Hugo Sousa

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.

SLC19A1 80G allele as a biomarker of methotrexate-related gastrointestinal toxicity in Portuguese rheumatoid arthritis patients

AIM The aim of our study was to characterize the association of clinicopathological variables and the SLC19A1/RFC-1 G80A polymorphism in methotrexate (MTX)-related toxicity in Portuguese patients with rheumatoid arthritis. PATIENTS & METHODS The study included 233 consecutively recruited patients with rheumatoid arthritis under MTX treatment. The SLC19A1 G80A polymorphism was evaluated by PCR-RFLP. RESULTS Statistical analysis revealed that SLC19A1 80G carriers had increased risk of gastrointestinal toxicity (odds ratio [OR]: 2.61, p = 0.019) and that regular folic acid supplementation was associated with both overall and gastrointestinal toxicity protection (OR: 0.15, p < 0.001 and OR: 0.19, p < 0.001, respectively). Multivariate analysis confirmed the association of SLC19A1 80G and regular folic acid supplementation to gastrointestinal toxicity (OR: 5.53 and 0.13, respectively). Moreover, a multivariate Cox regression model demonstrated a higher risk of earlier gastrointestinal toxicity in SLC19A1 80G carriers (hazard ratio: 3.63, p = 0.002). CONCLUSION SLC19A1 G80A genotyping may be a useful tool for clinicians to identify patients at higher risk for developing gastrointestinal toxicity related to MTX treatment.

MicroRNAs as biomarkers of cervical cancer development: a literature review on miR-125b and miR-34a

MicroRNAs are non-coding RNAs with important functions in several biological processes, such as, regulation of cell cycle, immune response, inflammation, and apoptosis. In fact, deregulation and abnormal expression of these molecules is associated with human pathologies including cancer and several have already emerged as potential prognostic biomarkers in different neoplasias. miR-34a is directly regulated by p53 and acts as tumor suppressor while miR-125b plays a significant role in immune response and apoptosis. In cervical carcinogenesis, HPV proteins seem to interact with both miR-34a and miR-125b changing its expression and promoting persistent infection and cervical cancer development. In this review we describe the potential role of miR-125b and miR-34a in cervical carcinogenesis, including interaction with HPV and mechanism of deregulation. Additionally, their clinical applications in cervical cancer as prognostic/predictive biomarkers are also briefly discussed.

Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

Background Therapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients. Methods Clinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches. Results Considering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp− carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp− carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp− alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes. Conclusion Our study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences.

Future perspectives of Smartphone applications for rheumatic diseases self-management

Abstract Rheumatic diseases (RD) self-management interventions are designed to improve health-related quality of life, health care utilization, and perceived self-efficacy. Despite these demonstrated good results, there are several issues that hinder or render less appealing these interventions. One economically and socially viable solution is exploiting the potential of Smartphone technology. This potential comes from Smartphones pervasive presence in actual society, combined with the advantages of being personal, intuitive, and computationally powerful, with capability to support applications and assist its user throughout different activities of daily living and environments persistently. With their global acceptance increasing quickly, there is a great opportunity for mobile health in using Smartphone applications for RD self-management. Besides the potential of such applications, research on the development and evaluation of such applications is in the early stages. Therefore, it is important to foresee its future applicability in order to meet the needs of the twenty-first century.

SLC19A1, SLC46A1 and SLCO1B1 Polymorphisms as Predictors of Methotrexate-Related Toxicity in Portuguese Rheumatoid Arthritis Patients

Methotrexate (MTX) is used for rheumatoid arthritis (RA) treatment showing a wide toxicity profile. This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding for MTX transporters with the occurrence of MTX-related toxicity (overall and gastrointestinal). A total of 233 Portuguese RA patients were genotyped for 23 SNPs. Haplotype analyses were performed and a toxicogenetic risk index (TRI) was created for SNPs that revealed to be statistically significant. Regarding MTX overall toxicity, an increased risk was associated to SLC19A1 rs7499 G carriers (p = 0.017), SLC46A1 rs2239907 GG (p = 0.030) and, SLCO1B1 rs4149056 T carriers (p = 0.040) and TT (p = 0.019). TRI revealed that patients with Index 3 were 18-fold more likely to present an adverse drug reaction when compared to those with Index 1 (p = 0.001). For MTX gastrointestinal toxicity, results demonstrated an increased risk associated with SLC19A1 rs7499 G carriers (p = 0.012) and GG (p = 0.045), SLC19A1 rs1051266 G carriers (p = 0.034), SLC19A1 rs2838956 A carriers (p = 0.049) and, SLCO1B1 rs4149056 T carriers (p = 0.042) and TT (p = 0.025). Haplotype analyses showed association between GGAG haplotype for SLC19A1 rs7499, rs1051266, rs2838956 and rs3788200 with MTX gastrointestinal toxicity (p = 0.029). TRI revealed that patients with Index 4 were 9-fold more likely to present a gastrointestinal disorder when compared to those with Index 1 (p = 0.020). This study demonstrated that SLC19A1, SLC46A1 and SLCO1B1 genotypes may help to identify patients with increased risk of MTX-related overall toxicity and that SLC19A1 and SLCO1B1 genotypes, and SLC19A1 haplotypes may help to identify patients with increased risk of MTX-related gastrointestinal toxicity.

miR-34a and miR-125b Expression in HPV Infection and Cervical Cancer Development

We aimed to characterize miR-125b and miR-34a expression in 114 women with different cervical lesions: normal epithelium with (n = 20) and without (n = 29) HPV infection; LSIL (n = 28); HSIL (n = 29); and ICC (n = 8). miRNA expression analysis was performed by comparing the distinct groups with the reference group (women with normal epithelium without HPV). For miR-125b, we observed a twofold (2−ΔΔCt = 2.11; P = 0.038) increased expression among women with normal epithelium with HPV infection and a trend of downregulation in different cervical lesions including an 80% reduction (2−ΔΔCt = 0.21; P = 0.004) in ICC. Similarly, miR-34a expression analysis revealed an increased expression (2−ΔΔCt = 1.69; P = 0.049) among women with normal cervix and HPV infection, and despite no significant correlation with cervical lesions, its expression was increased by twofold (2−ΔΔCt = 2.08; P = 0.042) in ICC. Moreover, miR-125b levels were able to predict invasive cancers with 88% sensitivity and 69% specificity. Results showed that while miR-34a expression seems to be correlated with invasive cervical cancer, miR-125b expression is significantly changed within the different cervical lesions and their levels should be further investigated as possible predictive/prognostic biomarkers using a noninvasive approach.

Prediction of methotrexate clinical response in Portuguese rheumatoid arthritis patients: implication of MTHFR rs1801133 and ATIC rs4673993 polymorphisms.

Objective. Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods. Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results. Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion. Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment.