Linking TP53 codon 72 and P21 nt590 genotypes to the development of cervical and ovarian cancer Alexandra M. Santos a, *, Hugo Sousa a , Daniela Pinto a , Catarina Portela b , Deolinda Pereira b , Raquel Catarino a , Isabel Duarte a , Carlos Lopes a , Rui Medeiros a,c a Molecular Oncology Unit, Portuguese Institute of Oncology-Oporto, Rua Dr. Anto ´nio Bernardino Almeida, 4200-072 Porto, Portugal b Medical Oncology Department, Portuguese Institute of Oncology-Oporto, Rua Dr. Anto ´nio Bernardino Almeida, 4200-072 Porto, Portugal c ICBAS, Abel Salazar Institute for the Biomedical Sciences, Porto, Portugal ARTICLE INFO Article history: Received 26 October 2005 Received in revised form 20 December 2005 Accepted 3 January 2006 Available online 20 March 2006 Keywords: Cervical cancer Ovarian cancer TP53 codon 72 polymorphism p53 P21 3 0 UTR polymorphism p21 ABSTRACT TP53 and its downstream effector gene P21 are two important genes in cell cycle regulation. Genetic alterations on p53 and attenuation of p21 expression result in progression through cell cycle G1 checkpoint, which can lead to cancer development. We analysed the fre- quency of TP53 codon 72 and 3 0 UTR P21 polymorphisms in 681 blood samples from 371 cer- vical cancer patients, 122 ovarian cancer patients and 188 healthy controls using AS-PCR and PCR–RFLP. Approximately twofold increased risk of ovarian cancer (OC) was observed for TP53 Pro carriers (P = 0.038), with a significantly higher risk for advanced OC (P = 0.018). Furthermore, among the P21 CC genotypes, TP53 P allele was also associated with a twofold increased risk of OC (P = 0.014) and to a threefold increased risk for advanced OC (P = 0.003) with an attributable proportion of 44.2%. These results were confirmed in an age-adjusted logistic regression analysis. No association was found between these polymorphisms and cervical cancer. Our results suggest that the TP53 codon 72 genotypes may be considered as a molecular marker, contributing to a genetic profile for ovarian cancer in women. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction Cervical cancer (CC) and ovarian cancer (OC) are the most fre- quent gynaecologic malignancies among women worldwide. In Portugal, CC has a relatively high incidence rate (standard- ized European rate) of 17/100,000 with around 950 new cases each year, whereas OC has approximately 600 new cases each year, with an incidence rate of 9.9/100,000. Mortality rates due to CC and OC are 5.9/100,000 deaths 5.4/100,000, respectively. 1,2 Persistent infection with high risk Human papillomavirus (HPV), a sexually transmitted agent, was established as a nec- essary but not sufficient cause for CC development. 3,4 How- ever, less is known regarding the etiologic factors in the development of OC. 5 Nonetheless, as cancer is a multistep disease, it is believed that genetic variations, as polymor- phisms, may be associated to different cancer susceptibilities, as well as important prognostic and predictive factors. 6–8 TP53 is a tumour suppressor gene, located at chromosome 17p13, referred as altered in 50–55% of cancer cases. 9,10 The p53 protein, encoded by the TP53 gene, is known as the cellu- lar gatekeeper for growth and division, as it plays an essential role in safeguarding the integrity of the genome. 11 This pro- tein is involved in processes as cell cycle arrest, gene tran- scription, DNA repair and apoptosis. If a mutation occurs, normal p53 functions may not be activated leading to cell cy- cle pathways or loss of apoptosis control and, as a conse- quence, to unchecked cell proliferation. High risk HPV oncoprotein E6 binds to p53 to promote its degradation via ubiquitin dependent proteolysis. 12 Thus, inactivation of p53 by HPV-E6 is analogous to a functional p53 mutation. 13 0959-8049/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2006.01.015 * Corresponding author: Tel.: +351 22 508 4000x5414; fax: +351 22 508 4001. E-mail address: alexandrambsantos@gmail.com (A.M. Santos). EUROPEAN JOURNAL OF CANCER 42 (2006) 958 – 963 available at www.sciencedirect.com journal homepage: www.ejconline.com