Tumour necrosis factor alpha 308 G/A is a risk marker for the progression from high-grade lesions to invasive cervical cancer.

Tumour necrosis factor alpha (TNF-α) is a strong pro-inflammatory cytokine with important functions on immune response to viral infections. A single nucleotide polymorphism on the -308 position of the promoter region of TNFA gene characterised by a G > A transition has been associated with different TNF-α levels and therefore with differential susceptibility for the development several diseases. A cross-sectional case-control study was performed with 509 women with cancer from the northern region of Portugal, including 205 healthy women and 337 women with different cervical lesions including invasive cervical. The -308G > A polymorphism genotyping was performed with TaqMan® SNP Genotyping Assay and studied for its association with cervical cancer development. This study showed increased frequency of the -308A allele in women with any cervical lesions. Statistical analysis revealed that -308A carriers are associated with an almost 2-fold increased risk for invasive cervical cancer development (p = 0.005; odds ratio (OR) = 1.87). Similar results were found when comparing the risk of progression between preinvasive lesions and invasive cervical cancer development (p = 0.002; OR = 2.41). Our results reveal that -308 TNFA AA individuals are at increased risk of invasive cervical cancer development and more important, that the risk is significantly increased for the progression from premalignant lesion to invasive cancer. Considering previous data and this study, this polymorphism confirms to be a significant marker in our population.

IL-1RN VNTR polymorphism as a susceptibility marker for nasopharyngeal carcinoma in Portugal.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare malignancy in Western countries that is widely associated with the infection by Epstein-Barr virus (EBV). Several studies have showed that a common allele (allele 2) of the 86-bp variable number of tandem repeats (VNTR) polymorphism within intron 2 of the interleukin 1 receptor antagonist (IL-1RN) gene is associated with several disorders, including viral-associated cancers. METHODS: We have developed a hospital-based case-control study to characterise the role of the IL-1RN 86-bp VNTR polymorphism in the development of NPC with 112 patients with the disease and 433 healthy individuals from the northern region of Portugal. IL-1RN genotypes were combined according to the number of repeats: allele 2 (A2), the short allele that corresponds to two repeats, and L, the long allele that corresponds to three or more repeats. RESULTS: Our study revealed that 31.2% of NPC patients were IL-1RN A2*A2, compared with 9.7% observed in the control group. The statistical analysis revealed that IL-1RN*A2 homozygosity for the A2 allele was associated with a fourfold increased risk for NPC development (p<0.001). Additionally, cumulative hazard analysis revealed that estimated median age of onset of NPC is significantly (p<0.001) different for A2*A2 homozygous versus non-A2*A2 (57.0 vs. 74.0, respectively). CONCLUSIONS: This is the first study to evaluate the role of the IL-1RN VNTR in NPC development in Portugal. Our study indicates IL-1RN*A2 homozygosity as a significant risk marker in our population and that it should be further investigated for the potential role in the definition of a susceptibility profile for NPC onset.

IL-1RN VNTR polymorphism and genetic susceptibility to cervical cancer in Portugal.

Human Papillomavirus infection is considered as the main etiological factor of cervical cancer (ICC), although, the role of host genetic factors in ICC susceptibility has been increasing. Immunological response is crucial for the prevention of viral associated diseases. Interleukin 1 receptor antagonist (IL-1RN) is considered to be an important regulator of host immunity and several studies have shown a potential role of a 86 bp VNTR polymorphism within intron 2 of the IL-1RN gene in host immune response variability. We investigated the role of this polymorphism in cervical cancer development in Portugal with a case-control study developed with peripheral blood samples from 196 healthy women and 340 women with cervical lesions from the Northern Region of Portugal. We observed that IL-1RN Allele 2 homozygosis was significantly higher in cases than in controls. In fact, IL-1RN A2*A2 homozygous revealed to be associated with an increased risk of HSIL + ICC (OR = 1.90; 95 % IC 1.13-3.21; p = 0.015). Furthermore, we also observed that median age of onset of HSIL + ICC was significantly different (46.0 vs 52.0) in IL-1RN A2*A2 homozygous comparing to non-A2*A2 (p = 0.028). Our results indicated that IL-1RN A2 allele is associated with an increased susceptibility to cervical cancer development, probably by increasing predisposition to shorter immune responses.

Is there a biological plausability for p53 codon 72 polymorphism influence on cervical cancer development?

The interaction between HPV E6 and p53 protein is known as the most important event in HPV-associated carcinogenesis. Some in vitro studies suggested that p53 genetic variants are targeted for ubiquitin-proteasome degradation induced by E6 with different abilities. A common p53 variant at position 72 (R72P) has leaded to the development of several studies regarding its role on cervical cancer development. However, only few reports have shown an association between the Arginine (R) variant at position 52 of p53 and increased susceptibility to HPV E6 mediated degradation and thus to increased cancer susceptibility. We revised the literature in order to obtain plausible data to discuss about these evidences for cervical cancer susceptibility. The more recent studies, including meta-analysis reviews, point out that there is no association of this p53 variant and cervical cancer development. This variant seems to be differently segregated in different ethnic/geographical locations; therefore, there might be a possible role of this genetic variant associated with a certain genetic background, which can explain why some studies reveal increased risk of cervical cancer development associated with Arginine p53 variant.

Genetic risk markers for nasopharyngeal carcinoma in Portugal: tumor necrosis factor alpha -308G >A polymorphism.

The tumor necrosis factor-alpha (TNF-α) is a strong proinflammatory cytokine produced by the activated macrophages in the immune response to viral infections. A common polymorphism on the promoter region of TNFA gene (-308G >A) has been associated with different susceptibilities to the development of several diseases including viral-associated neoplasias. Data suggest that the A allele has been associated with higher levels of TNF-α and, therefore, leads to increased risk of cancer development. We have performed a case-control study considering the role of the -308G >A polymorphism in 750 individuals from the northern region of Portugal, including 123 patients with nasopharyngeal carcinoma (NPC) and 627 healthy individuals. Our study revealed an increased frequency of the -308A TNFA allele in patients with NPC. The statistical analysis for recessive model revealed that -308AA genotype is associated with increased risk for the development of NPC (odds ratio = 2.46; 95% confidence interval, 0.98-6.17; p = 0.047); moreover, this effect was stronger in undifferentiated types, which are virtually 100% caused by the Epstein-Barr virus (odds ratio = 2.75; 95% confidence interval, 1.09-6.90; p = 0.025). These results reveal that in our population -308 TNFA AA genotype can represent a risk marker for NPC development and contributes for the definition of genetic susceptibility profiles for individuals at risk of development of a viral infection and associated neoplasia.

Is the p53 codon 72 polymorphism a key biomarker for cervical cancer development? A meta-analysis review within European populations.

Human papillomavirus (HPV) is the necessary cause for cervical cancer development, and the interaction of HPV-E6 with p53 is known as the most important event in HPV-associated carcinogenesis. In vitro studies have suggested that HPV-E6 interacts more efficiently with the arginine (Arg) p53 variant at position 72 as it appears to be more susceptible to degradation through the ubiquitin proteasome pathway. However, few reports have corroborated this data, and the role of the p53 codon 72 polymorphism in the development of cervical cancer requires further elucidation. We performed a meta-analysis review of all studies published within European populations to summarize the overall risk of this polymorphism considering the influence of the geographical/ethnic location as an important factor in defining a genetic profile and the susceptibility for cervical cancer development. Our analysis revealed that the p53 Arg/Arg genotype does not seem to represent a risk marker for the development of cervical lesions in the majority of the European countries analysed. However, in countries with low incidence rates of cervical cancer, this polymorphism might represent a significant genetic marker.

Linkage of TP53 codon 72 pro/pro genotype as predictive factor for nasopharyngeal carcinoma development.

Genetic predisposition has been suggested as a cofactor for cancer aetiology and a polymorphism in TP53 codon 72 has been associated as a susceptibility factor for several cancers. Nasopharyngeal carcinoma is a rare neoplasia in western civilizations and genetic predisposition might play an important role in its development. We evaluated the linkage of the polymorphic variants (Arg/Pro) on TP53 codon 72 with nasopharyngeal cancer development in a case-control study with 392 individuals from a northern Portuguese population, including 107 patients with nasopharyngeal carcinoma and 285 healthy controls. This study revealed a three-fold risk for carriers of Pro/Pro genotype either against carriers of Arg/Arg (OR=2.62; 95% CI=1.10-6.30; P=0.016) or total Arg carriers (OR=2.67; 95% CI=1.21-5.90; P=0.012). Moreover, step-wise logistic regression analysis identified Pro/Pro genotype (OR=3.1; 95% CI=1.3-7.3; P=0.009), age >49 at diagnosis (OR=2.5; 95% CI=1.6-4.0; P<0.001) and male gender (OR=2.7; 95% CI=1.6-4.4; P<0.001) as predictive factors for the development of nasopharyngeal carcinoma. These results confirm the data from Asiatic populations suggesting that Pro/Pro genotype represents a stable risk factor for nasopharyngeal carcinoma development in Portugal and that TP53 codon 72 polymorphism can contribute as a genetic susceptibility marker, providing additional information to improve the knowledge about nasopharyngeal carcinoma aetiology.

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

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 frequency of TP53 codon 72 and 3'UTR P21 polymorphisms in 681 blood samples from 371 cervical 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.

TP53 and P21 polymorphisms: response to cisplatinum/paclitaxel-based chemotherapy in ovarian cancer.

Ovarian cancer (OC) is the most lethal gynaecologic cancer and its standard treatment consists of platinum-based chemotherapy after cytoreductive surgery. The p53 protein plays a critical role on different cellular processes in response to DNA damage and it is responsible for transcriptional induction of the P21 gene. We have analysed 114 blood samples in order to investigate the effect of the TP53 codon 72 and the P21 3'UTR polymorphisms in response to cisplatinum/paclitaxel chemotherapy for OC treatment. The genotypes of the TP53 codon 72 and P21 3'UTR polymorphism were identified using AS-PCR and PCR-RFLP, respectively. Our results indicate that the TP53 P allele is associated with a worse prognosis (P=0.011) while P21 polymorphism genotypes did not reveal any statistically significant result (P>0.05). Furthermore, simultaneous carriers of the TP53 AA genotype and the P21 CC genotype demonstrate a longer progression-free interval (P=0.020). This study suggests that the characterisation of a genetic profile can contribute to the definition of a better chemotherapy treatment.

TP53 codon 72 polymorphism and risk for cervical cancer in Portugal.

High-risk human papillomavirus are essential for the development of cervical cancer; however, TP53 is the most frequently altered tumor suppressor gene among tumors and is described as a cofactor for cervical carcinogenesis. TP53 has two common polymorphic forms encoding either proline or arginine, at position 72, and the presence of homozygous arginine has been reported as a risk factor for cervical cancer in many populations. We evaluated the effect of this TP53 polymorphism in a northern Portuguese population. We analyzed blood samples of 385 women; 20 with low-grade squamous intraepithelial lesion (SIL), 56 with high-grade SIL, 164 with invasive cervical cancer, and 145 healthy controls, using allele specific-polymerase chain reaction methodology. We observed an increased frequency of the Arg/Arg genotype in the cancer group, but no statistical significance was found between cases and controls (P>0.05). Our results indicate that there is no association between the presence of the Arg allele in codon 72 of TP53 polymorphism and risk of cervical cancer in our population.