.3%) patients. These data are consistent with the frequency of TP53 mutations observed in other studies. The spectrum of nucleotide substitutions found in DLBCL specimens corresponded to that described in the IARC TP53 Mutation Database. According to bioinformatic data and to reported experiments in vitro, most of the mutations detected result in the production of functionally inactive p53. Our results show that DLBCL progression is accompanied by the functional selection for mutations in TP53 exons 5–8.
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Abbreviations
- NHL:
-
non-Hodgkin lymphoma
- DLBCL:
-
diffuse large B-cell lymphoma
References
Hollstein M., Hainaut P. 2010. Massively regulated genes: The example of TP53. J. Pathol. 220 (2), 164–173.
Hofstetter G., Berger A., Berger R., Zoric A., Braicu E.I., Reimer D., Fiegl H., Marth C., Zeimet A.G., Ulmer H., Moll U., Zeillinger R., Concin N. 2012. The N-terminally truncated p53 isoform 40p53 influences prognosis in mucinous ovarian cancer. Int. J. Gynecol. Cancer. 22 (3), 372–379.
Marcel V., Dichtel-Danjoy M.L., Sagne C., Hafsi H., Ma D., Ortiz-Cuaran S., Olivier M., Hall J., Mollereau B., Hainaut P., Bourdon J.C. 2011. Biological functions of p53 isoforms through evolution: Lessons from animal and cellular models. Cell Death Differ. 18 (12), 1815–1824.
Xu-Monette Z.Y., Medeiros L.J, Li Y., Orlowski R.Z., Andreeff M., Bueso-Ramos C.E., Greiner T.C., McDonnell T.J., Young K.H. 2012. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood. 119 (16), 3668–3683.
Leroy B., Fournier J.L., Ishioka C., Monti P., Inga A., Fronza G., Soussi T. 2013. The TP53 website: An integrative resource centre for the TP53 mutation database and TP53 mutant analysis. Nucleic Acids Res. 41, D962–D969.
Peller S., Rotter V. 2003. TP53 in hematological cancer: low incidence of mutations with significant clinical relevance. Hum. Mutat. 21 (3), 277–284.
Cheung K.J., Horsman D.E., Gascoyne R.D. 2009. The significance of TP53 in lymphoid malignancies: Mutation prevalence, regulation, prognostic impact and potential as a therapeutic target. Br. J. Haematology. 146, 257–269.
Sturm I., Bosanquet A.G., Hermann S., Guner D., Dorken B., Daniel P.T. 2003. Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy. Cell Death Differ. 10 (4), 477–484.
Campo E., Swerdlow S.H., Harris N.L., Pileri S., Stein H., Jaffe E.S. 2011. The 2008 WHO classification of lymphoid neoplasms and beyond: Evolving concepts and practical applications. Blood. 117 (19), 5019–5032.
Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., Thiele J., Vardiman J.W. 2008. Diffuse Large B-Cell Lymphoma, Not Otherwise Specified. WHO Classification of Tumors of Haematopoetic and Lymphoid Tissues, 4th ed. Lyon.
Young K.H., Leroy K., Møller M.B., Colleoni G.W., Sánchez-Beato M., Kerbauy F.R., Haioun C., Eickhoff J.C., Young A.H., Gaulard P., Piris M.A., Oberley T.D., Rehrauer W.M., Kahl B.S., Malter J.S., et al. 2008. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: An international collaborative study. Blood. 112, 3088–3098.
Gisselbrecht C., Glass B., Mounier N., Singh Gill D., Linch D.C., Trneny M., Bosly A., Ketterer N., Shpilberg O., Hagberg H., Ma D., Brière J., Moskowitz C.H., Schmitz N. 2010. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J. Clin. Oncol. 28 (27), 4184–4190.
http://p53.fr.
Edlund K., Larsson O., Ameur A., Bunikis I., Gyllensten U., Leroy B., Sundström M., Micke P., Botling J., Soussi T. 2012. Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors. Proc. Natl. Acad. Sci. U. S. A. 109 (24), 9551–9556.
Frebourg T., Barbier N., Kassel J., Ng Y.S., Romero P., Friend S.H. 1992. A functional screen for germ line p53 mutations based on transcriptional activation. Cancer Res. 52, 6976–6978.
Tennis M., Krishnan S., Bonner M., Ambrosone C.B., Vena J.E., Moysich K., Swede H., McCann S., Hall P., Shields P.G., Freudenheim J.L. 2006. Method of p53 mutation analysis in breast tumors by a DNA microarray. Cancer Epidemiol. Biomarkers Prev. 15 (1), 80–85.
Petitjean A., Mathe E., Kato S., Ishioka C., Tavtigian S.V., Hainaut P., Olivier M. 2007. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: Lessons from recent developments in the IARC TP53 database. Hum. Mutat. 28, 622–629.
Adzhubei I., Jordan D.M., Sunyaev S.R. 2013. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet., Ch. 7: Unit7.20.
Dekairelle A.F., Tombal B., Cosyns J.P., Gala J.L. 2005. Assessment of the transcriptional activity of p53 improves the prediction of recurrence in superficial transitional cell carcinoma of the bladder. Clin. Cancer Res. 11 (13), 4724–4732.
Monti P., Campomenosi P., Ciribilli Y., Iannone R., Inga A., Abbondandolo A., Resnick M.A., Fronza G. 2002. Tumour p53 mutations exhibit promoter selective dominance over wild type p53. Oncogene. 21, 1641–1648.
Dearth L.R., Qian H., Wang T., Baroni T.E., Zeng J., Chen S.W., Yi S.Y., Brachmann R.K. 2007. Inactive full-leng the p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers. Carcinogenesis. 28 (2), 289–298.
Campomenosi P., Monti P., Aprile A., Abbondandolo A., Frebourg T., Gold B., Crook T., Inga A., Resnick M.A., Iggo R., Fronza G. 2001. P53 mutants can often transactivate promoters containin gap21 but not Bax or PIG3 responsive elements. Oncogene. 20, 3573–3579.
Smardova J. 1999. FASAY: A simple functional assay in yeast for identification of p53 mutation in tumors. Neoplasm. 46 (2), 80–88.
Fogh J., Fogh J.M., Orfeo T. 1977. One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J. Natl. Cancer Inst. 59 (1), 221–226.
Kumar P., Henikoff S., Ng P.C. 2009. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4 (7), 1073–1081.
Shiraishi K., Kato S., Han S.Y., Liu W., Otsuka K., Sakayori M., Ishida T., Takeda M., Kanamaru R., Ohuchi N., Ishioka C. 2004. Isolation of temperaturesensitive p53 mutations from a comprehensive missense mutation library. J. Biol. Chem. 279 (1), 348–355.
Kakudo Y., Shibata H., Otsuka K., Kato S., Ishioka C. 2005. Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s. Cancer Res. 65 (6), 2108–2114.
Monti P., Campomenosi P., Ciribilli Y., Iannone R., Aprile A., Inga A., Tada M., Menichini P., Abbondandolo A., Fronza G. 2003. Characterization of the p53 mutants ability to inhibit p73b transactivation using a yeast-based functional assay. Oncogene. 22, 5252–5260.
Dearth L.R., Qian H., Wang T., Baroni T.E., Zeng J., Chen S.W., Yi S.Y., Brachmann R.K. 2007. Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers. Carcinogenesis. 28 (2), 289–298.
Miyaki M., Iijima T., Ohue M., Kita Y., Hishima T., Kuroki T., Iwama T., Mori T. 2003. A novel case with germline p53 gene mutation having concurrent multiple primary colon tumours. Gut. 52 (2), 304–306.
Leroy B., Fournier J.L., Ishioka C., Monti P., Inga A., Fronza G., Soussi T. 2013. The TP53 website: An integrative resource centre for the TP53 mutation database and TP53 mutant analysis. Nucleic Acids Res. 41 (Database issue), D962–D969.
http://www.hgmd.cf.ac.uk/ac/.
Lehman T.A., Haffty B.G., Carbone C.J., Bishop L.R., Gumbs A.A., Krishnan S., Shields P.G., Modali R., Turner B.C. 2000. Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer. Cancer Res. 60 (4), 1062–1069.
Zhang Y., Hu Y., Fang J.Y., Xu J. 2016. Gain-of-function miRNA signature by mutant p53 associates with poor cancer outcome. Oncotarget [Epub ahead of print]. doi 10.18632/oncotarget.7090
Slingerland J.M., Jenkins J.R., Benchimol S. 1993. The transforming and suppressor functions of p53 alleles: Effects of mutations that disrupt phosphorylation, oligomerization and nuclear translocation. EMBO J. 12 (3), 1029–1037.
Amin N.A., Malek S.N. 2016. Gene mutations in chronic lymphocytic leukemia. Semin. Oncol. 43 (2), 215–221.
Kandioler D., Mittlböck M., Kappel S., Puhalla H., Herbst F., Langner C., Wolf B., Tschmelitsch J., Schippinger W., Steger G., Hofbauer F., Samonigg H., Gnant M., Teleky B., Kührer I. 2015. TP53 mutational status and prediction of benefit from adjuvant 5-fluorouracil in stage iii colon cancer patients. EBioMedicine. 2 (8), 823–828.
Young K.H., Weisenburger D.D., Dave B.J., Smith L., Sanger W., Iqbal J., Campo E., Delabie J., Gascoyne R.D., Ott G., Rimsza L., Muller-Hermelink H.K., Jaffe E.S., Rosenwald A., Staudt L.M., et al. 2007. 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. 110, 4396–4405.
Stefancikova L., Moulis M., Fabian P., Vasova I., Zedek F., Ravcukova B., Muzik J., Kuglik P., Vranova V., Falkova I., Hrabalkova R., Smardova J. 2011. Prognostic impact of p53 aberrations for R-CHOP-treated patients with diffuse large B-cell lymphoma. Int. J. Oncol. 39, 1413–1420.
Zenz T., Eichhorst B., Busch R., Denzel T., Habe S., Winkler D., Buhler A., Edelmann J., Bergmann M., Hopfinger G., Hensel M., Hallek M., Dohner H., Stilgenbauer S. 2010. TP53 mutation and survival in chronic lymphocytic leukemia. J. Clin. Oncol. 28, 4473–4479.
Barnas C., Martel-Planche G., Furukawa Y., Hollstein M., Montesano R., Hainaut P. 1997. Inactivation of the p53 protein in cell lines derived from human esophageal cancers. Int. J. Cancer. 71 (1), 79–87.
Glick B.R., Pasternak J.J. Molecular Biotechnology: Principles and Applications of Recombinant DNA. Washington, DC: ASM Press, 2003.
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Original Russian Text © E.N. Voropaeva, T.I. Pospelova, M.I. Voevoda, V.N. Maksimov, 2017, published in Molekulyarnaya Biologiya, 2017, Vol. 51, No. 1, pp. 64–72.
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Voropaeva, E.N., Pospelova, T.I., Voevoda, M.I. et al. Frequency, spectrum, and functional significance of TP53 mutations in patients with diffuse large B-cell lymphoma. Mol Biol 51, 53–60 (2017). https://doi.org/10.1134/S0026893316060224
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DOI: https://doi.org/10.1134/S0026893316060224