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1.
Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.
Adams, CD, Richmond, R, Ferreira, DLS, Spiller, W, Tan, V, Zheng, J, Würtz, P, Donovan, J, Hamdy, F, Neal, D, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2019;(1):208-216
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Abstract
BACKGROUND Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). METHODS The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
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Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study.
Yoshino, T, Portnoy, DC, Obermannová, R, Bodoky, G, Prausová, J, Garcia-Carbonero, R, Ciuleanu, T, García-Alfonso, P, Cohn, AL, Van Cutsem, E, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2019;(1):124-131
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Abstract
BACKGROUND : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. PATIENTS AND METHODS Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. RESULTS RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). CONCLUSIONS In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. CLINICALTRIALS.GOV NUMBER NCT01183780.
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Systematic Review and Meta-Analysis of the Prognostic Value of Serum High-Density Lipoprotein Cholesterol Levels for Solid Tumors.
Hao, B, Bi, B, Sang, C, Yu, M, Di, D, Luo, G, Zhang, X
Nutrition and cancer. 2019;(4):547-556
Abstract
Numerous studies have demonstrated that serum high-density lipoprotein cholesterol (HDL-C) levels correlate strongly with cancer patient survival. However, other studies have had the opposite results. We therefore conducted a systematic review and meta-analysis to assess the prognostic value of HDL-C levels in people with cancer. We searched PubMed, Embase, and the Cochrane Library (last update by December 28, 2017) for studies evaluating the effect of serum HDL-C levels on cancer patient prognosis. Data from 25 studies covering13,140 patients were included. Combined hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were assessed using fixed-effects and random-effects models. High serum HDL-C levels were associated with better OS (pooled HR = 0.70; 95% confidence interval (CI) (0.60-0.82). In the subgroup, the relative high level of HDL-C yielded a favorable outcome in most of tumor types. However, in the nasopharyngeal carcinoma subgroup, the correlation was not significant (combined HR = 1.31; 95% CI (0.91-1.90)). High serum HDL-C levels were associated with better DFS (pooled HR = 0.64; 95% confidence interval (CI) (0.50-0.81)). This meta-analysis demonstrates that high serum HDL-C levels are associated with better OS in patients with solid tumors, but not nasopharyngeal carcinoma; and high serum HDL-C levels are associated with better DFS.
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Role of systemic inflammatory response markers in urological malignancy.
Ohno, Y
International journal of urology : official journal of the Japanese Urological Association. 2019;(1):31-47
Abstract
The systemic inflammatory response is associated with survival in patients with a variety of cancers. This inflammatory response is measured in the peripheral blood, and can be monitored using two categories of indices: concentration of specific serum proteins (albumin, C-reactive protein) and differential blood cell count (neutrophils, lymphocytes and platelets). Furthermore, combinations of these indices, such as the Glasgow Prognostic Score, which consists of the serum C-reactive protein and albumin level; the neutrophil-to-lymphocyte ratio; the platelet-to-lymphocyte ratio; and the prognostic nutritional index, which is based on peripheral blood lymphocyte count and serum albumin level, have also been evaluated and compared in cancer research. To date, there are hundreds of studies that have shown the prognostic value of systemic inflammatory response markers in patients with urological cancer. Most studies have evaluated the prognostic and predictive role of the pretreatment value of the markers, although some have focused on the role of the post-treatment value at specific points during the clinical course. The advantages of systemic inflammatory response markers are that they are easily measurable and inexpensive in the clinical setting. However, it is important to consider how clinicians use these markers in clinical practice. The present review provides a concise overview regarding systemic inflammatory markers in urological cancers, specifically C-reactive protein, Glasgow Prognostic Score/modified Glasgow Prognostic Score, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and prognostic nutritional index.
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Changes in metabolic parameters and cardiovascular risk factors after therapeutic control of acromegaly vary with the treatment modality. Data from the Bicêtre cohort, and review of the literature.
Briet, C, Ilie, MD, Kuhn, E, Maione, L, Brailly-Tabard, S, Salenave, S, Cariou, B, Chanson, P
Endocrine. 2019;(2):348-360
Abstract
CONTEXT Untreated acromegaly is associated with increased morbidity and mortality due to malignant, cardiovascular, and cerebrovascular disorders. Effective treatment of acromegaly reduces excess mortality, but its impact on cardiovascular risk factors and metabolic parameters are poorly documented. AIM: We analyzed changes in cardiovascular risk factors and metabolic parameters in patients receiving various treatment modalities. PATIENTS AND METHODS We retrospectively studied 96 patients with acromegaly, both at diagnosis and after IGF-I normalization following surgery alone (n = 51) or medical therapy with first generation somatostatin analogues (SSA, n = 23), or pegvisomant (n = 22). Duration of follow-up was 77 (42-161) months, 75 (42-112) months, and 62 (31-93) months, in patients treated with surgery alone, SSA, and pegvisomant, respectively. In all the cases except four, patients treated medically had underwent previous unsuccessful surgery. RESULTS IGF-I normalization was associated with increased body weight, decreased systolic blood pressure (SBP) in hypertensive patients, decreased fasting plasma glucose (FPG) and HOMA-IR and HOMA-B levels, increased HDL cholesterol (HDLc); whereas, LDL cholesterol (LDLc) was not significantly different. Plasma PCSK9 levels were unchanged in patients with available values. Cardiovascular and metabolic changes varied with the treatment modality: surgery, but not pegvisomant, had a beneficial effect on SBP; FPG decreased after surgery but increased after SSA; the decline in HOMA-IR was only significant after surgery; pegvisomant significantly increased LDLc and total cholesterol; whereas SA increased HDLc and had no effect on LDLc levels. CONCLUSION Treatments used to normalize IGF-I levels in patients with acromegaly could have differential effects on cardiovascular risk factors and metabolic parameters.
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Quantifying the association between acute leukemia and serum zinc, copper, and selenium: a meta-analysis.
Kim, S, Freeland-Graves, JH, Babaei, M, Sachdev, PK, Beretvas, SN
Leukemia & lymphoma. 2019;(6):1548-1556
Abstract
Acute leukemia is a clonal malignant disorder that occurs when immature blast cells accumulate in bone marrow. Zinc (Zn) and copper (Cu) are related to normal lymphocyte maturation and immune function regulation. Selenium (Se) is protective against oxidative damage. The aim of this meta-analysis is to statistically synthesize results from studies that have investigated the levels of Zn, Cu, and Se in acute leukemia patients. The effect size, delta, was used to standardize the raw data. The robust variance estimation (RVE) method was performed to measure the pooled effect size and variance. Results suggest significant negative differences for levels of serum Zn (p < .05, delta = -1.21; 95% CI, -2.13--0.28) and Se (p < .05, delta = -1.84; 95% CI, -3.39--0.29) and significantly positive differences between serum Cu levels (p < .01, delta = 1.94; 95% CI, 1.02-2.87) in acute leukemia, as compared to the controls.
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CE-MS-based urinary biomarkers to distinguish non-significant from significant prostate cancer.
Frantzi, M, Gomez Gomez, E, Blanca Pedregosa, A, Valero Rosa, J, Latosinska, A, Culig, Z, Merseburger, AS, Luque, RM, Requena Tapia, MJ, Mischak, H, et al
British journal of cancer. 2019;(12):1120-1128
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Abstract
BACKGROUND Prostate cancer progresses slowly when present in low risk forms but can be lethal when it progresses to metastatic disease. A non-invasive test that can detect significant prostate cancer is needed to guide patient management. METHODS Capillary electrophoresis/mass spectrometry has been employed to identify urinary peptides that may accurately detect significant prostate cancer. Urine samples from 823 patients with PSA (<15 ng/ml) were collected prior to biopsy. A case-control comparison was performed in a training set of 543 patients (nSig = 98; nnon-Sig = 445) and a validation set of 280 patients (nSig = 48, nnon-Sig = 232). Totally, 19 significant peptides were subsequently combined by a support vector machine algorithm. RESULTS Independent validation of the 19-biomarker model in 280 patients resulted in a 90% sensitivity and 59% specificity, with an AUC of 0.81, outperforming PSA (AUC = 0.58) and the ERSPC-3/4 risk calculator (AUC = 0.69) in the validation set. CONCLUSIONS This multi-parametric model holds promise to improve the current diagnosis of significant prostate cancer. This test as a guide to biopsy could help to decrease the number of biopsies and guide intervention. Nevertheless, further prospective validation in an external clinical cohort is required to assess the exact performance characteristics.
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NID2 can serve as a potential prognosis prediction biomarker and promotes the invasion and migration of gastric cancer.
Yu, ZH, Wang, YM, Jiang, YZ, Ma, SJ, Zhong, Q, Wan, YY, Wang, XW
Pathology, research and practice. 2019;(10):152553
Abstract
BACKGROUND Nidogen-2 (NID2) is a ubiquitous component in the basement membrane and plays an important role in the development of malignant tumors. However, the specific function and mechanism of the NID2 gene in gastric cancer remains unclear. In this study, we aimed to investigate the role of NID2 in gastric cancer(GC). METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of NID2 in 67 GC tissues and adjacent normal tissues. The relationship between NID2 expression and clinicopathological features was further analyzed. In addition, we evaluated the expression of NID2 in GC based on data from the GEPIA and Kaplan-Meier Plotter database and compared the database results with our own experimental results. Invasion and wound healing assays were used to detect the function of NID2 in MKN45 and SGC7901 cells. Finally, the NID2 network and its possible related genes are constructed by the bioinformatics framework. RESULTS The expression level of NID2 was found to be significantly over-expressed in gastric cancer cells and tissues compared with normal controls and positively associated with TNM stage, showing a poor prognosis of GC patients. In vitro experiments indicated that NID2 was able to promote the ability of invasion and migration in GC cells. Bioinformatics prediction showed NID2 might regulate the progression of GC via protein digestion and absorption, amoebiasis, PI3K-AKt-signaling pathway, focal adhesion and ECM-receptor interaction pathways. CONCLUSION Our study demonstrates that up-regulated NID2 plays an important role in promoting the invasion and migration of GC cells and has a potential of being a novel biomarker for diagnosis, treatment and prognosis of GC in the future.
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Oncogenic Y68 frame shift mutation of PTEN represents a mechanism of docetaxel resistance in endometrial cancer cell lines.
Zhang, H, Wang, S, Cacalano, N, Zhu, H, Liu, Q, Xie, M, Kamrava, M, Konecny, G, Jin, S
Scientific reports. 2019;(1):2111
Abstract
In this study, we aimed to identify mutations of key genes associated with docetaxel resistance in nine endometrial cancer cell lines. Endometrial cancers are associated with several critical gene mutations, including PIK3A, PTEN, and KRAS. Different gene mutations in endometrial cancer cells have varied responses to anticancer drugs and cancer therapies. The most frequently altered gene in endometrioid endometrial carcinoma tumors is PTEN. PTEN protein has lipid phosphatase and protein phosphatase activity, as well as other functions in the nucleus. Although the tumor-suppressive function of PTEN has mainly been attributed to its lipid phosphatase activity, a role for PTEN protein phosphatase activity in cell cycle regulation has also been suggested. Various tumor type-specific PTEN mutations are well documented. Here, nine endometrioid endometrial cancer cell lines with PIK3A, PTEN, and KRAS gene mutations were treated with docetaxel and radiation. One mutation with a docetaxel drug-resistant effect was a truncated form of PTEN. Among PTEN mutations in endometrial cancer cells, the Y68 frame shift mutation of PTEN constitutes a major mechanism of resistance to docetaxel treatment. The molecular mechanism involves truncation of the 403 amino acid PTEN protein at amino acid 68 by the Y68 frame shift, leading to the loss of PTEN protein phosphatase and lipid phosphatase activities.
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Genes CEP55, FOXD3, FOXF2, GNAO1, GRIA4, and KCNA5 as potential diagnostic biomarkers in colorectal cancer.
Hauptman, N, Jevšinek Skok, D, Spasovska, E, Boštjančič, E, Glavač, D
BMC medical genomics. 2019;(1):54
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading causes of death by cancer worldwide and in need of novel potential diagnostic biomarkers for early discovery. METHODS We conducted a two-step study. We first employed bioinformatics on data from The Cancer Genome Atlas to obtain potential biomarkers and then experimentally validated some of them on our clinical samples. Our aim was to find a methylation alteration common to all clusters, with the potential of becoming a diagnostic biomarker in CRC. RESULTS Unsupervised clustering of methylation data resulted in four clusters, none of which had a known common genetic or epigenetic event, such as mutations or methylation. The intersect among clusters and regulatory regions resulted in 590 aberrantly methylated probes, belonging to 198 differentially expressed genes. After performing pathway and functional analysis on differentially expressed genes, we selected six genes: CEP55, FOXD3, FOXF2, GNAO1, GRIA4 and KCNA5, for further experimental validation on our own clinical samples. In silico analysis demonstrated that CEP55 was hypomethylated in 98.7% and up-regulated in 95.0% of samples. Genes FOXD3, FOXF2, GNAO1, GRIA4 and KCNA5 were hypermethylated in 97.9, 81.1, 80.3, 98.4 and 94.0%, and down-regulated in 98.3, 98.9, 98.1, 98.1 and 98.6% of samples, respectively. Our experimental data show CEP55 was hypomethylated in 97.3% of samples and down-regulated in all samples, while FOXD3, FOXF2, GNAO1, GRIA4 and KCNA5 were hypermethylated in 100.0, 90.2, 100.0, 99.1 and 100.0%, and down-regulated in 68.0, 76.0, 96.0, 95.2 and 84.0% of samples, respectively. Results of in silico and our experimental analyses showed that more than 97% of samples had at least four methylation markers altered. CONCLUSIONS Using bioinformatics followed by experimental validation, we identified a set of six genes that were differentially expressed in CRC compared to normal mucosa and whose expression seems to be methylation dependent. Moreover, all of these six genes were common in all methylation clusters and mutation statuses of CRC and as such are believed to be an early event in human CRC carcinogenesis and to represent potential CRC biomarkers.