Linking TP53 codon 72 and P21 nt590 genotypes to the development of cervical and ovarian cancer

Santos, Alexandra M.; Sousa, Hugo; Pinto, Daniela; Portela, Catarina; Pereira, Deolinda; Catarino, Raquel; Duarte, Isabel Margarida; Lopes, Carlos; Medeiros, Rui

doi:10.1016/j.ejca.2006.01.015

Cited by 37 publications

(30 citation statements)

References 25 publications

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“…Therefore, gene polymorphisms of DNA repair factors are therefore obvious candidates for determinants of repair capacity and chemotherapy efficacy (Sancar, 1995). Moreover, the functional variants caused by SNPs in genes encoding drugmetabolizing enzymes, transporters, ion channels, drug receptors, cell cycle proteins and DNA repair are known to be associated with individual variation in survival, drug responses, and toxicity (Henson et al, 2006;Costa et al, 2008;Nogueira et al, 2010;Catarino et al, 2008;Craveiro et al, 2012;Santos et al, 2006;Medeiros et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Role of the RAD51 G172T polymorphism in the clinical outcome of cervical cancer patients under concomitant chemoradiotherapy

Nogueira¹,

Catarino²,

Faustino³

et al. 2012

Gene

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Introduction: Cervical cancer is one of the most common cancers diagnosed in women worldwide. Mammalian cells are constantly exposed to a wide variety of genotoxic agents from both endogenous and exogenous sources. The RAD51 protein is required for meiotic and mitotic recombination and plays a central role in homology-dependent recombinational repair of double-strand breaks (DSBs). Given the functional relevance of the DNA repair system on carcinogenesis, potential associations between genetic polymorphisms of DNA repair genes, cancer risk and response to therapy have been intensively evaluated. This is the first study evaluating the role of the RAD51 G172T genetic variants in cancer prognosis and clinical outcome of cervical cancer patients. Material and methods: We analyzed RAD51 G172T polymorphism genotypes in cervical cancer patients who underwent a platinum-based chemotherapy in combination with radiotherapy. Genotyping was performed by Taqman™ Allelic Discrimination methodology. Results and discussion: Concerning the overall survival rates found using Kaplan-Meier method and Log Rank Test, we observed that the mean survival rates were statistically different according to the patients RAD51 genotypes. The group of patients carrying the T allele present a higher mean survival rate than the other patients (102.3 months vs. 86.4 months, P = 0.020). Using the Cox regression analysis, we found an increased overall survival time for T-carrier patients, when compared with GG genotype, with tumor stage, age and presence of lymph nodes as covariates [hazard ratio (HR), 0.373; 95% CI, 0.181-0.770; P = 0.008]. Among patients (n = 193), RAD51 genotype frequency distributions were not under the influence of clinicopathologic characteristics, namely, treatment response (P = 0.508), recurrence (P = 0.150) and tumor stage (P = 0.250). Conclusions: This is the first study evaluating the role of the RAD51 G172T genetic variants in cancer prognosis and clinical outcome of cervical cancer patients. Our results indicate an influence of the RAD51 genetic variants in overall survival of cervical cancer. Thereby, RAD51 G172T genotypes may provide additional prognostic information in cervical cancer patients who underwent cisplatin-based chemotherapy in combination with radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Role of the RAD51 G172T polymorphism in the clinical outcome of cervical cancer patients under concomitant chemoradiotherapy

Nogueira¹,

Catarino²,

Faustino³

et al. 2012

Gene

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“…At the same time, cells expressing the TP53 Pro allele were able to repair the DNA damage much more effectively than cells expressing TP53 Arg allele (25); ii) Patients with homozygous Arg allele showed lower survival rates compared to heterozygous. It is important refer that the Arg variant has been correlated with a higher affinity of binding and degradation of TP53 protein by E6 oncoprotein of HPV-16/HPV-18 (38,(49)(50)(51). One of the better well-known functions of the HPV E6 is the ability to increase the tolerance of normal response to DNA damage or then the independent regulation of cellular growth (52,53).…”

Section: Discussionmentioning

confidence: 99%

TP53 Arg72Pro polymorphism is associated with increased overall survival but not response to therapy in Portuguese/Caucasian patients with advanced cervical cancer

et al. 2018

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Abstract. Identification of mechanisms that influence the therapeutic response and survival in patients with cancer is important. It is known that the genetic variability of the host, including presence of genetic polymorphisms in genes involved in DNA damage response, serves a crucial role in the prognosis of these patients. The present hospital-based retrospective cohort study aimed to evaluate the influence of TP53 Arg72Pro (rs1042522) polymorphism in the clinical outcome of 260 Caucasian patients diagnosed with cervical cancer and treated with concomitant radiotherapy and chemotherapy. The polymorphism genotyping was assessed using allelic discrimination by quantiative polymerase chain reaction. The results indicate that the TP53 Arg72Pro polymorphism did not significantly impact the response to therapy (P=0.571) nor disease-free survival (P=0.081). However, the polymorphism did influence overall survival, as increased median survival time was observed for patients carrying Arg/Pro genotype when compared with patients with Arg/Arg and Pro/Pro genotypes (126 months vs. 111 months, respectively; P=0.047). To conclude, the present findings suggest that a pharmacogenomic profile based on the genetic background of patients, including the analysis of the TP53 genotypes, may individualize treatment nad assist in the selection of therapies that may improve clinical outcome and lower toxicity for the patients.

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“…TP53, kromozom 17p13'de yerleşim gösteren bir tümör baskılayıcı ("supressor") gendir ve TP53 proteinini kodlar; büyüme ve bölünmede hücresel bekçi ("gatekeeper") olarak bilinir (3). TP53, hücresel proliferasyon, apoptozis ve farklı-laşmanın düzenlenmesine katılan "encode" fosfoproteinlerdendir; hücre döngüsü arresti, gen transkripsiyonu ve DNA tamirinde de yer alır (3).…”

Section: Introductionunclassified

“…TP53, hücresel proliferasyon, apoptozis ve farklı-laşmanın düzenlenmesine katılan "encode" fosfoproteinlerdendir; hücre döngüsü arresti, gen transkripsiyonu ve DNA tamirinde de yer alır (3). TP53, hücre proliferasyonu üzerinde duraklatıcı ("inhibitör") etki gösterir ve böylece p21 ekspresyonu indüklenir.…”

Section: Introductionunclassified

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Tp53 Expression And Ki-67 Proliferation Index In Surface Epithelial Tumors Of The Ovary And Their Relationship With The Histopathological Prognostic Parameters

Özkara¹,

Filinte²

2010

TUTFD

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ÖZETAmaç: Malign, "borderline" ve benign epitelyal over tümörlerinde TP53 ve Ki-67 ekspresyonlarını; karsinomlarda histopatolojik parametrelerle iliş-kisini; farklı özelliklerdeki olgu gruplarında TP53 ve Ki-67 ekspresyonlarını araştırmak; overde karsinogenezi tartışmak. Gereç ve Yöntemler:Yüz'ü malign, 27'si "borderline" ve 31'i benign, toplam 158 epitelyal over tümörü ve 42 non-tümöral over dokusunda standart immunohistokimya tekniği kullanıldı.Bulgular: TP53 aşırı-ekspresyonu, "borderline" tümörlere (%40.7) kıyasla malignlerde (%61.0); 50 yaş üstündeki; yüksek dereceli, az/indiferansiye ve seröz; solid yapılanmalı seröz, yüksek pleomorfizm dereceli seröz ve non-seröz, yüksek mitotik indeksli non-seröz subtiplerde; lenf nodu tutulumu gösteren, ileri evredeki karsinomlarda daha yüksekti (p<0.05). Ortalama Ki-67 indeksleri, malignlerde %41.3, "borderline" tümörlerde %17.2 olup; fark anlamlıydı. Karsinomların Ki-67 indeksleri, dereceleri yükseldik-çe artarken; lenf nodu tutulumlu olgularda azalma gösterdi. Karsinomların farklı subtiplerinin, derecelerine, lenf nodu tutulumları ve evrelerine göre, TP53 ekspresyonları ve Ki-67 indeksleriyle ilişkilerinde farklılıklar saptandı.Sonuç: TP53 aşırı-ekspresyonunun, malign ve "borderline" over tümör-lerinin gelişimindeki rolünü desteklemektedir. Karsinomlarda, TP53 ekspresyonunun derecesi, yaş, histopatolojik subtip, derece, pleomorfizm, yapılanma özelliği, mitotik aktivite, lenf nodu tutulumu ve evre ile ilişkili olarak farklılık; Ki-67 proliferasyon indeksi ile de korelasyon göstermekte-dir. Malign epitelyal over tümörlerinin bu biyolojik parametrelere göre de ayrılması, gelecekte daha olguya özgün tedavi protokollerinin belirlenmesinde, özellikle erken evrede önemli olabilir. Material and Methods: Standard immunohistochemistry was performed in 100 malignant, 27 borderline and 31 benign tumors and 42 non-tumoral ovarian epithelia.Results: TP53 overexpression was higher in malignant (61.0%) than in borderline tumors (40.7%); in malignant cases above 50 years-of-age, with high grade and in undifferentiated and serous subtypes. Carcinomas with solid architecture in serous, high mitosis in non-serous and high pleomorphism in both subtypes; lymph node involvement, and advanced stage also showed higher expressions of TP53 (p<0.05). The mean Ki-67 index was 41.3% in malignant and 17.2% in borderline tumors. Ki-67 index tended to increase with increasing grade, and decrease with lymph node involvement. The coexpression of proteins according to grade, lymph node involvement and stage in different subtypes, showed significant differences and correlations.Conclusion: Our findings support the role of TP53 overexpression in development of "borderline" and malignant epithelial ovarian tumors. The degree of TP53 expression differed in terms of histopathological parameters; and was correlated with Ki-67 index. Especially in early stages, these biological factors could provide additional information to stratify patients for case specific therapies.

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Linking TP53 codon 72 and P21 nt590 genotypes to the development of cervical and ovarian cancer

Cited by 37 publications

References 25 publications

Role of the RAD51 G172T polymorphism in the clinical outcome of cervical cancer patients under concomitant chemoradiotherapy

Role of the RAD51 G172T polymorphism in the clinical outcome of cervical cancer patients under concomitant chemoradiotherapy

TP53 Arg72Pro polymorphism is associated with increased overall survival but not response to therapy in Portuguese/Caucasian patients with advanced cervical cancer

Tp53 Expression And Ki-67 Proliferation Index In Surface Epithelial Tumors Of The Ovary And Their Relationship With The Histopathological Prognostic Parameters

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