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.     

The association between two genetic polymorphisms in ITGB3 and increase risk of venous thromboembolism in cancer patients in Eastern Province of Saudi Arabia

Venous thromboembolism (VTE) is one of the major complications in most cancer patients leading to poor prognosis and short survival. Several common clinical risk factors coexist in cancer patients are used as risk predictive biomarkers to help in the management and prevention of VTE. These include cancer site and stage, chemotherapy regimen and elevated biological markers. However, Genetic polymorphisms in genes controlling coagulation and fibrinolysis are significantly associated with VTE if detected, then they might be more sensitive individual predictive biomarkers for VTE risk assessment. This study was conducted to evaluate the association between ITGB3 rs3809865 and rs5918 with VTE risk as well as monitor the effect of VTE on overall survival of these cancer patients. In this retrospective case-control study, 195 cancer patients’ formalin-fixed paraffin embedded tissue (FFPE) samples were collected (controls n = 157, case n = 38) using the stored data through Jan 2010 to Sep 2018 from King Fahad Specialist Hospital in Dammam. Samples were genotyped using TaqMan genotyping assay, then logistic regression analysis and Chi-square were used to predict the association between risk factors and VTE. Survival Comparison was tested by the log-rank test. Genetic polymorphisms in ITGB3 (rs3809865 and rs5918) found not to be associated with VTE increasing risk in cancer patients (p>0.05). While the advanced stage was potentially increasing the risk of VTE events (OR 5.1 CI 2.01–12.9p = 0.001). Patients with VTE showed a poor overall survival reflected by the median survival rate of only three years compared to seven years for cancer patients without VTE. This study highlighted the potential influence of VTE on prognosis and survival of cancer patients and raised the importance of exploring risk predictive biomarkers in our population. This will improve the risk prediction biomarkers leading to implementing safe and effective thrombosis prophylaxis strategies.     

Vascular endothelial growth factor polymorphisms -1154 G/A and -460 C/T are not associated with VEGF mRNA expression and susceptibility to sporadic colon cancer

Vascular endothelial growth factor (VEGF) is important mediator of angiogenesis, and its expression in colorectal tumors is related to tumor progression. VEGF expression has been detected in normal mucosa, primary colon cancers, and metastatic tumors, and patients with low VEGF expression have a better survival rate. In addition, anti-VEGF monoclonal antibody improves overall survival when used in combination with existing metastatic colorectal cancer therapy. Therefore, prediction of VEGF production based on individual genetic background might be important for predicting the course of the disease and the efficacy of anticancer treatment. The number of studies evaluating the influence of VEGF polymorphisms on cancer susceptibility is growing; however, their results are often conflicting. In addition, these studies are rarely accompanied with the expression analysis examining the influence of these polymorphisms on mRNA expression in tumor tissue. In this study, we have examined the influence of VEGF polymorphisms -1154 G/A and -460 C/T on VEGF mRNA expression and susceptibility to sporadic colon cancer by real-time PCR-SNP and mRNA expression analysis. The study included population control group consisting of 160 unrelated volunteers and a group of 160 patients with sporadic colon cancer. According to our results, -1154 G/A and -460 C/T do not influence VEGF mRNA expression in colorectal tumors and susceptibility to sporadic colon cancer, although the role of other polymorphisms cannot be excluded.     

Phenotype,function and clinical implications of myeloid-derived suppressor cells in cancer patients

The involvement of a smouldering microenvironment is currently considered a cancer hallmark and a required step for tumour cells to disable specific immunity while promoting angiogenesis and stroma remodelling. Nevertheless, the molecular pathways driving such aberrant interactions in human cancer and their actual implication in disease progression are still poorly defined. Here, we will report about the remarkable efforts devoted by our group as well as many other scientists to dissect this process focusing on tumour-mediated activation of myeloid dysfunctional pathways occurring in cancer patients. Indeed, myeloid-derived suppressor cells (MDSC), playing a crucial role as cellular regulators of immune responses, have been extensively shown to restrain tumour immunity through a vast array of molecular mechanisms and to promote tumour progression in different murine models. Although in mice the phenotypic features of these cells were defined initially rather generally by Gr1⁺ and CD11b⁺ co-expression, more recent studies have unravelled the actual complexity of this population and the existence of different cell subsets. This complexity is even more remarked in the human setting, where heterogeneous populations of myeloid cells with variable phenotype and immunosuppressive features have been described in patients affected by different types of tumours. The lack of homogeneous properties of human MDSC has made these cells a controversial and still unacknowledged player in cancer-related immune suppression and disease progression. Nevertheless, with the efforts of the scientific community, MDSC will soon reveal their key role thereby becoming novel targets for innovative therapeutic strategies.     

Exosomes and their importance in metastasis,diagnosis, and therapy of colorectal cancer

Extracellular vesicles are known as actual intermediaries of intercellular communications, such as biological signals and cargo transfer between different cells. A variety of cells release the exosomes as nanovesicular bodies. Exosomes contain different compounds such as several types of nucleic acids and proteins. In this study, we focused on exosomes in colorectal cancer as good tools that can be involved in various cancer-related processes. Furthermore, we summarize the advantages and disadvantages of exosome extraction methods and review related studies on the role of exosomes in colorectal cancer. Finally, we focus on reports available on relations between mesenchymal stem cell–derived exosomes and colorectal cancer. Several cancer-related processes such as cancer progression, metastasis, and drug resistance of colorectal cancer are related to the cargoes of exosomes. A variety of molecules, especially proteins, microRNAs, and long noncoding RNAs, play important roles in these processes. The microenvironment features, such as hypoxia, also have very important effects on the properties of the origin cell–derived exosomes. On the other hand, exosomes derived from colorectal cancer cells also interfere with cancer chemoresistance. Furthermore, today it is known that exosomes and their contents can likely be very effective in noninvasive colorectal cancer diagnosis and therapy. Thus, exosomes, and especially their cargoes, play different key roles in various aspects of basic and clinical research related to both progression and therapy of colorectal cancer.     

Risk of Venous Thromboembolism in Patients with Cancer: A Systematic Review and Meta-Analysis

Background

People with cancer are known to be at increased risk of venous thromboembolism (VTE), and this risk is believed to vary according to cancer type, stage of disease, and treatment modality. Our purpose was to summarise the existing literature to determine precisely and accurately the absolute risk of VTE in cancer patients, stratified by malignancy site and background risk of VTE.

Methods and Findings

We searched the Medline and Embase databases from 1 January 1966 to 14 July 2011 to identify cohort studies comprising people diagnosed with one of eight specified cancer types or where participants were judged to be representative of all people with cancer. For each included study, the number of patients who developed clinically apparent VTE, and the total person-years of follow-up were extracted. Incidence rates of VTE were pooled across studies using the generic inverse variance method. In total, data from 38 individual studies were included. Among average-risk patients, the overall risk of VTE was estimated to be 13 per 1,000 person-years (95% CI, 7 to 23), with the highest risk among patients with cancers of the pancreas, brain, and lung. Among patients judged to be at high risk (due to metastatic disease or receipt of high-risk treatments), the risk of VTE was 68 per 1,000 person-years (95% CI, 48 to 96), with the highest risk among patients with brain cancer (200 per 1,000 person-years; 95% CI, 162 to 247). Our results need to be considered in light of high levels of heterogeneity, which exist due to differences in study population, outcome definition, and average duration of follow-up between studies.

Conclusions

VTE occurs in greater than 1% of cancer patients each year, but this varies widely by cancer type and time since diagnosis. The absolute VTE risks obtained from this review can aid in clinical decision-making about which people with cancer should receive anticoagulant prophylaxis and at what times. Please see later in the article for the Editors'' Summary.     

Targeting tumor microenvironment in ovarian cancer: Premise and promise

Ovarian cancer is the leading cause of gynecological cancer-related mortality globally. The majority of ovarian cancer patients suffer from relapse after standard of care therapies and the clinical benefits from cancer therapies are not satisfactory owing to drug resistance. Certain novel drugs targeting the components of tumor microenvironment (TME) have been approved by US Food and Drug Administration in solid cancers. As such, the passion is rekindled to exploit the role of TME in ovarian cancer progression and metastasis for discovery of novel therapeutics for this deadly disease. In the current review, we revisit the recent mechanistic insights into the contributions of TME to the development, progression, prognosis prediction and therapeutic efficacy of ovarian cancer via modulating cancer hallmarks. We also explored potentially promising predictive and prognostic biomarkers for ovarian cancer patients.     

Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance

Tissue kallikrein (KLK1) and kallikrein-related peptidases (KLK2-15) comprise a family of 15 highly conserved secreted serine proteases with similar structural characteristics and a wide spectrum of functional properties. Both gene expression and protein activity of KLKs are rigorously controlled at various levels via diverse mechanisms, including extensive steroid hormone regulation, to exert their broad physiological role. Nevertheless, deregulated expression, secretion, and function of KLK family members has been observed in several pathological conditions and, particularly, in endocrine-related human malignancies, including those of the prostate, breast, and ovary. The cancer-related abnormal activity of KLKs upon substrates such as growth factors, cell adhesion molecules, cell surface receptors, and extracellular matrix proteins facilitate both tumorigenesis and disease progression to the advanced stages. The well-documented relationship between KLK status and the clinical outcome of cancer patients has led to their identification as promising diagnostic, prognostic, and treatment response monitoring biomarkers for these complex disease entities. The main objective of this review is to summarize the existing knowledge concerning the role of KLKs in prostate, breast, and ovarian cancers and to highlight their continually evolving biomarker capabilities that can provide significant benefits for the management of cancer patients.     

Association between polymorphisms of XRCC1 and ADPRT genes and ovarian cancer survival with platinum-based chemotherapy in Chinese population

The role of DNA repair gene polymorphisms in cancer development, progression, and response to treatment has received increased attention. We conducted a prospective study to determine whether associations exist between two polymorphisms in XRCC1 and ADPRT and the outcomes of Chinese ovarian cancer patients treated with platinum-based chemotherapy. A total of 335 new cases of ovarian cancer were consecutively collected between May 2005 and May 2007. Follow-up lasted for 4?years, and the outcome measure was survival time. Individuals carrying XRCC1 194Trp/Trp had a longer survival time than did those with the Arg/Arg genotype. Similarly, those carrying XRCC1 399 Gln/Gln genotypes had 0.44-fold the risk of death than those with the Arg/Arg genotype. The combination of XRCC1 194 Trp allele and 399 Gln allele could decrease the death risk of ovarian cancer. In summary, this study is the first to evaluate the associations between polymorphisms in DNA repair gene polymorphism and the risk of ovarian cancer in Chinese population. Our study found a significant association between XRCC1 Arg399Gln and XRCC1 Arg194Trp polymorphism and the clinical outcome of ovarian cancer. Furthermore, studies with larger sample sizes are still needed to confirm these associations in Chinese population.     

The association between estrogen receptor alpha polymorphisms and the risk of prostate cancer in Slovak population

The aim of our study was to evaluate the effect of two polymorphisms in the estrogen receptor alpha, PvuII and XbaI, on the development of prostate cancer within Slovak population, as well as their correlation with selected clinical characteristics. The study was performed using 311 prostate cancer patients and 256 healthy male controls. Both polymorphisms were significantly associated with higher risk of prostate cancer development. At the same time, the CC genotype of PvuII polymorphism (OR = 1.98; 95 % CI 0.94–4.21; p = 0.05) and the AG genotype of XbaI polymorphism (OR = 1.74; 95 % CI 1.0–3.02; p = 0.04) significantly contributed to the development of low-grade carcinoma, while the AG and GG genotypes of the XbaI polymorphism contributed mainly to the development of high-grade prostate cancer (OR = 1.83; 95 % CI 1.12–3.01; p = 0.01 and OR = 2.13; 95 % CI 1.06–4.19; p = 0.03, respectively). Similarly, the AG and GG genotypes of XbaI polymorphism showed significant association with prostate cancer in patients with serum PSA level ≥10 ng/ml. Both polymorphisms were found at the same time to be more frequent in patients diagnosed before the age of 60. We conclude on the basis of these results that PvuII and XbaI polymorphisms of estrogen receptor alpha might be associated with prostate cancer risk within Slovak population. Although this is a pilot study and, as such, more detailed investigations are needed to confirm the role of these polymorphisms in prostate cancer development and progression within said Slovak population, our results might still provide a valuable basis for further research with larger patient groups.     

miR-888 is an expressed prostatic secretions-derived microRNA that promotes prostate cell growth and migration

microRNAs (miRNAs) are a growing class of small non-coding RNAs that exhibit widespread dysregulation in prostate cancer. We profiled miRNA expression in syngeneic human prostate cancer cell lines that differed in their metastatic potential in order to determine their role in aggressive prostate cancer. miR-888 was the most differentially expressed miRNA observed in human metastatic PC3-ML cells relative to non-invasive PC3-N cells, and its levels were higher in primary prostate tumors from cancer patients, particularly those with seminal vesicle invasion. We also examined a novel miRNA-based biomarker source called expressed prostatic secretions in urine (EPS urine) for miR-888 expression and found that its levels were preferentially elevated in prostate cancer patients with high-grade disease. These expression studies indicated a correlation for miR-888 in disease progression. We next tested how miR-888 regulated cancer-related pathways in vitro using human prostate cancer cell lines. Overexpression of miR-888 increased proliferation and migration, and conversely inhibition of miR-888 activity blocked these processes. miR-888 also increased colony formation in PC3-N and LNCaP cells, supporting an oncogenic role for this miRNA in the prostate. Our data indicates that miR-888 functions to promote prostate cancer progression and can suppress protein levels of the tumor suppressor genes RBL1 and SMAD4. This miRNA holds promise as a diagnostic tool using an innovative prostatic fluid source as well as a therapeutic target for aggressive prostate cancer.     

1st National Congress of the Italian Proteome Society

Transgelin is an abundant protein of smooth muscle cells, where its role has been primarily studied. As a protein affecting dynamics of the actin cytoskeleton via stabilization of actin filaments, transgelin is both directly and indirectly involved in many cancer-related processes such as migration, proliferation, differentiation or apoptosis. Transgelin was previously reviewed as a tumor suppressor; however, recent data based on a number of proteomics studies indicate its pro-tumorigenic role, for example, in colorectal or hepatocellular cancer. We summarize these contradictory observations in both clinical and functional proteomics projects and analyze the role of transgelin in tumors in detail. Generally, the expression and biological role of transgelin seem to differ among various types of tumor cells and stroma, and possibly change during tumor progression. We also overview the recent data on transgelin-2, a sequence homolog of transgelin, whose role in the tumor development might be contradictory to the role of transgelin.     

Manganese superoxide dismutase in breast cancer: From molecular mechanisms of gene regulation to biological and clinical significance

Breast cancer is one of the most common malignancies of all cancers in women worldwide. Many difficulties reside in the prediction of tumor metastatic progression because of the lack of sufficiently reliable predictive biological markers, and this is a permanent preoccupation for clinicians. Manganese superoxide dismutase (MnSOD) may represent a rational candidate as a predictive biomarker of breast tumor metastatic progression, because its gene expression is profoundly altered between early and advanced breast cancer, in contrast to expression in the normal mammary gland. In this review, we report the characterization of some gene polymorphisms and molecular mechanisms of SOD2 gene regulation, which allows a better understanding of how MnSOD is decreased in early breast cancer and increased in advanced breast cancer. Several studies display the biological significance of MnSOD level in proliferation as well as in invasive and angiogenic abilities of breast tumor cells by controlling superoxide anion radical (O₂^•−) and hydrogen peroxide (H₂O₂). Particularly, they report how these reactive oxygen species may activate some signaling pathways involved in breast tumor growth. Emerging understanding of these findings provides an interesting framework for guiding translational research and suggests a way to define precisely the clinical interest of MnSOD as a prognostic and/or predicting marker in breast cancer, by associating with some regulators involved in SOD2 gene regulation and other well-known biomarkers, in addition to the typical clinical parameters.     

Polymorphisms in p53 and the p53 pathway: roles in cancer susceptibility and response to treatment

The p53 tumour suppressor protein lies at the crossroads of multiple cellular response pathways that control the fate of the cell in response to endogenous or exogenous stresses and inactivation of the p53 tumour suppressor signalling pathway is seen in most human cancers. Such aberrant p53 activity may be caused by mutations in the TP53 gene sequence producing truncated or inactive mutant proteins, or by aberrant production of other proteins that regulate p53 activity, such as gene amplification and overexpression of MDM2 or viral proteins that inhibit or degrade p53. Recent studies have also suggested that inherited genetic polymorphisms in the p53 pathway influence tumour formation, progression and/or response to therapy. In some cases, these variants are clearly associated with clinico-pathological variables or prognosis of cancer, whereas in other cases the evidence is less conclusive. Here, we review the evidence that common polymorphisms in various aspects of p53 biology have important consequences for overall tumour susceptibility, clinico-pathology and prognosis. We also suggest reasons for some of the reported discrepancies in the effects of common polymorphisms on tumourigenesis, which relate to the complexity of effects on tumour formation in combination with other oncogenic changes and other polymorphisms. It is likely that future studies of combinations of polymorphisms in the p53 pathway will be useful for predicting tumour susceptibility in the human population and may serve as predictive biomarkers of tumour response to standard therapies.     

Gastrointestinal polyposis syndromes

Colorectal cancer is one of the leading causes of cancer-related death in the Western society, and the incidence is rising. Rare hereditary gastrointestinal polyposis syndromes that predispose to colorectal cancer have provided a model for the investigation of cancer initiation and progression in the general population. Many insights in the molecular genetic basis of cancer have emerged from the study of these syndromes. This review discusses the genetics and clinical manifestations of the three most common syndromes with gastrointestinal polyposis and an increased risk of colorectal cancer: familial adenomatous polyposis (FAP), juvenile polyposis (JP) and Peutz-Jeghers syndrome (PJS).     

The ATM gene and breast cancer: is it really a risk factor?

The genetic determinants for most breast cancer cases remain elusive. Whilst mutations in BRCA1 and BRCA2 significantly contribute to familial breast cancer risk, their contribution to sporadic breast cancer is low. In such cases genes frequently altered in the general population, such as the gene mutated in Ataxia telangiectasia (AT), ATM may be important risk factors. The initial interest in studying ATM heterozygosity in breast cancer arose from the findings of epidemiological studies of AT families in which AT heterozygote women had an increased risk of breast cancer and estimations that 1% of the population are AT heterozygotes. One of the clinical features of AT patients is extreme cellular sensitivity to ionising radiation. This observation, together with the finding that a significant proportion of breast cancer patients show an exaggerated acute or late normal tissue reactions after radiotherapy, has lead to the suggestion that AT heterozygosity plays a role in radiosensitivity and breast cancer development. Loss of heterozygosity in the region of the ATM gene on chromosome 11, has been found in about 40% of sporadic breast tumours. However, screening for ATM mutations in sporadic breast cancer cases, showing or not adverse effects to radiotherapy, has not revealed the magnitude of involvement of the ATM gene expected. Their size and the use of the protein truncation test to identify mutations limit many of these studies. This latter parameter is critical as the profile of mutations in AT patients may not be representative of the ATM mutations in other diseases. The potential role of rare sequence variants within the ATM gene, sometimes reported as polymorphisms, also needs to be fully assessed in larger cohorts of breast cancer patients and controls in order to determine whether they represent cancer and/or radiation sensitivity predisposing mutations.     

Epigenome-Wide Association Studies (EWAS) in Cancer

After completion of the human genome, genome-wide association studies were conducted to identify single nucleotide polymorphisms (SNPs) associated with cancer initiation and progression. Most of the studies identified SNPs that were located outside the coding region, and the odds ratios were too low to implement in clinical practice. Although the genome gives information about genome sequence and structure, the human epigenome provides functional aspects of the genome. Epigenome-wide association studies (EWAS) provide an opportunity to identify genome-wide epigenetic variants that are associated with cancer. However, there are problems and issues in implementing EWAS to establish an association between epigenetic profiles and cancer. Few challenges include selection and handling of samples, choice of population and sample size, accurate measurement of exposure, integrating data, and insufficient information about the role of repeat sequences. The current status of EWAS, challenges in the field, and their potential solutions are discussed in this article.     

Genetic variations in VDR associated with prostate cancer risk and progression in a Korean population

Low levels of vitamin D are implicated as a potential risk factor for prostate cancer, and the vitamin D receptor (VDR) gene may be important in the onset and progression of prostate cancer. In this study, sequence variants in the VDR gene were investigated in a Korean study cohort to determine whether they are associated with prostate cancer risk. We evaluated the association between 47 single nucleotide polymorphisms (SNPs) in the VDR gene and prostate cancer risk as well as clinical characteristics (prostate-specific antigen level, clinical stage, pathological stage and Gleason score) in Korean men (272 prostate cancer patients and 173 benign prostatic hyperplasia patient who underwent a prostate biopsy, which was negative for malignancy) using unconditional logistic regression. The statistical analysis suggested that two VDR sequence variants (rs2408876 and rs2239182) had a significant association with prostate cancer risk (odds ratio [OR]. 1.41; p = 0.03; OR, 0.73; p = 0.05, respectively). Logistic analyses of the VDR polymorphisms with several prostate cancer related factors showed that several SNPs were significant; nine SNPs to PSA level, three to clinical stage, two to pathological stage, and three SNPs to the Gleason score. The results suggest that some VDR gene polymorphisms in Korean men might not only be associated with prostate cancer risk but also significantly related to prostate cancer-related risk factors such as PSA level, tumor stage, and Gleason score. However, current limitation for small cohort with not-healthy control group might have false positive effects; therefore it should be overcome via further large-scale validating studies.     

Impact of D-Dimer for Prediction of Incident Occult Cancer in Patients with Unprovoked Venous Thromboembolism

BackgroundUnprovoked venous thromboembolism (VTE) is related to a higher incidence of occult cancer. D-dimer is clinically used for screening VTE, and has often been shown to be present in patients with malignancy. We explored the predictive value of D-dimer for detecting occult cancer in patients with unprovoked VTE.MethodsWe retrospectively examined data from 824 patients diagnosed with deep vein thrombosis or pulmonary thromboembolism. Of these, 169 (20.5%) patients diagnosed with unprovoked VTE were selected to participate in this study. D-dimer was categorized into three groups as: <2,000, 2,000–4,000, and >4,000 ng/ml. Cox regression analysis was employed to estimate the odds of occult cancer and metastatic state of cancer according to D-dimer categories.ResultsDuring a median 5.3 (interquartile range: 3.4–6.7) years of follow-up, 24 (14%) patients with unprovoked VTE were diagnosed with cancer. Of these patients, 16 (67%) were identified as having been diagnosed with metastatic cancer. Log transformed D-dimer levels were significantly higher in those with occult cancer as compared with patients without diagnosis of occult cancer (3.5±0.5 vs. 3.2±0.5, P-value = 0.009, respectively). D-dimer levels >4,000 ng/ml was independently associated with occult cancer (HR: 4.12, 95% CI: 1.54–11.04, P-value = 0.005) when compared with D-dimer levels <2,000 ng/ml, even after adjusting for age, gender, and type of VTE (e.g., deep vein thrombosis or pulmonary thromboembolism). D-dimer levels >4000 ng/ml were also associated with a higher likelihood of metastatic cancer (HR: 9.55, 95% CI: 2.46–37.17, P-value <0.001).ConclusionElevated D-dimer concentrations >4000 ng/ml are independently associated with the likelihood of occult cancer among patients with unprovoked VTE.