gms | German Medical Science

50. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds)
12. Jahrestagung der Deutschen Arbeitsgemeinschaft für Epidemiologie (dae)

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie
Deutsche Arbeitsgemeinschaft für Epidemiologie

12. bis 15.09.2005, Freiburg im Breisgau

Association between TP53 and p21 genetic polymorphisms and acute side effects of radiotherapy in breast cancer patients

Meeting Abstract

  • Xiang-Lin Tan - German Cancer Research Center, Heidelberg
  • Odilia Popanda - German Cancer Research Center, Heidelberg
  • Christine B. Ambrosone - Roswell Park Cancer Institute, New York
  • Silke Kropp - German Cancer Research Center, Heidelberg
  • Irmgard Helmbold - German Cancer Research Center, Heidelberg
  • Peter Schmezer - German Cancer Research Center, Heidelberg
  • Jenny Chang-Claude - German Cancer Research Center, Heidelberg

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie. Deutsche Arbeitsgemeinschaft für Epidemiologie. 50. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 12. Jahrestagung der Deutschen Arbeitsgemeinschaft für Epidemiologie. Freiburg im Breisgau, 12.-15.09.2005. Düsseldorf, Köln: German Medical Science; 2005. Doc05gmds299

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/gmds2005/05gmds059.shtml

Veröffentlicht: 8. September 2005

© 2005 Tan et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Introduction

There is clear evidence that the variation in normal tissue reactions to radiotherapy (RT) is, at least in part, determined by genetic factors [1], [2]. p53 and p21 play an important role in G1/S checkpoint control in response to ionizing radiation [3]. TP53 and p21 should be good candidate genes to modify patient-to-patient variability in normal tissue response to RT. Based on this hypothesis, the association between TP53 Arg72Pro, p53PIN3 A1/A2 (where the A2 allele carries a 16bp duplication in intron 3) and p21 Ser31Arg polymorphisms and the risk of developing acute skin toxicity after RT was evaluated.

Materials and Methods

In a prospective study of 446 patients (average age 60.3±9.0 years) receiving RT after breast conserving surgery, the development of acute skin reaction according to the Common Toxicity Criteria was documented at regular intervals during treatment [4]. p53PIN3 A1/A2 polymorphism was determined by standard PCR analysis, and TP53 Arg72Pro and p21 Ser31Arg polymorphisms were determined by rapid capillary PCR with melting curve analysis using fluorescence labelled hybridization probes in a LightCycler (Roche Diagnostics, Mannheim, Germany). The development of acute skin toxicity (moist desquamation) associated with the genetic polymorphisms was modelled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose.

Results

Overall, the development of acute skin toxicity, which presented in 77 patients, was not significantly associated with the polymorphisms studied. Risks were however differential by body mass index. Compared to non-carriers, TP53 72Pro carriers had a marginally significant association with the risk of acute skin toxicity after RT in normal weight women (hazard ratios (HR) 0.46, 95% confidence interval (CI), 0.18-1.18) but not in overweight women (HR 1.07, 95%CI 0.61-1.89) (p value for interaction=0.14). The results were in accordance with that of allele-specific risk analysis. Compared to TP53 72Arg, HR of TP53 72Pro is 0.45 (95%CI, 0.19-1.07) in normal weight women and 1.19 (95%CI, 0.76-1.85) in overweight women (p value for interaction=0.06). These results were confirmed by haplotype analysis for TP53. Compared to the common ArgA1 haplotype, both ProA1 and ProA2 haplotypes had a decreased risk of developing acute skin toxicity in normal weight women (HR 0.48 95%CI 0.17-1.37; HR 0.48, 95%CI 0.15-1.57 respectively). Furthermore, the potential combined protective effects of TP53 72Pro and p21 31Ser alleles were investigated using the group of Arg/Arg carriers in TP53 and Arg carriers in p21 as reference group. TP53 72Pro carriers were also found to have a potentially decreased risk of developing acute skin toxicity in normal weight women (HR 0.52 or 0.33 according to the status of p21).

Discussion

Our data indicate that TP53 72Pro may be protective against the development of acute skin toxicity after RT in patients with normal weight. Functional analysis of the 2 variants showed that the 72Arg form of TP53 induced apoptosis more efficiently than the 72Pro form; in contrast, the 72Pro form appeared to induce a higher level of G1 arrest than the 72Arg form [5]. In general, cells in G2- and M-phases are most sensitive to radiation, while cells in G1- and late S-phase are less sensitive. Our results might be explained by 72Pro inducing a high level of G1 arrest to permit more time to repair damaged DNA, thus reducing the risk of adverse reactions. Future large studies are warranted to further test our findings. In conclusion, TP53 72Pro, with a protective effect in our study, should be further combined with other genetic polymorphisms to evaluate the genetic factors of normal tissue reaction to RT.

Acknowledgements

This study was supported by the Bundesamt für Strahlenschutz, Salzgitter, Germany and the USAMRMC FY01 Breast Cancer Research Program.


Literatur

1.
Bentzen SM, Overgaard J. Patient-to-patient variability in the expression of radiation-induced normal tissue injury. Semin Radiat Oncol 1994; 4: 68-80.
2.
Tucker SL, Turesson I, Thames HD. Evidence for individual differences in the radiosensitivity of human skin. Eur J Cancer 1992; 28A: 1783-91
3.
Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 1995; 377: 552-7.
4.
Twardella D, Popanda O, Helmbold I, Ebbeler R, Benner A, von Fournier D, Haase W, Sautter-Bihl ML, Wenz F, Schmezer P, Chang-Claude J. Personal characteristics, therapy modalities and individual DNA repair capacity as predictive factors of acute skin toxicity in an unselected cohort of breast cancer patients receiving radiotherapy. Radiother Oncol 2003; 69: 145-53.
5.
Pim D, Banks L. p53 polymorphic variants at codon 72 exert different effects on cell cycle progression. Int J Cancer 2004; 108: 196-99.