Haemostatic Gene Expression in Cancer-Related Immunothrombosis: Contribution for Venous Thromboembolism and Ovarian Tumour Behaviour.

Ovarian cancer (OC) is the deadliest gynaecological malignancy. Identifying new prognostic biomarkers is an important research field. Haemostatic components together with leukocytes can drive cancer progression while increasing the susceptibility to venous thromboembolism (VTE) through immunothrombosis. Unravelling the underlying complex interactions offers the prospect of uncovering relevant OC prognostic biomarkers, predictors of cancer-associated thrombosis (CAT), and even potential targets for cancer therapy. Thus, this study evaluated the expression of F3, F5, F8, F13A1, TFPI1, and THBD in peripheral blood cells (PBCs) of 52 OC patients. Those with VTE after tumour diagnosis had a worse overall survival (OS) compared to their counterparts (mean OS of 13.8 ± 4.1 months and 47.9 ± 5.7 months, respectively; log-rank test, p = 0.001). Low pre-chemotherapy F3 and F8 expression levels were associated with a higher susceptibility for OC-related VTE after tumour diagnosis (χ2, p < 0.05). Regardless of thrombogenesis, patients with low baseline F8 expression had a shorter progression-free survival (PFS) than their counterparts (adjusted hazard ratio (aHR) = 2.54; p = 0.021). Among those who were not under platelet anti-aggregation therapy, low F8 levels were also associated with a shorter OS (aHR = 6.16; p = 0.006). Moving forward, efforts should focus on external validation in larger cohorts.

Pioneering the implementation of a precision oncology strategy in Portugal: the Precision Oncology Platform trial.

BACKGROUND AND PURPOSE: The Precision Oncology Platform (POP) trial represents the effort of the Portuguese Oncology Institute of Porto (IPO Porto) for joining other leading European institutions in both 'Personalised Cancer Medicine for all EU citizens' (PCM4EU), and 'PRecisIon Cancer MEdicine RepurpOsing SystEm Using Pragmatic Clinical Trials' (PRIME-ROSE) consortia, enabling the development of the Portuguese version of the Drug Rediscovery Protocol (DRUP)-like Clinical Trial (DLCT), based on the experience of the DRUP trial developed in The Netherlands. PATIENTS/MATERIAL AND METHODS: The POP trial is a phase II, pragmatic multicentric, non-randomised, open-label study, designed entirely like the other DLCTs. Its primary objective is to describe anti-tumour activity of targeted anticancer drugs in patients with advanced malignancies harbouring actionable molecular alterations. The primary endpoint is disease control rate (DCR). Secondary endpoints encompass treatment-related grade ≥3 adverse events, objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory objectives will assess biomarkers, resource use and costs, and patient-reported outcome measures (PROMs). INTERPRETATION: The POP trial will offer access to innovative treatments for patients without further therapeutic options and provide evidence on efficacy and safety of molecularly-guided treatments. Methodologically, it represents a pioneer approach in Portugal, including a pay-for-performance model embedded in the clinical trial. The POP trial represents a unique opportunity to integrate clinical research within cancer care, pursuing an evidence-based precision oncology strategy, and facilitating its rational and cost-effective implementation into the Portuguese healthcare system.

Paradigm Shift: A Comprehensive Review of Ovarian Cancer Management in an Era of Advancements.

Ovarian cancer (OC) is the female genital malignancy with the highest lethality. Patients present a poor prognosis mainly due to the late clinical presentation allied with the common acquisition of chemoresistance and a high rate of tumour recurrence. Effective screening, accurate diagnosis, and personalised multidisciplinary treatments are crucial for improving patients' survival and quality of life. This comprehensive narrative review aims to describe the current knowledge on the aetiology, prevention, diagnosis, and treatment of OC, highlighting the latest significant advancements and future directions. Traditionally, OC treatment involves the combination of cytoreductive surgery and platinum-based chemotherapy. Although more therapeutical approaches have been developed, the lack of established predictive biomarkers to guide disease management has led to only marginal improvements in progression-free survival (PFS) while patients face an increasing level of toxicity. Fortunately, because of a better overall understanding of ovarian tumourigenesis and advancements in the disease's (epi)genetic and molecular profiling, a paradigm shift has emerged with the identification of new disease biomarkers and the proposal of targeted therapeutic approaches to postpone disease recurrence and decrease side effects, while increasing patients' survival. Despite this progress, several challenges in disease management, including disease heterogeneity and drug resistance, still need to be overcome.

Cancer-associated thrombosis: What about microRNAs targeting the tissue factor coagulation pathway?

Cancer patients are often diagnosed with venous thromboembolism (VTE), a cardiovascular disease that substantially decreases their quality of life and survival rate. Haemostasis in these patients is deregulated, which is reflected in the common presentation of a blood hypercoagulation state. Despite the inconsistent results, existing evidence suggests that the expression of microRNAs (miRNAs) is deregulated in the context of venous thrombogenesis in the general population. However, few miRNAs are known to be linked to cancer-associated VTE due to the lack of studies with oncological patients. Parallelly, coagulation factor III, also known as tissue factor (TF), tissue factor pathway inhibitor 1 (TFPI1) and tissue factor pathway inhibitor 2 (TFPI2) have been proposed to have a central role in cancer-associated VTE and tumour progression. Yet, contrary to what was expected, the role of miRNAs targeting the TF coagulation pathway (or extrinsic coagulation pathway) is poorly explored in cancer-induced thrombogenesis. In this review, in addition to miRNAs implicated in VTE, TF and TFPI1/2-targeting miRNAs were revised. Future studies should clarify the implications of these non-coding RNAs in tumour coagulome.

Venous thromboembolism-related genetic determinant F11 rs4253417 is a potential prognostic factor in ischaemic stroke.

Ischaemic stroke (IS) and venous thromboembolism (VTE) are two forms of thromboembolism that, although distinct, seem to share numerous risk factors. Concerning genetic risk factors, while many VTE genetic markers have been reported, inclusively by genome-wide association studies (GWAS), the identification and validation of genetic determinants underlying IS pathogenesis have been challenging. Considering that IS and VTE shared biological pathways and aetiological factors, the severity of IS might be also influenced by VTE-related genetic variants. Thus, the present study was designed to analyse the impact of six VTE GWAS-identified genetic variants on the clinical outcome of 363 acute IS patients. Results revealed that the single-nucleotide polymorphism (SNP) F11 rs4253417 was an independent predictor of the 5-year risk of death among patients with total anterior circulation infarct (TACI). Namely, the ones carrying the SNP C allele presented a fourfold increase in the 5-year risk of death compared to TT genotype carriers (CC/CT vs. TT; adjusted HR, 4.240; 95% CI, 1.260-14.270; P = 0.020). This SNP is known to be associated with coagulation factor XI (FXI) levels, thus with implications in haemostasis and inflammation. As such, F11 rs4253417 might be a promising prognostic biomarker among TACI patients to aid in clinical decision-making. However, additional investigation is required to confirm the study's results and dissect the underlying mechanisms.

Long Non-Coding RNAs: Bridging Cancer-Associated Thrombosis and Clinical Outcome of Ovarian Cancer Patients.

Ovarian cancer (OC) and venous thromboembolism (VTE) have a close relationship, in which tumour cells surpass the haemostatic system to drive cancer progression. Long non-coding RNAs (lncRNAs) have been implicated in VTE pathogenesis, yet their roles in cancer-associated thrombosis (CAT) and their prognostic value are unexplored. Understanding how these lncRNAs influence venous thrombogenesis and ovarian tumorigenesis may lead to the identification of valuable biomarkers for VTE and OC management. Thus, this study evaluated the impact of five lncRNAs, namely MALAT1, TUG1, NEAT1, XIST and MEG8, on a cohort of 40 OC patients. Patients who developed VTE after OC diagnosis had worse overall survival compared to their counterparts (log-rank test, p = 0.028). Elevated pre-chemotherapy MEG8 levels in peripheral blood cells (PBCs) predicted VTE after OC diagnosis (Mann-Whitney U test, p = 0.037; Χ2 test, p = 0.033). In opposition, its low levels were linked to a higher risk of OC progression (adjusted hazard ratio (aHR) = 3.00; p = 0.039). Furthermore, low pre-chemotherapy NEAT1 levels in PBCs were associated with a higher risk of death (aHR = 6.25; p = 0.008). As for the remaining lncRNAs, no significant association with VTE incidence, OC progression or related mortality was observed. Future investigation with external validation in larger cohorts is needed to dissect the implications of the evaluated lncRNAs in OC patients.

Implications of venous thromboembolism GWAS reported genetic makeup in the clinical outcome of ovarian cancer patients.

Ovarian cancer (OC) represents the most lethal gynaecological neoplasia. Conversely, venous thromboembolism (VTE) and OC are intricately connected, with many haemostatic components favouring OC progression. In light of this bilateral relationship, genome-wide association studies (GWAS) have reported several single-nucleotide polymorphisms (SNPs) associated with VTE risk that could be used as predictors of OC clinical outcome for better therapeutic management strategies. Thus, the present study aimed to analyse the impact of VTE GWAS-identified SNPs on the clinical outcome of 336 epithelial ovarian cancer (EOC) patients. Polymorphism genotyping was performed using the TaqMan® Allelic Discrimination methodology. Carriers with the ZFPM2 rs4734879 G allele presented a significantly higher 5-year OS, 10-year OS and disease-free survival (DFS) compared to AA genotype patients with FIGO I/II stages (P = 0.009, P = 0.001 and P = 0.003, respectively). Regarding SLC19A2 rs2038024 polymorphism, carriers with the CC genotype presented a significantly lower 5-year OS, 10-year OS and DFS compared to A allele carriers in the same FIGO subgroup (P < 0.001, P = 0.004 and P = 0.005, respectively). As for CNTN6 rs6764623 polymorphism, carriers with the CC genotype presented a significantly lower 5-year OS compared to A allele carriers with FIGO I/II stages (P = 0.015). As for OTUD7A rs7164569, F11 rs4253417 and PROCR rs10747514, no significant impact on EOC patients' survival was observed. However, future studies are required to validate these results and uncover the biological mechanisms underlying our results.

Dataset of GWAS-identified variants underlying venous thromboembolism susceptibility and linkage to cancer aggressiveness.

Venous thromboembolism (VTE) is a common cardiovascular disease, for which several single nucleotide polymorphisms (SNPs) underlying susceptibility were identified. Apart from candidate gene approach, genome-wide association studies (GWAS) have contributed to the identification of novel VTE-associated SNPs, including some with no clear role in the haemostatic system. These genetic variants constitute potential cancer-related biomarkers, particularly predictive and prognostic biomarkers, as a two-way association between VTE and cancer is well established. The present dataset comprises the data obtained from GWAS performed to identify genetic variants associated with VTE risk. Furthermore, this dataset also comprises data regarding previously reported candidate gene and validation reports performed in adults of European ancestry that also analysed the VTE GWAS-identified variants. Lastly, to evaluate the impact of these genetic variants in carcinogenesis, a broad search was made, which has let us to establish putative links between several VTE-associated genes and cancer hallmarks in a review article entitled "Venous thromboembolism GWAS reported genetic makeup and the hallmarks of cancer: linkage to ovarian tumour behaviour".

The emergent phenomenon of aspirin resistance: insights from genetic association studies.

Despite the clinical benefits of aspirin, the interindividual variation in response to this antiplatelet drug is considerable. The manifestation of aspirin resistance (AR) is frequently observed, although this complex process remains poorly understood. While AR etiology is likely to be multifactorial, genetic factors appear to be preponderant. According to several genetic association studies, both genome-wide and candidate gene studies, numerous SNPs in cyclooxygenase, thromboxane and platelet receptors-related genes have been identified as capable of negatively affecting aspirin action. Thus, it is essential to understand the clinical relevance of AR-related SNPs as potential predictive and prognostic biomarkers as they may be essential to defining the AR phenotype.

Venous thromboembolism GWAS reported genetic makeup and the hallmarks of cancer: Linkage to ovarian tumour behaviour.

Venous thromboembolism (VTE) is a common cardiovascular disease thought to be the outcome of an intricate interplay between acquired and inherited factors that act together to modify disease risk. Over the years, several single-nucleotide polymorphisms (SNPs) in candidate genes have been associated with disease risk, including F5 rs6025, F2 rs1799963, FGG rs2066865, ABO genetic variants, among others less common. More recently, genome-wide association studies (GWAS) have contributed to the identification of novel VTE-associated SNPs, some of them located in novel genes with no clear role in the haemostatic system, such as SLC44A2 rs2288904 and TSPAN15 rs78707713. Given the existence of a tight relationship between VTE and cancer, with both pathologies sharing biological pathways that allow one to promote the other, these SNPs constitute potential prognostic and predictive biomarkers currently needed for better management of cancer patients. Among solid tumours, ovarian cancer (OC) is one of the most frequently associated with VTE. Indeed, haemostatic components might have a significant impact in OC progression, and therefore, the clinical and biological implications of VTE-associated SNPs should be assessed in patients with this neoplasia.

Pharmacogenomics in epithelial ovarian cancer first-line treatment outcome: validation of GWAS-associated NRG3 rs1649942 and BRE rs7572644 variants in an independent cohort.

The identification of predictive biomarkers for the first-line treatment of epithelial ovarian cancer (EOC) remains a challenge. Although genome-wide association studies (GWAS) have identified several genetic polymorphisms as predictors of EOC clinical outcome, the subsequent validation has not yet been performed. This study aims to validate the influence of Neuregulin 3 (NRG3) rs1649942 and Brain and reproductive organ-expressed (TNFRSF1A modulator) (BRE) rs7572644 GWAS-identified variants in an independent cohort of EOC patients from the North region of Portugal (n = 339) submitted to first-line treatment. Polymorphism genotypes were determined by real-time PCR using validated assays. Patients carrying the NRG3 rs1649942 A allele presented a significantly longer overall survival (OS) when compared to GG-genotype patients (log-rank test, P = 0.011) in the FIGO IV stage subgroup. No impact was observed for early-stage patients or considering disease-free survival (DFS) as an outcome. For FIGO I/II stage patients, BRE rs7572644 C allele carriers exhibit a decreased OS (P = 0.014) and DFS (P = 0.032) when compared to TT-homozygous patients. Furthermore, a Multivariate Cox regression analysis revealed a three-fold increase in the risk of death (HR, 3.09; P = 0.015) and recurrence (HR, 3.33; P = 0.009) for FIGO I/II C allele carriers. No significant impact was observed for late-stage patients. The BRE rs7572644 and NRG3 rs1649942 genetic variants were validated in an independent cohort of EOC Portuguese patients, particularly in specific subgroups considering FIGO staging. Further functional post-GWAS analyses are indispensable to understand the biological mechanisms underlying the observed results.

Canine mammary tumor risk is associated with polymorphisms in RAD51 and STK11 genes.

Cancer is a complex disease involving genetic and phenotypic changes. Several single nucleotide polymorphisms (SNPs) have been associated with the risk of breast cancer development in women; however, little is known regarding their influence on canine mammary tumor risk. We assessed the influence of SNPs in genes related to human breast cancer susceptibility, with respect to the risk of development of mammary tumors in dogs. Sixty-seven canine SNPs in proto-oncogenes, tumor suppressor genes, genes involved in DNA repair, and in hormonal metabolism were evaluated in 212 bitches with mammary tumors and in 161 bitches free of mammary neoplasia. A significant association with mammary neoplasia risk was identified for 2 SNPs in RAD51 ( rs23623251 and rs23642734) and one SNP in the STK11 gene ( rs22928814). None of the other SNPs were related to the risk of mammary tumor development. The identification of genetic profiles associated with risk of mammary neoplasia is of great importance, supporting the implementation of specific clinical management strategies in high-risk animals.

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

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.

Relationship between clinical toxicities and ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms in cervical cancer patients.

BACKGROUND: Several studies have suggested that there are single nucleotide polymorphisms (SNPs) that can be considered potential biomarkers in the prognosis and therapeutic response of cancer patients. The present study investigated the association between ERCC1 rs3212986 and XRCC3 rs861539 polymorphisms and clinical toxicities induced by chemoradiotherapy (CRT) in cervical cancer. METHODS: This hospital-based retrospective cohort study included 260 patients with cervical cancer, FIGO stages Ib2-IVa, who underwent CRT (cisplatin). Genetic polymorphisms analysis was performed by allelic discrimination with real-time polymerase chain reaction (RT-PCR). RESULTS: Our results indicated a link between ERCC1 rs3212986 and the onset of late gastrointestinal toxicity (p = 0.038). Furthermore, using a recessive model (AA vs. CC/CA), we found that patients carrying AA homozygous genotype presented a fourfold increased risk of developing late gastrointestinal toxicity when compared with patients with the C allele (odds ratio = 3.727, 95% confidence interval, 1.199-11.588; p = 0.017). No association was found regarding the XRCC3 rs861539 polymorphism and any clinical toxicity event. CONCLUSIONS: This is the first study evaluating the relationship between these polymorphisms and clinical toxicities in cervical cancer patients submitted to CRT with cisplatin. These results may contribute toward a better understanding of the influence of genetic polymorphisms in genes associated with DNA repair in the clinical response to CRT of patients with cervical cancer.

Rethinking ovarian cancer genomics: where genome-wide association studies stand?

Genome-wide association studies (GWAS) allow the finding of genetic variants associated with several traits. Regarding ovarian cancer (OC), 15 GWAS have been conducted since 2009, with the discovery of 49 SNPs associated with disease susceptibility and 46 with impact in the clinical outcome of patients (p < 5.00 × 10-2). Among them, 14 variants reached the genome-wide significance (p < 5.00 × 10-8). Despite the results obtained, they should be validated in independent sets. So far, five validation studies have been conducted which could confirm the association of 12 OC susceptibility SNPs. Consequently, post-GWAS studies are crucial unravel the biological plausibility of GWAS' findings and the allelic spectrum of OC.

Genetic variants as ovarian cancer first-line treatment hallmarks: A systematic review and meta-analysis.

BACKGROUND: The potential predictive value of genetic polymorphisms in ovarian cancer first-line treatment is inconsistently reported. We aimed to review ovarian cancer pharmacogenetic studies to update and summarize the available data and to provide directions for further research. METHODS: A systematic review followed by a meta-analysis was conducted on cohort studies assessing the involvement of genetic polymorphisms in ovarian cancer first-line treatment response retrieved through a MEDLINE database search by November 2016. Studies were pooled and summary estimates and 95% confidence intervals (CI) were calculated using random or fixed-effects models as appropriate. RESULTS: One hundred and forty-two studies gathering 106871 patients were included. Combined data suggested that GSTM1-null genotype patients have a lower risk of death compared to GSTM1-wt carriers, specifically in advanced stages (hazard ratio (HR), 0.68; 95% CI, 0.48-0.97) and when submitted to platinum-based chemotherapy (aHR, 0.61; 95% CI, 0.39-0.94). ERCC1 rs11615 and rs3212886 might have also a significant impact in treatment outcome (aHR, 0.67; 95% CI, 0.51-0.89; aHR, 1.28; 95% CI, 1.01-1.63, respectively). Moreover, ERCC2 rs13181 and rs1799793 showed a distinct ethnic behavior (Asians: aHR, 1.41; 95% CI, 0.80-2.49; aHR, 1.07; 95% CI, 0.62-1.86; Caucasians: aHR, 0.10; 95% CI, 0.01-0.96; aHR, 0.18; 95% CI, 0.05-0.68, respectively). CONCLUSION(S): The definition of integrative predictive models should encompass genetic information, especially regarding GSTM1 homozygous deletion. Justifying additional pharmacogenetic investigation are variants in ERCC1 and ERCC2, which highlight the DNA Repair ability to ovarian cancer prognosis. Further knowledge could aid to understand platinum-treatment failure and to tailor chemotherapy strategies.

Base excision repair pathway: PARP1 genotypes as modulators of therapy response in cervical cancer patients.

CONTEXT: Genetic polymorphisms in genes of the base excision repair (BER) pathway appear to modulate the therapy response of cancer patients. PARP1 protein recognizes the DNA strand damage and facilitates the subsequent recruitment of BER proteins. Few studies have reported an association between PARP1 Val762Ala polymorphism (rs1136410) and cancer therapy response. OBJECTIVE: The purpose of our study was to determine whether PARP1 Val762Ala polymorphism have prognostic value in patients with cervical cancer. MATERIALS AND METHODS: Two hundred and sixty adult patients, with histologically confirmed cervical cancer, at FIGO-stages IB2-IVA, primarily treated with concurrent chemotherapy (cisplatin) and radiotherapy. Overall survival (OS) and disease-free survival (DFS) were the primary end points of the analysis. The PARP1 Val762Ala genetic variants were analyzed by allelic discrimination by real-time PCR. RESULTS: We observed that peri- and postmenopausal women carrying the C-allele present a statistically significant lower OS and DFS (log-rank test, p = 0.008 and p = 0.006, respectively) among those with early stage cervical cancer. Cox regression analysis confirmed these results, after adjustment for other prognostic factors (for OS: HR, 3.70; 95%CI, 1.32-10.38; p = 0.013 and for DFS: HR, 3.97; 95%CI, 1.59-9.93; p = 0.003). CONCLUSIONS: This is the first study evaluating the effect of PARP1 Val762Ala polymorphism in treatment response in cervical cancer patients. PARP1 genotypes may contribute as an independent prognostic factor in cervical cancer, being useful in predicting the clinical outcome.

Improvement of a predictive model in ovarian cancer patients submitted to platinum-based chemotherapy: implications of a GST activity profile.

PURPOSE: The success of chemotherapy in ovarian cancer (OC) is directly associated with the broad variability in platinum response, with implications in patients survival. This heterogeneous response might result from inter-individual variations in the platinum-detoxification pathway due to the expression of glutathione-S-transferase (GST) enzymes. We hypothesized that GSTM1 and GSTT1 polymorphisms might have an impact as prognostic and predictive determinants for OC. METHODS: We conducted a hospital-based study in a cohort of OC patients submitted to platinum-based chemotherapy. GSTM1 and GSTT1 genotypes were determined by multiplex PCR. RESULTS: GSTM1-null genotype patients presented a significantly longer 5-year survival and an improved time to progression when compared with GSTM1-wt genotype patients (log-rank test, P = 0.001 and P = 0.013, respectively). Multivariate Cox regression analysis indicates that the inclusion of genetic information regarding GSTM1 polymorphism increased the predictive ability of risk of death after OC platinum-based chemotherapy (c-index from 0.712 to 0.833). Namely, residual disease (HR, 4.90; P = 0.016) and GSTM1-wt genotype emerged as more important predictors of risk of death (HR, 2.29; P = 0.039; P = 0.036 after bootstrap). No similar effect on survival was observed regarding GSTT1 polymorphism, and there were no statistically significant differences between GSTM1 and GSTT1 genotypes and the assessed patients' clinical-pathological characteristics. CONCLUSION: GSTM1 polymorphism seems to have an impact in OC prognosis as it predicts a better response to platinum-based chemotherapy and hence an improved survival. The characterization of the GSTM1 genetic profile might be a useful molecular tool and a putative genetic marker for OC clinical outcome.

DNA repair system and renal cell carcinoma prognosis: under the influence of NBS1.

Nibrin (NBS1) is a protein involved in the maintenance of genomic stability and in DNA repair mechanisms. The NBS1 E185Q polymorphism (rs1805794) has been investigated in several studies, including its influence in the pathogenesis of renal cell carcinoma (RCC), although its prognostic value is still not determined for these patients. The purpose of the present work was to determine the role of NBS1 E185Q polymorphism as a prognostic factor/genetic marker of survival in patients with RCC. We conducted a hospital-based study analyzing 172 caucasian patients with histopathological diagnosis of RCC, for which polymorphism genotyping was performed by TaqMan(®) Allelic Discrimination methodology. In this study, we have found that male patients, non-metastatic at diagnosis and NBS1 C allele carriers (GC/CC) showed a lower 5-years survival when compared with GG genotype patients (P = 0.045). Furthermore, for carriers of low-activity NBS1 C allele, multivariate Cox regression analysis revealed almost a fourfold increase in risk of death at 5 years, after adjustment for age, histological type, Fuhrman's grade, tumor size and vascular permeation (HR 3.92; 95 % CI 1.33-11.57; P = 0.013). There were no statistically significant differences between the NBS1 E185Q genotypes and the assessed patients' clinical-pathological characteristics. Our results demonstrate for the first time the impact of NBS1 E185Q polymorphism in RCC prognosis suggesting that, for RCC male patients non-metastatic at diagnosis, this polymorphism might be a putative genetic marker in the clinical outcome.

Restoring TGFß1 pathway-related microRNAs: possible impact in metastatic prostate cancer development.

In developed countries, prostate cancer (PC) is the neoplasia more frequently diagnosed in men. The signaling pathway induced by the transforming growth factor ß1 (TGFß1) has an important role in cell growth, differentiation, and development, the downregulation of this pathway being associated with cancer development. In PC, the activation of this signaling pathway is lost, resulting in favoring of tumor growth, proliferation, and evasion of apoptosis. Several studies have shown that microRNAs (miRNAs), small non-coding RNA, are closely associated with the development, invasion, and metastasis, suggesting that they have a critical role in cancer development. Recently, Smad proteins, the signal transducers of the TGFß1 signaling pathway, were found to regulate miRNA expression, through both transcriptional and posttranscriptional mechanisms. In this review, we summarize the mechanisms underlying Smad-mediated regulation of miRNA biogenesis and the effects on cancer development, particularly in PC. We identify that TGFß1-related miR-143, miR-145, miR-146a, and miR-199a may have a key role in the development of prostate cancer metastasis and the restoration of their expression may be a promising therapeutic strategy for PC treatment.