Eduardo Breda

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.

Association of the A870G cyclin D1 gene polymorphism with genetic susceptibility to nasopharyngeal carcinoma.

Nasopharyngeal cancer (NPC) is multifactorial, and the genetic background may be a crucial etiologic factor. Cyclin D1 (CCND1) is a key regulator of the cell cycle, and its altered activity is associated with the development of cancer.

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.

Oncogenic virus-associated neoplasia: a role for cyclin D1 genotypes influencing the age of onset of disease?

Cyclin D1 (CCND1) is a key regulatory protein at the G1/S checkpoint of the cell cycle. The purpose of our study was to assess the role of CCND1 genotypes influencing the age of onset of oncogenic virus-associated neoplasia. We conducted a hospital-based case-control study of 581 individuals, including 247 controls and 334 cases (108 nasopharyngeal and 226 cervical cancer cases). The polymorphism analysis was performed in blood samples by PCR-RFLP methodology. Age-adjusted logistic regression analysis indicates that individuals carrying two G-alleles have an increased genetic susceptibility for the development of oncogenic virus-associated cancers (aOR=2.02, 95% CI 1.30-3.14, P=0.002). Moreover, our results indicate that the waiting time for onset of oncogenic virus-associated neoplasia in patients homozygous (GG) for CCND1 genotypes (52 years) was 12 years earlier in comparison with patients carrying AG or AA genotypes (60 years) (log-rank test: P=0.0003). Our results may be important in contributing to a more extensive knowledge of the mechanisms involved in oncogenic virus-associated carcinogenesis, as CCND1 may be an important target for the development of new strategies for cancer treatment and prevention.

Transoral laser microsurgery for laryngeal carcinoma: Survival analysis in a hospital‐based population

Although already established for treatment for early‐stage laryngeal cancers, transoral laser microsurgery indications for more advanced tumors are not unanimous. Additionally, no outcomes concerning the Portuguese population are currently accessible.

Detecção de Epstein-Barr vírus no carcinoma da nasofaringe: implicações numa área de baixo risco

UNLABELLED Several studies have been published concerning Epstein-barr virus (EBV) infection and nasopharyngeal cancer (NPC) development. The incidences of histological types are different according to endemic or non-endemic regions. Latent EBV infection is found in almost all cases of NPC in endemic regions, but normally absent in type I carcinomas, more common in non-endemic regions. AIM The purpose of this hospital-based study was to analyze the presence of EBV in nasopharyngeal tumor tissues and in peripheral blood of nasopharyngeal cancer patients and healthy individuals, in a low risk, non-endemic area. METHODS EBV detection in samples of nasopharyngeal cancer patients and healthy individuals. RESULTS This study indicates that the frequency of EBV positive cases in peripheral blood is higher in advanced tumor stages. CONCLUSIONS The incidence rates of NPC have a distinct distribution. Since the prevalence of this disease is low in occidental countries, little is known about the biology of these tumors in non-endemic areas. We observed statistically significant differences in EBV detection between the NPC patient group and the control group. This study may help to understand the biological mechanisms of NPC and the correlation of EBV infection with this disease, in a low risk, non-endemic region.

Role of the MDM2 SNP309 polymorphism in the initiation and early age of onset of nasopharyngeal carcinoma

Recent studies refer that amplification/overexpression of the principal negative regulator of p53 (Mdm2) is frequently found in several malignancies. Several studies have associated a polymorphism (SNP309 T/G) in the promoter region of MDM2 with higher levels of this protein, which will favor p53‐pathway abolishment, cell‐cycle escape, and development of cancer. We aimed to study if MDM2 SNP309 T/G polymorphism contributes to the development of nasopharyngeal carcinoma (NPC). We have developed a case–control study with 124 patients with NPC and 509 healthy individuals from the north of Portugal to determine the genetic distribution of the MDM2 SNP309 polymorphism in DNA extracted from peripheral blood samples. Statistical analysis was performed to compare categorical variables adjusted for age and gender by multivariate logistic regression. Genotype‐specific distributions according to age of onset were tested by Kaplan–Meier method and analyzed by Cox‐regression proportional hazard model adjusted for gender. This study revealed that MDM2 SNP309 GG homozygous represent an increased risk adjusted for age and gender to develop NPC (OR = 2.15), with particular effect in undifferentiated types (OR = 2.46) and early clinical stages (OR = 3.32). We also found that median age of onset of NPC was significantly different (55.2 vs. 61.6) with increased effect in undifferentiated types (55.2 vs. 61.9) and early clinical stages (55.3 vs. 65.3). Our study suggests that MDM2 SNP309 can be considered a risk marker for the development of NPC mainly in early ages probably as an initiation marker for potential cancer development.

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.

Characterization of the Clinical Evolution of Nasopharyngeal Carcinoma in a Portuguese Population

OBJECTIVE Characterization of the clinical evolution of nasopharyngeal cancer (NPC) patients in a Portuguese population during 31 years of follow-up. MATERIALS AND METHOD Three hundred and twenty patients with epidermoid nasopharyngeal carcinoma were selected for this study. Histological subtypes were analyzed along with survival rates after different treatment schemes and according to AJCC and UICC staging classification systems. RESULTS The most frequent histological subtype was undifferentiated nasopharyngeal carcinoma. The AJCC-2001 staging classification was considered the most suitable system for survival prediction. Better survival rates were found in patients treated with adjuvant chemotherapy (cisplatin and 5-fluorouracil) and these findings were similar to other published results. CONCLUSIONS Although adjuvant chemotherapy may reduce the likelihood of distant metastasis, the latter is still the main cause of death in our study. The distant metastasis rate remains the crucial problem and bringing it down is an ever closer goal and a challenge for the future.

Caracterización de la evolución clínica del carcinoma de la nasofaringe en una población portuguesa

Objetivo Caracterizacion de la evolucion clinica del carcinoma de la nasofaringe en una poblacion portuguesa en 31 anos de seguimiento. Material y metodo Trescientos veinte enfermos portadores de carcinoma epidermoide nasofaringeo fueron seleccionados para este trabajo. Los siguientes parametros fueron analizados: variante histologica, tasas de supervivencia despues de diferentes modalidades de tratamiento y diferentes estadios (AJCC y UICC). Resultados La variante histologica mas frecuente fue el carcinoma indiferenciado del tipo nasofaringeo. La clasificacion de la AJCC de 2001 se considero la mas adecuada para el pronostico de los enfermos. Los enfermos tratados con quimioterapia adyuvante han obtenido mejores tasas de supervivencia, sobre todo los que recibieron tratamiento con cisplatino y 5-fluorouracilo (resultados similares a los obtenidos en otros trabajos). Conclusiones Aunque la quimioterapia adyuvante reduzca la probabilidad de metastasis a distancia, continua siendo la principal causa de muerte constatada en nuestro estudio. La tasa de metastasis a distancia sigue siendo el problema crucial, y disminuirla es una meta cada vez mas proxima y un desafio para el futuro.