p53 status and response to radiotherapy in rectal cancer: a prospective multilevel analysis

E Lopez-Crapez, F Bibeau, S Thézenas, M Ychou, J Simony-Lafontaine, A Thirion, D Azria, J Grenier, P Senesse, E Lopez-Crapez, F Bibeau, S Thézenas, M Ychou, J Simony-Lafontaine, A Thirion, D Azria, J Grenier, P Senesse

Abstract

The aim of this study was to evaluate, in a prospective study, the predictive role of p53 status analysed at four different levels in identifying the response to preoperative radiotherapy in rectal adenocarcinoma. Before treatment, 70 patients were staged and endoscopic forceps biopsies from the tumour area were taken. p53 status was assessed by total cDNA sequencing, allelic loss analysis, immunohistochemistry, and p53 antibodies. Neoadjuvant treatment was based on preoperative radiotherapy or radiochemotherapy. Response to therapy was evaluated after surgery by both pathologic downstaging and histologic tumour regression grade. In all, 35 patients (50.0%) had p53 gene mutations; 44.4% of patients had an allelic loss; nuclear p53 overexpression was observed in 39 patients (55.7%); and p53 antibodies were detected in 11 patients (16.7%). In the multilevel analysis of p53 status, gene mutations correlated with both nuclear protein overexpression (P < 0.0001) and loss of heterozygosity (P = 0.013). In all, 29 patients (41.4%) were downstaged by pathologic analysis, and 19 patients (29.2%) were classified as tumour regression grade 1. Whatever the method of evaluation of treatment response, no correlation between p53 alterations and response to radiotherapy was observed. Our results do not support the use of p53 alterations alone as a predictive marker for response to radiotherapy in rectal carcinoma.

References

    1. Angelopoulou K, Stratis M, Diamandis EP (1997) Humoral immune response against p53 protein in patients with colorectal carcinoma. Int J Cancer 70: 46–51
    1. Ara S, Lee PS, Hansen MF, Saya H (1990) Codon 72 polymorphism of the TP53 gene. Nucleic Acids Res 18: 4961
    1. Baas IO, Mulder JW, Offerhaus GJ, Vogelstein B, Hamilton SR (1994) An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms. J Pathol 172: 5–12
    1. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244: 217–221
    1. Bazan V, Migliavacca M, Tubiolo C, Macaluso M, Zanna I, Corsale S, Amato A, Calo V, Dardanoni G, Morello V, La Farina M, Albanese I, Tomasino RM, Gebbia N, Russo A (2002) Have p53 gene mutations and protein expression a different biological significance in colorectal cancer? J Cell Physiol 191: 237–246
    1. Becouam Y, Blanc-Vincent MP, Lasser P, Dubois JB, Ducreux M, Giovannini M, Rougier P (1999) Standards, options and recommendations for the management of patients with primary adenocarcinoma of the rectum. National Federation of Centers for the Fight against Cancer. Presse Med 28: 1367–1374
    1. Bosari S, Viale G, Bossi P, Maggioni M, Coggi G, Murray JJ, Lee AK (1994) Cytoplasmic accumulation of p53 protein: an independent prognostic indicator in colorectal adenocarcinomas. J Natl Cancer Inst 86: 681–687
    1. Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW, Vogelstein B (1999) Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest 104: 263–269
    1. Buschmann T, Fuchs SY, Lee CG, Pan ZQ, Ronai Z (2000) SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53. Cell 101: 753–762
    1. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281: 1677–1679
    1. Chiarugi V, Magnelli L, Cinelli M (1998) Role of p53 mutations in the radiosensitivity status of tumor cells. Tumori 84: 517–520
    1. Cote RJ, Esrig D, Groshen S, Jones PA, Skinner DG (1997) p53 and treatment of bladder cancer. Nature 385: 123–125
    1. Crawford LV, Pim DC, Bulbrook RD (1982) Detection of antibodies against the cellular protein p53 in sera from patients with breast cancer. Int J Cancer 30: 403–408
    1. Delmolino L, Band H, Band V (1993) Expression and stability of p53 protein in normal human mammary epithelial cells. Carcinogenesis 14: 827–832
    1. El Deiry WS (2003) The role of p53 in chemosensitivity and radiosensitivity. Oncogene 22: 7486–7495
    1. Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB, Herman JG (2000) Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res 60: 129–133
    1. Fei P, El Deiry WS (2003) p53 and radiation responses. Oncogene 22: 5774–5783
    1. Frattini M, Balestra D, Suardi S, Oggionni M, Alberici P, Radice P, Costa A, Daidone MG, Leo E, Pilotti S, Bertario L, Pierotti MA (2004) Different genetic features associated with colon and rectal carcinogenesis. Clin Cancer Res 10: 4015–4021
    1. Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855–4878
    1. Gualberto A, Aldape K, Kozakiewicz K, Tlsty TD (1998) An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci USA 95: 5166–5171
    1. Hahn M, Serth J, Fislage R, Wolfes H, Allhoff E, Jonas V, Pingoud A (1993) Polymerase chain reaction detection of a highly polymorphic VNTR segment in intron 1 of the human p53 gene. Clin Chem 39: 549–550
    1. Hainaut P, Soussi T, Shomer B, Hollstein M, Greenblatt M, Hovig E, Harris CC, Montesano R (1997) Database of p53 gene somatic mutations in human tumors and cell lines: updated compilation and future prospects. Nucleic Acids Res 25: 151–157
    1. Heriot AG, Grundy A, Kumar D (1999) Preoperative staging of rectal carcinoma. Br J Surg 86: 17–28
    1. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253: 49–53
    1. Iacopetta B (2003) TP53 mutation in colorectal cancer. Hum Mutat 21: 271–276
    1. Inga A, Cresta S, Monti P, Aprile A, Scott G, Abbondandolo A, Iggo R, Fronza G (1997) Simple identification of dominant p53 mutants by a yeast functional assay. Carcinogenesis 18: 2019–2021
    1. Jones MH, Nakamura Y (1992) Detection of loss of heterozygosity at the human TP53 locus using a dinucleotide repeat polymorphism. Genes Chromosomes Cancer 5: 89–90
    1. Kemp CJ, Sun S, Gurley KE (2001) p53 induction and apoptosis in response to radio- and chemotherapy in vivo is tumor-type-dependent. Cancer Res 61: 327–332
    1. Kressner U, Glimelius B, Bergstrom R, Pahlman L, Larsson A, Lindmark G (1998) Increased serum p53 antibody levels indicate poor prognosis in patients with colorectal cancer. Br J Cancer 77: 1848–1851
    1. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB (1992) Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 89: 7491–7495
    1. Lechpammer M, Lukac J, Lechpammer S, Kovacevic D, Loda M, Kusic Z (2004) Humoral immune response to p53 correlates with clinical course in colorectal cancer patients during adjuvant chemotherapy. Int J Colorectal Dis 19: 114–120
    1. Lee JM, Bernstein A (1993) p53 mutations increase resistance to ionizing radiation. Proc Natl Acad Sci USA 90: 5742–5746
    1. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88: 323–331
    1. Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T (1994) p53 status and the efficacy of cancer therapy in vivo. Science 266: 807–810
    1. McDaniel T, Carbone D, Takahashi T, Chumakov P, Chang EH, Pirollo KF, Yin J, Huang Y, Meltzer SJ (1991) The MspI polymorphism in intron 6 of p53 (TP53) detected by digestion of PCR products. Nucleic Acids Res 19: 4796
    1. Milas L, Fan Z, Andratschke NH, Ang KK (2004) Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys 58: 966–971
    1. Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P (1989) Mutations in the p53 gene occur in diverse human tumour types. Nature 342: 705–708
    1. Pai HH, Rochon L, Clark B, Black M, Shenouda G (1998) Overexpression of p53 protein does not predict local-regional control or survival in patients with early-stage squamous cell carcinoma of the glottic larynx treated with radiotherapy. Int J Radiat Oncol Biol Phys 41: 37–42
    1. Poller DN, Baxter KJ, Shepherd NA (1997) p53 and Rb1 protein expression: are they prognostically useful in colorectal cancer? Br J Cancer 75: 87–93
    1. Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B (1997) A model for p53-induced apoptosis. Nature 389: 300–305
    1. Pruschy M, Rocha S, Zaugg K, Tenzer A, Hess C, Fisher DE, Glanzmann C, Bodis S (2001) Key targets for the execution of radiation-induced tumor cell apoptosis: the role of p53 and caspases. Int J Radiat Oncol Biol Phys 49: 561–567
    1. Rau B, Sturm I, Lage H, Berger S, Schneider U, Hauptmann S, Wust P, Riess H, Schlag PM, Dorken B, Daniel PT (2003) Dynamic expression profile of p21WAF1/CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy. J Clin Oncol 21: 3391–3401
    1. Rebischung C, Gerard JP, Gayet J, Thomas G, Hamelin R, Laurent-Puig P (2002) Prognostic value of p53 mutations in rectal carcinoma. Int J Cancer 100: 131–135
    1. Rodel C, Grabenbauer GG, Papadopoulos T, Bigalke M, Gunther K, Schick C, Peters A, Sauer R, Rodel F (2002) Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer. Int J Radiat Oncol Biol Phys 52: 294–303
    1. Saw RP, Morgan M, Koorey D, Painter D, Findlay M, Stevens G, Clarke S, Chapuis P, Solomon MJ (2003) p53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced rectal cancer treated with preoperative adjuvant therapy. Dis Colon Rectum 46: 192–202
    1. Sjogren S, Inganas M, Norberg T, Lindgren A, Nordgren H, Holmberg L, Bergh J (1996) The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 88: 173–182
    1. Soussi T (2000) p53 Antibodies in the sera of patients with various types of cancer: a review. Cancer Res 60: 1777–1788
    1. Swedish Rectal Cancer Trial (1997) Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336: 980–987
    1. Takeda A, Shimada H, Nakajima K, Imaseki H, Suzuki T, Asano T, Ochiai T, Isono K (2001) Monitoring of p53 autoantibodies after resection of colorectal cancer: relationship to operative curability. Eur J Surg 167: 50–53
    1. Tang R, Changchien CR, Wu MC, Fan CW, Liu KW, Chen JS, Chien HT, Hsieh LL (2004) Colorectal cancer without high microsatellite instability and chromosomal instability – an alternative genetic pathway to human colorectal cancer. Carcinogenesis 25: 841–846
    1. Tang R, Ko MC, Wang JY, Changchien CR, Chen HH, Chen JS, Hsu KC, Chiang JM, Hsieh LL (2001) Humoral response to p53 in human colorectal tumors: a prospective study of 1,209 patients. Int J Cancer 94: 859–863
    1. Tannapfel A, Nusslein S, Fietkau R, Katalinic A, Kockerling F, Wittekind C (1998) Apoptosis, proliferation, bax, bcl-2 and p53 status prior to and after preoperative radiochemotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 41: 585–591
    1. Thirion A, Rouanet P, Thezenas S, Detournay D, Grenier J, Lopez-Crapez E (2002) Interest of investigating p53 status in breast cancer by four different methods. Oncol Rep 9: 1167–1172
    1. Wheeler JM, Warren BF, Mortensen NJ, Ekanyaka N, Kulacoglu H, Jones AC, George BD, Kettlewell MG (2002) Quantification of histologic regression of rectal cancer after irradiation: a proposal for a modified staging system. Dis Colon Rectum 45: 1051–1056
    1. Wheeler JM, Dodds E, Warren BF, Cunningham C, George BD, Jones AC, Mortensen NJ (2004) Preoperative chemoradiotherapy and total mesorectal excision surgery for locally advanced rectal cancer: correlation with rectal cancer regression grade. Dis Colon Rectum 47: 2025–2031
    1. Yin Y, Stephen CW, Luciani MG, Fahraeus R (2002) P53 stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products. Nat Cell Biol 4: 462–467

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