© 2007 European Society for Medical Oncology
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TP53 mutations and codon 72 genotype—impact on survival among ovarian cancer patients
Ovarian cancer is associated with the highest mortality rate among gynaecological malignancies. Most patients present with advanced disease, and the understanding of the underlying biology is still sparse. The tumour suppressor gene TP53 is found mutated in a high percentage of ovarian tumours, indicating its importance in cancer development, acting as a checkpoint control for recognising damaged DNA, and inducing repair or apoptosis [1]. However, the impact of TP53 alterations on the prognosis for patients with ovarian cancer is still under debate [2]. In addition to mutations, several reports have indicated the importance of the genetic polymorphisms in the gene. Most emphasis has been given the codon 72 polymorphism of the TP53 gene, encoding either a proline or an arginine residue. TP53 protein with proline is structurally different from the one with arginine, and it seems to have a functional difference in inducing both apoptosis and cell cycle repair, in addition to affecting the function of somatic TP53 sequence variants [3, 4]. Previous findings indicate that ovarian cancer patients with the Pro tumour genotype and non-missense sequence variants or missense sequence variants affecting L2 or L3 of the TP53 protein have significantly poorer disease-specific survival compared to those with wild-type or other sequence [1].According to a model differentiating TP53 mutations, patients with missense mutations affecting amino acids directly involved in DNA or zinc binding display a very aggressive clinical phenotype [5]. In contrast, missense mutations outside any conserved or structural domain do not affect the clinical outcome (risk of disseminated disease and death). Null mutations and the remaining missense mutations display an intermediate aggressive clinical phenotype.
In this study, we have evaluated this TP53 mutation classification system, modifying it by including the codon 72 genotype of the patients into the analyses.
The study population consisted of 109 patients with advanced ovarian cancer as previously described [1] (approved by our Institutional Review Board and Regional Ethical Review Board, ref no S-01127). The DNA isolation, restriction fragment length polymorphism and mutation analyses were carried out as reported [1]. Progression-free survival was defined as the time interval elapsing between diagnosis and relapse of disease, whereas disease-specific survival was defined as the time between diagnosis and death of ovarian cancer. The method of Kaplan–Meier and the log-rank test were used to estimate and compare survival rates. Follow-up of patients alive without relapse ranged from 2 to 116 months.
We reclassified our dataset of 109 patients and analysed for survival differences. Of the 109 cases, 31 were classified in the group with best prognosis [median progression-free survival 18 months (95% confidence interval (CI) 12.2–23.8), median disease-specific survival 42.1 months (95% CI 19.1–65.1)], 61 cases were classified as intermediate aggressive [median progression-free survival 17.7 months (95% CI 13.1–22.2), median disease-specific survival 36 months (95% CI 24.5–47.3)] and 17 tumours had characteristics of very aggressive tumours [median progression-free survival 14.4 months (95% CI 8.8–20.0), median disease-specific survival 25.7 (95% CI 10.3–41.0)]. No significant disease-specific survival rate difference was observed (Figure 1).
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When taking the codon 72 genotype into consideration by adding the seven tumours from the intermediate aggressive group revealing a tumour Pro genotype into the aggressive group (missense mutations affecting amino acids directly involved in DNA or zink binding), we revealed three groups with significantly different both progression-free and disease-specific survival by using Kaplan–Meier survival analysis (Figure 2). The 54 cases in the new intermediate prognosis group had a median progression-free survival of 17.7 months (95% CI 11.3–24.1) and a median disease-specific survival of 39.1 months (95% CI 27.8–50.4). The 24 cases classified as most aggressive, revealed a median progression-free survival of 13.4 months (95% CI 8.5–18.2) and a disease-specific survival of 19.6 months (95% CI 10.3–28.9). In a Cox proportional hazard analysis, separation of TP53 mutations according to these criteria was an independent poorer prognostic factor for progression-free survival (P = 0.022, hazard ratio = 5.26) and a trend regarding disease-specific survival (P = 0.054, hazard ratio = 3.72), International Federation of Gynaecology and Obstetrics stage, residual tumour after surgery, age, histology and grade taken into consideration.
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When combining this classification with insight about the influence of TP53 codon 72, we identified groups of patients with obvious differences in clinical behaviour. Better tools to differentiate the prognosis in ovarian cancer would be of great value, as a more personalised treatment could be possible. However, the results need to be validated in separate dataset.
1 Department of Gynecologic Oncology
2 Department of Genetics
3 Department of Medical Informatics, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo
4 Medical Faculty, University of Oslo, Oslo
5 Department of Oncology, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway
* E-mail: ahelland{at}labmed.uio.no
Acknowledgements
Conflict of interest: No conflict of interest for the authors.
References
1. Wang Y, Kringen P, Kristensen GB, et al. Effect of the codon 72 polymorphism (c.215G>C, p.Arg72Pro) in combination with somatic sequence variants in the TP53 gene on survival in patients with advanced ovarian carcinoma. Hum Mutat (2004) 24:21–34.[CrossRef][Web of Science][Medline]
2. Kroger N, Milde-Langosch K, Riethdorf S, et al. Prognostic and predictive effects of immunohistochemical factors in high-risk primary breast cancer patients. Clin Cancer Res (2006) 12:159–168.
3. Langerød A, Bukholm IR, Bregard A, et al. The TP53 codon 72 polymorphism may affect the function of TP53 mutations in breast carcinomas but not in colorectal carcinomas. Cancer Epidemiol Biomarkers Prev (2002) 11:1684–1688.
4. Dumont P, Leu JI, Della Pietra AC, et al. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet (2003) 33:357–365.[CrossRef][Web of Science][Medline]
5. Alsner J, Yilmaz M, Guldberg P, et al. Heterogeneity in the clinical phenotype of TP53 mutations in breast cancer patients. Clin Cancer Res (2000) 6:3923–3931.
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