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Background: Primary live cancer (PLC), including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). This meta-analysis was conducted to evaluate the diagnostic efficacy of blood methylated septin 9 gene (mSEPT9) for PLC and to analyze its performance across various subgroups. Methods: We conducted a comprehensive search across PubMed, the Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI), covering research up to May 10, 2024. The pooled sensitivity, specificity, diagnostic odds ratios, and area under the summary receiver operating characteristic (AUC) were calculated for the diagnostic performance of mSEPT9 for PLC. The quality of the studies was assessed using the QUADAS-2 tool, and the meta-analysis was performed using Stata16.0 software. Results: Ten articles with 2,182 participants were included in the meta-analysis. The pooled sensitivity of mSEPT9 for detecting primary liver cancer was 0.51 (95% confidence interval [CI]: 0.37-0.65), and the pooled specificity was 0.93 (95% CI: 0.78-0.98). The pooled diagnostic odds ratio was 13 (95% CI: -58), and the area under the Summary Receiver Operator Characteristic Curve was 0.75 (95% CI: 0.71-0.79). Subgroup analyses showed that ICC, case-control studies, qPCR and Asian populations had higher specificities (0.99 [95% CI: 0.97–1.00], 0.93 [95% CI: 0.91-0.95], 0.90 [95% CI: 0.88-0.92] and 0.94 [95% CI: 0.92-0.96], respectively) and diagnostic odds ratios (62.04 [95% CI: 6.53-589.53], 17.62 [95% CI: 4.03-76.99], 13.03 [95% CI: 2.01-84.63] and 14.19 [95% CI: 2.42-83.11], respectively) compared to hepatocellular carcinoma, cohort Study, and Euramerican populations. Conclusions: This study confirmed that mSEPT9 in blood has high specificity and moderate sensitivity for detecting primary liver cancer. The diagnostic performance of mSEPT9 varied across different subgroups, limiting its use as an independent screening tool and necessitating its use in conjunction with other methods for confirmatory diagnostics. Systematic review registration: https://www.crd.york.ac.uk/prospero/ , identifier CRD42024549669. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a prevalent malignancy with a high mortality rate, primarily due to liver metastasis. This study explores the role of centromere protein N (CENP-N) in mediating the methylation of septin 9 (SEPT9) and its subsequent effects on aerobic glycolysis and liver metastasis in CRC. We employed in vitro and in vivo experiments, including single-cell RNA sequencing, methylation-specific PCR (MSP), ChIP assays, and various functional assays to assess the impact of CENP-N and SEPT9 on CRC cell proliferation, migration, invasion, and metabolic reprogramming. Our data reveal that CENP-N directly interacts with SEPT9, enhancing its methylation at specific lysine residues. This modification significantly upregulates key glycolytic enzymes, thereby promoting aerobic glycolysis, CRC cell proliferation, and migration. In vivo studies further demonstrate that the CENP-N/SEPT9 axis facilitates liver metastasis of CRC, as confirmed by fluorescence imaging and histological analysis. This study identifies a novel pathway where CENP-N-mediated methylation of SEPT9 drives metabolic reprogramming and metastasis in CRC. These findings suggest potential therapeutic targets for inhibiting CRC progression and liver metastasis, offering new insights into CRC pathogenesis. [ABSTRACT FROM AUTHOR]

Background: SEPT9 is a pivotal cytoskeletal GTPase that regulates diverse biological processes encompassing mitosis and cytokinesis. While previous studies have implicated SEPT9 in tumorigenesis and development; comprehensive pan-cancer analyses have not been performed. This study aims to systematically explore its role in cancer screening, prognosis, and treatment, addressing this critical gap. Methods: Gene and protein expression data containing clinical information were obtained from public databases for pan-cancer analyses. Additionally, clinical samples from 90 patients with lung squamous cell carcinoma (LUSC) were used to further experimentally validate the clinical significance of SEPT9. In addition, the molecular docking tool was used to analyze the affinities between SEPT9 protein and drugs. Results: SEPT9 is highly expressed in various cancers, and its aberrant expression correlates with genetic alternations and epigenetic modifications, leading to adverse clinical outcomes. Take LUSC as an example, additional dataset analyses and immunohistochemical experiments further confirm the diagnostic and prognostic values as well as the clinical relevance of the SEPT9 gene and protein. Functional enrichment, single-cell expression, and immune infiltration analyses revealed that SEPT9 promotes malignant tumor progression and modulates the immune microenvironments, enabling patients to benefit from immunotherapy. Moreover, drug sensitivity and molecular docking analyses showed that SEPT9 is associated with the sensitivity and resistance of multiple drugs and has stable binding activity with them, including Vorinostat and OTS-964. To harness its prognostic and therapeutic potential in LUSC, a mitotic spindle-associated prognostic model including SEPT9, HSF1, ARAP3, KIF20B, FAM83D, TUBB8, and several clinical characteristics, was developed. This model not only improves clinical outcome predictions but also reshapes the immune microenvironment, making immunotherapy more effective for LUSC patients. Conclusion: This is the first study to systematically analyze the role of SEPT9 in cancers and innovatively apply the mitotic spindle-associated model to LUSC, fully demonstrating its potential as a valuable biomarker for cancer screening and prognosis, and highlighting its application value in promoting immunotherapy and chemotherapy, particularly for LUSC. [ABSTRACT FROM AUTHOR]

Background: Hereditary Neuralgic Amyotrophy (HNA) is an autosomal dominant disorder characterized by episodes of severe pain and amyotrophy affecting the brachial plexus as well as other sites. Mutations in the SEPTIN9 gene have been identified as genetic abnormality for HNA. Although the genetic mutations are known, their pathogenesis for the causation of this disorder is not exactly elucidated. Objective: In this study, we have investigated the phenotypic and genetic features in a large pedigree with HNA. Methods: We report the clinical spectrum and genetic analysis of a family with 9 affected members. Clinical heterogeneity has been reported in the individuals having mutations in SEPTIN9 gene. After taking informed consent, we have done genetic analysis of 6 affected and 4 unaffected members of the family to identify the molecular abnormalities of SEPTIN9 gene. Results and Conclusions: Genetic analysis has identified the presence of NM_001113491.2:p.Arg106Trp mutation in SEPTIN9 gene. The same mutation has been identified in 6 affected members of the family. Molecular simulation study has revealed that the mutation has significantly altered the conformation of septin-9 protein, thereby impairing the microtubule binding and bundling ability. Although the affected members shared a common recurrent mutation, they have a wide spectrum of clinical variability. This may be due to the variable penetrance of the mutation and different epigenetic influences in the family. This is the first genetically confirmed case series of HNA reported from India. [ABSTRACT FROM AUTHOR]

Septins, a family of GTP-binding proteins that assemble into higher order structures, interface with the membrane, actin filaments and microtubules, and are thus important regulators of cytoarchitecture. Septin 9 (SEPT9), which is frequently overexpressed in tumors and mutated in hereditary neuralgic amyotrophy (HNA), mediates the binding of septins to microtubules, but the molecular determinants of this interaction remained uncertain. We demonstrate that a short microtubule-associated protein (MAP)-like motif unique to SEPT9 isoform 1 (SEPT9_i1) drives septin octamer-microtubule interaction in cells and in vitro reconstitutions. Septin-microtubule association requires polymerizable septin octamers harboring SEPT9_i1. Although outside of the MAP-like motif, HNA mutations abrogate this association, identifying a putative regulatory domain. Removal of this domain from SEPT9_i1 sequesters septins on microtubules, promotes microtubule stability and alters actomyosin fiber distribution and tension. Thus, we identify key molecular determinants and potential regulatory roles of septin-microtubule interaction, paving the way to deciphering themechanisms underlying septin-associated pathologies. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the significant global health concerns with an increase in cases. Regular screening tests are crucial for early detection as it is often asymptomatic in the initial stages. Liquid biopsies, a non-invasive approach that examines biomarkers in biofluids, offer a promising future in diagnosing and screening cancer. Circulating-tumour DNA (ctDNA) is the genetic material in biofluids released into the circulatory system by cells. ctDNA is a promising marker for monitoring patients since cancer cells display distinct DNA methylation patterns compared to normal cells. The potential of our research to contribute to early detection and improved patient outcomes is significant. Aims: The primary objective of this research project was to explore the HAND1 methylation levels in plasma ctDNA as a potential biomarker for diagnosing CRC and evaluate the methylation level of the well-established gene SPET9 to compare it with the methylation level of HAND1. Materials and methods: Plasma samples were collected from 30 CRC patients and 15 healthy individuals, with CRC samples obtained pre-treatment. ctDNA was extracted and treated with bisulfite for methylation status assessment. Quantitative methylation-specific PCR (qMS-PCR) was performed for HAND1 and SEPT9, using β-actin (ACTB gene) as a reference. The study aims to evaluate the potential of these genes as diagnostic biomarkers for CRC, contributing to early detection and improved patient outcomes. Results: Our study yielded significant results: 90% of CRC patients (27 out of 30) had hypermethylation in the SEPT9 gene, and 83% (25 out of 30) exhibited hypermethylation in the HAND1 gene. The methylation levels of both genes were significantly higher in CRC patients than in healthy donors. These findings underscore the potential of SEPT9 and HAND1 methylation as promising biomarkers for diagnosing CRC, potentially leading to early detection and improved patient outcomes. Conclusion: These findings highlight the potential of SEPT9 and HAND1 methylation as promising biomarkers for diagnosing CRC. However, further research and validation studies are needed to confirm these findings and to explore their clinical utility in CRC diagnosis and management. [ABSTRACT FROM AUTHOR]

Simple Summary: This study tackles the challenges of assessing treatment response in advanced prostate cancer. The standard test, measuring the PSA protein in blood, lacks reliability in some patients. We explored a method examining genetic material in blood samples. We focused on two methylation markers, SHOX2 and SEPT9, as proxies of circulating tumor DNA. We collected blood samples from 11 patients with advanced prostate cancer undergoing different treatments. The results showed that all markers showed a response to treatment, especially SHOX2. This suggests that tracking advanced prostate cancer through liquid biopsy might harbor potential to monitor treatment effectiveness. This study is designed as a feasibility assessment and starting point, and more research with a larger group of patients is needed for confirmation. Background: Metastatic prostate cancer (mPCA) poses challenges in treatment response assessment, particularly in cases where prostate-specific antigen (PSA) levels do not reliably indicate a response. Liquid biopsy, focusing on circulating cell-free DNA (ccfDNA) methylation analysis as a proxy for circulating tumor DNA, offers a non-invasive and cost-effective approach. This study explores the potential of two methylation markers, short stature homeobox 2 (SHOX2) and Septin 9 (SEPT9), as on-mPCA-treatment biomarkers. Methods: Plasma samples were collected from 11 mPCA patients undergoing various treatments. Quantitative assessment of hypermethylated SHOX2 (mSHOX2) and SEPT9 (mSEPT9) levels in ccfDNA was conducted through methylation-specific real-time PCR. Early and overall dynamics of PSA, mSHOX2, and mSEPT9 were analyzed. Statistical evaluation employed Wilcoxon tests. Results: mSHOX2 demonstrated a significant decline post-treatment in patients with a radiographic treatment response as well as in an early treatment setting. mSEPT9 and PSA exhibited non-significant declines. In individual cases, biomarker dynamics revealed unique patterns compared to PSA. Discussion: mSHOX2 and mSEPT9 exhibit dynamics on mPCA treatment. This proof-of-concept study lays the groundwork for further investigation into these markers as valuable additions to treatment response monitoring in mPCA. Further validation in larger cohorts is essential for establishing clinical utility. [ABSTRACT FROM AUTHOR]

Background: The methylation SEPT9 (mSEPT9) appeared to be effective for hepatocellular carcinoma (HCC) detection. However, its performance in high-risk population has not been validated. We designed a pilot study and aimed to investigate the performance of mSEPT9, AFP, PIVKA-II and their combination in hepatic cirrhosis (HC) population. Methods: A training cohort was established including 103 HCC and 114 HC patients. 10 ml blood was collected from each patient with K2EDTA tubes, and 3–4 ml plasma was extracted for subsequent tests. The performance of mSEPT9, AFP, PIVKA-II and their combination was optimized by the training cohort. Test performance was prospectively validated with a validation cohort, including 51 HCC and 121 HC patients. Results: At the optimal thresholds in the training cohort, the sensitivity, specificity and area under curve (AUC) was 72.82%, 89.47%, 0.84, and 48.57%, 89.92%, 0.79, and 63.64%, 95.95%, 0.79 for mSEPT9, AFP and PIVKA-II, respectively. The combined test significantly increased the sensitivity to 84.47% (P < 0.05) at the specificity of 86.84% with an AUC of 0.91. Stage-dependent performance was observed with all single markers and their combination in plasma marker levels, positive detection rate (PDR) and AUC. Moderate correlation was found between mSEPT9 and AFP plasma levels (r = 0.527, P < 0.0001). Good complementarity was found between any two of the three markers, providing optimal sensitivity in HCC detection when used in combination. Subsequent validation achieved a sensitivity, specificity and AUC of 65.31%, 92.86%, 0.80, and 44.24%, 89.26%, 0.75, and 62.22%, 95.27%, 0.78 for mSEPT9, AFP and PIVKA-II, respectively. The combined test yielded a significantly increased sensitivity of 84.00% (P < 0.05) at 85.57% specificity, with an AUC at 0.89. Conclusions: The performance was optimal by the combination of mSEPT9, AFP, PIVKA-II compared with any single marker, and the combination may be effective for HCC opportunistic screening in HC population. [ABSTRACT FROM AUTHOR]

Background: The methylation SEPT9 (mSEPT9) appeared to be effective for hepatocellular carcinoma (HCC) detection. However, its performance in high-risk population has not been validated. We designed a pilot study and aimed to investigate the performance of mSEPT9, AFP, PIVKA-II and their combination in hepatic cirrhosis (HC) population. Methods: A training cohort was established including 103 HCC and 114 HC patients. 10 ml blood was collected from each patient with K2EDTA tubes, and 3–4 ml plasma was extracted for subsequent tests. The performance of mSEPT9, AFP, PIVKA-II and their combination was optimized by the training cohort. Test performance was prospectively validated with a validation cohort, including 51 HCC and 121 HC patients. Results: At the optimal thresholds in the training cohort, the sensitivity, specificity and area under curve (AUC) was 72.82%, 89.47%, 0.84, and 48.57%, 89.92%, 0.79, and 63.64%, 95.95%, 0.79 for mSEPT9, AFP and PIVKA-II, respectively. The combined test significantly increased the sensitivity to 84.47% (P < 0.05) at the specificity of 86.84% with an AUC of 0.91. Stage-dependent performance was observed with all single markers and their combination in plasma marker levels, positive detection rate (PDR) and AUC. Moderate correlation was found between mSEPT9 and AFP plasma levels (r = 0.527, P < 0.0001). Good complementarity was found between any two of the three markers, providing optimal sensitivity in HCC detection when used in combination. Subsequent validation achieved a sensitivity, specificity and AUC of 65.31%, 92.86%, 0.80, and 44.24%, 89.26%, 0.75, and 62.22%, 95.27%, 0.78 for mSEPT9, AFP and PIVKA-II, respectively. The combined test yielded a significantly increased sensitivity of 84.00% (P < 0.05) at 85.57% specificity, with an AUC at 0.89. Conclusions: The performance was optimal by the combination of mSEPT9, AFP, PIVKA-II compared with any single marker, and the combination may be effective for HCC opportunistic screening in HC population. [ABSTRACT FROM AUTHOR]

Septins, a family of GTP-binding proteins that assemble into higher order structures, interface with the membrane, actin filaments and microtubules, and are thus important regulators of cytoarchitecture. Septin 9 (SEPT9), which is frequently overexpressed in tumors and mutated in hereditary neuralgic amyotrophy (HNA), mediates the binding of septins to microtubules, but the molecular determinants of this interaction remained uncertain. We demonstrate that a short microtubule-associated protein (MAP)-like motif unique to SEPT9 isoform 1 (SEPT9_i1) drives septin octamer-microtubule interaction in cells and in vitro reconstitutions. Septin-microtubule association requires polymerizable septin octamers harboring SEPT9_i1. Although outside of the MAP-like motif, HNA mutations abrogate this association, identifying a putative regulatory domain. Removal of this domain from SEPT9_i1 sequesters septins on microtubules, promotes microtubule stability and alters actomyosin fiber distribution and tension. Thus, we identify key molecular determinants and potential regulatory roles of septin-microtubule interaction, paving the way to deciphering themechanisms underlying septin-associated pathologies. [ABSTRACT FROM AUTHOR]

Septins, a family of GTP-binding proteins that assemble into higher order structures, interface with the membrane, actin filaments and microtubules, and are thus important regulators of cytoarchitecture. Septin 9 (SEPT9), which is frequently overexpressed in tumors and mutated in hereditary neuralgic amyotrophy (HNA), mediates the binding of septins to microtubules, but the molecular determinants of this interaction remained uncertain. We demonstrate that a short microtubule-associated protein (MAP)-like motif unique to SEPT9 isoform 1 (SEPT9_i1) drives septin octamer-microtubule interaction in cells and in vitro reconstitutions. Septin-microtubule association requires polymerizable septin octamers harboring SEPT9_i1. Although outside of the MAP-like motif, HNA mutations abrogate this association, identifying a putative regulatory domain. Removal of this domain from SEPT9_i1 sequesters septins on microtubules, promotes microtubule stability and alters actomyosin fiber distribution and tension. Thus, we identify key molecular determinants and potential regulatory roles of septin-microtubule interaction, paving the way to deciphering the mechanisms underlying septin-associated pathologies. [ABSTRACT FROM AUTHOR]

Septins, a family of GTP-binding proteins that assemble into higher order structures, interface with the membrane, actin filaments and microtubules, and are thus important regulators of cytoarchitecture. Septin 9 (SEPT9), which is frequently overexpressed in tumors and mutated in hereditary neuralgic amyotrophy (HNA), mediates the binding of septins to microtubules, but the molecular determinants of this interaction remained uncertain. We demonstrate that a short microtubule-associated protein (MAP)-like motif unique to SEPT9 isoform 1 (SEPT9_i1) drives septin octamer-microtubule interaction in cells and in vitro reconstitutions. Septin-microtubule association requires polymerizable septin octamers harboring SEPT9_i1. Although outside of the MAP-like motif, HNA mutations abrogate this association, identifying a putative regulatory domain. Removal of this domain from SEPT9_i1 sequesters septins on microtubules, promotes microtubule stability and alters actomyosin fiber distribution and tension. Thus, we identify key molecular determinants and potential regulatory roles of septin-microtubule interaction, paving the way to deciphering the mechanisms underlying septin-associated pathologies. [ABSTRACT FROM AUTHOR]

Background. Gastric cancer (GC) is one of the most prevalent cancers globally. This study was designed to evaluate the potential performance of plasma SEPT9 methylation (mSEPT9) as a noninvasive biomarker for the diagnosis of GC. Methods. A total of 182 participants, i.e., 60 patients with GC, 39 with chronic superficial gastritis (CSG), 27 with chronic atrophic gastritis (CAG), 30 with gastric ulcer (GU), and 26 with gastric polys (GP), were recruited. The mSEPT9 level was measured using real-time polymerase chain reaction. Results. As a diagnostic target, mSEPT9 (1/3 algorithm) had a sensitivity of 48.33 (95% confidence interval (CI): 35.40–61.48%) and a specificity of 86.89% (95% CI: 79.28–92.09%), and mSEPT9 (2/3 algorithm) had a sensitivity of 33.33 (95% CI: 22.02–46.79%) and a specificity of 98.36% (95% CI: 93.61–99.72%). The area under the receiver operating characteristic curve (ROC) curve of mSEPT9 was 0.698 (95% CI: 0.609–0.787) for the differentiation of GC from benign gastric diseases. The effectiveness of mSEPT9 (1/3 algorithm) was superior to that of CEA, CA19-9, and CA72-4. mSEPT9 was positively correlated with T, N, M, and the clinical stage of GC. Conclusions. Plasma mSEPT9 might serve as a useful and noninvasive biomarker for the diagnosis of GC. [ABSTRACT FROM AUTHOR]

Septins, a family of GTP-binding proteins that assemble into higher order structures, interface with the membrane, actin filaments and microtubules, and are thus important regulators of cytoarchitecture. Septin 9 (SEPT9), which is frequently overexpressed in tumors and mutated in hereditary neuralgic amyotrophy (HNA), mediates the binding of septins to microtubules, but the molecular determinants of this interaction remained uncertain. We demonstrate that a short microtubule-associated protein (MAP)-like motif unique to SEPT9 isoform 1 (SEPT9_i1) drives septin octamer-microtubule interaction in cells and in vitro reconstitutions. Septin-microtubule association requires polymerizable septin octamers harboring SEPT9_i1. Although outside of the MAP-like motif, HNA mutations abrogate this association, identifying a putative regulatory domain. Removal of this domain from SEPT9_i1 sequesters septins on microtubules, promotes microtubule stability and alters actomyosin fiber distribution and tension. Thus, we identify key molecular determinants and potential regulatory roles of septin-microtubule interaction, paving the way to deciphering themechanisms underlying septin-associated pathologies. [ABSTRACT FROM AUTHOR]

Abstract—Septin cytoskeletal proteins are involved in many cellular processes; changes in their expression are a marker of oncological diseases. In this regard, septins can be a potential target for the treatment of cancer cells. To search for new small molecules that affect the structural organization of septin filaments, a virtual screening of the PubChem database compound library was performed and a substance with the highest affinity, the flavonoid procyanidin B3, was selected among all the compounds. Molecular modeling showed that procyanidin B3 interacts with the septin monomer SEPT9 in the region of the G1 and G4 motifs, which are important for GTP binding, and prevents dimerization of septin monomers. Therefore, procyanidin B3 can be considered as a promising compound for affecting the structure of septin filaments in cancer cells. [ABSTRACT FROM AUTHOR]

Background & Objective: olorectal Cancer (CRC) is the third most common cancer after prostate (breast in women) and lung cancer; it is also the third cause of cancer deaths reported in both men and women in 2020. Currently, the most commonly used diagnostic tools for CRC are colonoscopy, serological methods, and other imaging techniques. Despite the benefits and abilities of these methods, each of them has disadvantages that reduce its functionality and acceptance. The aim of this study was identifying specific and non-invasive genetic biomarkers to diagnose colorectal cancer. Methods: In this study, changes in the expression of HLTF and SEPT9 genes were evaluated by Real Time PCR in blood and tissue samples of CRC patients. A total of 100 samples (50 Blood and 50 Tissue samples) were evaluated with a definite diagnosis of CRC in Firoozgar Hspital, Tehran, Iran, in 2018. The QPCR method was used to compare the expression of candidate genes between the patients group and control group in both samples. Sensitivity and specificity of the test were examined using ROC curve analysis. Results: The results showed a significant down-regulation in the expression of both selected genes in tissue and peripheral blood in the various stages of the CRC. The sensitivity and specifity of both genes was about 80%. Conclusion: The findings showed that the two candidate genes can be suggested as specific biomarkers for diagnosis of CRC using the peripheral blood as a noninvasive method. For a definite conclusion, more research is needed. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) represent a newly discovered class of endogenous non‐coding RNAs which are widely expressed and play important roles in disease progression. However, the function of circRNAs in oral squamous cell carcinoma (OSCC) still remains largely unknown. In this research, we found that circ_SEPT9 was highly expressed in OSCC cell lines and tumour tissues. Results showed that circ_SEPT9 promoted OSCC proliferation and tumour growth. And, circ_SEPT9 also enhanced the migration and invasion of OSCC cells. Mechanically, we found that circ_SEPT9 acted as a sponge for miR‐1225 to rescue PKN2 expression in OSCC cells. Inhibition of circ_SEPT9/miR‐1225/PKN2 pathway could effectively block the proliferation and metastasis of OSCC cells. Our study provides strong evidence that circ_SEPT9/miR‐1225/PKN2 axis is a promising target for OSCC treatment. [ABSTRACT FROM AUTHOR]

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Background: The early detection of digestive cancers and precancerous diseases remains a significant challenge. This study aimed to investigate the performance of the blood methylated SEPT9 (mSEPT9) assay, and the combination of this assay with serum protein markers, in hospital-based opportunistic screening strategies for digestive cancers. Methods: Opportunistic screening was performed in the participating hospitals on outpatients and inpatients who met specific inclusion criteria. We recruited a total of 2030 subjects, including 764 cancer patients [291 colorectal cancer (CRC), 239 gastric cancer (GC), 106 esophageal cancer (EC), and 128 hepatocellular carcinoma (HCC)], 423 subjects with precancerous diseases, and 843 normal subjects. All samples were transported to an authenticated clinical laboratory where the mSEPT9 tests were performed. Results: When used separately, the mSEPT9 detected CRC, GC, EC, and HCC, with a sensitivity of 76.6% [area under the receiver operating characteristic curve (AUC) = 0.86)], 47.7% (AUC = 0.76), 42.6% (AUC = 0.69), and 76.7% (AUC = 0.85) and a specificity of 94.6%, 92.3%, 92.5%, and 87.7%, respectively. The mSEPT9 assay also had potent ability to discriminate cancer from non-cancer subjects. The combination of mSEPT9 with CEA, CA724, SNCG, or AFP significantly enhanced the sensitivity for CRC, GC, EC, and HCC to 86.4% (AUC = 0.99, specificity = 92.8%), 63.6% (AUC = 0.86, specificity = 91.1%), 71.3% (AUC = 0.81, specificity = 82.1%), and 83.3% (AUC = 0.93, specificity = 85.1%), respectively. The performance of the mSEPT9 assay was influenced by cancer stage, patient age, pathological types, and the location of cancer. We also identified that mSEPT9 was an independent risk factor and was a valuable predictor for the long-term survival of digestive cancer patients, with a hazard ratio of 2.84, 2.07, 1.88, and 2.45, for CRC, GC, EC, and HCC, respectively. Conclusion: The blood mSEPT9 assay, whether used alone or in combination with serum protein markers, is effective for the opportunistic screening of digestive cancers. Furthermore, mSEPT9 is an independent risk factor and a predictive marker for the long-term survival of digestive cancer patients. [ABSTRACT FROM AUTHOR]

Background: Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited neurological disorders. A growing number of genes, involved in glial and neuronal functions, have been associated with different subtypes of CMT leading to improved diagnostics and understanding of pathophysiological mechanisms. However, some patients and families remain genetically unsolved. Methods: We report on a German family including four affected members over three generations with a CMT phenotype accompanied by cognitive deficits, predominantly with regard to visual abilities and episodic memory. Results: A comprehensive clinical characterization followed by a sequential diagnostic approach disclosed a heterozygous rare SEPT9 missense variant c.1406 T > C, p.(Val469Ala), that segregates with disease. SEPT9 has been linked to various intracellular functions, such as cytokinesis and membrane trafficking. Interestingly, SEPT9-mutations are known to cause hereditary neuralgic amyotrophy (HNA), a recurrent focal peripheral neuropathy. Conclusion: We, for the first time, present a SEPT9 variant associated to a CMT phenotype and suggest SEPT9 as new sufficient candidate gene in CMT. [ABSTRACT FROM AUTHOR]

BACKGROUND: Screening for colorectal cancer (CRC) is effective at reducing mortality, but nearly 35% of eligible patients do not get screened. New noninvasive screening methods may help increase CRC screening participation. Current CRC screening methods include blood-based screening with methylated Septin 9 (SEPT9) DNA (Epi proColon), stool-based screening with fecal immunochemical testing (FIT), and the multianalyte fecal test combining FIT and stool DNA (Cologuard). OBJECTIVES: To estimate the cost and clinical implications to health plans, including the clinical and fiscal implications of the use of blood-based screening with SEPT9 DNA, FIT, and FIT/stool DNA, for patients who are unwilling or unable to undergo other recommended screening methods, and to quantify the clinical and fiscal impacts on health plans of expanding CRC screening participation from today's level of 65% up to 80%. METHODS: We designed a simulation model to estimate the 3-year clinical and economic impacts for noninvasive screening scenarios and for no screening in the screening-nonadherent population. Clinical inputs were derived from SEPT9, FIT, and FIT/stool DNA validation studies in the peer-reviewed literature, the US census, and other sources in the peer-reviewed literature. We modeled a population of 1 million covered lives (aged 0-64 years) in a hypothetical health plan to estimate CRC, advanced adenoma, and nonadvanced adenoma diagnoses for different screening scenarios. We also modeled the expenditures related to screening, diagnostic follow-up, and treatment costs for CRC for a 15% increase (34,800 members) to 80% screening over the course of 3 years. RESULTS: In the health plan population, 232,000 members aged 50 to 64 years were eligible for screening, of whom 81,200 (35%) were unscreened. The number of cases of CRC that were detected was similar for each screening scenario, including 221 for SEPT9, 216 for FIT, and 193 for FIT/stool DNA versus 49 for no screening. The 3-year per-member per-month (PMPM) cost impact for screening versus no screening and the evaluation of positive tests for the scenarios was $0.67 for SEPT9, $0.33 for FIT, and $0.69 for FIT/stool DNA. Including the treatment costs for CRC, the PMPM costs increased to $1.08, $0.71, and $0.98, respectively. CONCLUSIONS: Our simulation model suggests that similar clinical detection rates are achievable with the 3 noninvasive blood- and stool-based screening methods. These results support a role for blood- and stool-based screening to increase participation in CRC screening. [ABSTRACT FROM AUTHOR]

Objective This study, a simple electrochemical nanogenosensor has been developed for the rapid and sensitive detection of methylated Septin 9 DNA as a useful biomarker for early colorectal cancer detection or screening. Methods The process consists of three main steps: (i) The surface modification of screen-printed carbon electrode (SPCEs) with a poly(l-Arg)/reduced graphene oxide composite film followed by immobilizing anti-5-methylcytosine antibody, (ii) preparation of probe-modified Fe3O4/N-trimethylchitosan/Au nanocomposites for the hybridization with complementary DNA sequences, (iii) capturing methylated DNA target by antibody-modified SPCEs and subsequent electrochemical detection through redox peak currents of gold nanoparticles which generated a concentration-dependent response. Results The surface modification of the electrode and hybridization with the methylated target were confirmed by cyclic voltammetry method and differential pulse voltammetry was used for quantitative evaluation of methylated target DNA. Conclusion The assay showed a wide linear range from 0.01 to 1000 pM with a low detection limit of 0.01 pM. [ABSTRACT FROM AUTHOR]

Background: SHOX2 and SEPT9 methylation in circulating cell-free DNA (ccfDNA) in blood are established powerful and clinically valuable biomarkers for diagnosis, staging, prognosis, and monitoring of cancer patients. The aim of the present study was to evaluate different quantification algorithms (relative quantification, absolute quantification, quasi-digital PCR) with regard to their clinical performance. Methods: Methylation analyses were performed in a training cohort (141 patients with head and neck squamous cell carcinoma [HNSCC], 170 control cases) and a testing cohort (137 HNSCC cases, 102 controls). DNA was extracted from plasma samples, bisulfite-converted, and analyzed via quantitative real-time PCR. SHOX2 and SEPT9 methylations were assessed separately and as panel [meanSEPT9/SHOX2] using the ΔCT method for absolute quantification and the ΔΔCT-method for relative quantification. Quasi-digital PCR was defined as the number of amplification-positive PCR replicates. The diagnostic (sensitivity, specificity, area under the curve (AUC) of the receiver operating characteristic (ROC)) and prognostic accuracy (hazard ratio (HR) from Cox regression) were evaluated. Results: Sporadic methylation in control samples necessitated the introduction of cutoffs resulting in 61-63% sensitivity/90-92% specificity (SEPT9/training), 53-57% sensitivity/87-90% specificity (SHOX2/training), and 64-65% sensitivity/90-91% specificity (meanSEPT9/SHOX2/training). Results were confirmed in a testing cohort with 54-56% sensitivity/88-90% specificity (SEPT9/testing), 43-48% sensitivity/93-95% specificity (SHOX2/ testing), and 49-58% sensitivity/88-94% specificity (meanSEPT9/SHOX2/testing). All algorithms showed comparable cutoff-independent diagnostic accuracy with largely overlapping 95% confidence intervals (SEPT9: AUCtraining = 0.79-0.80; AUCtesting = 0.74-0.75; SHOX2: AUCtraining = 0.78-0.81, AUCtesting = 0.77-0.79; meanSEPT9/SHOX2: AUCtraining = 0.81-0.84, AUCtesting = 0.80). The accurate prediction of overall survival was possible with all three algorithms (training cohort: HRSEPT9 = 1.23-1.90, HRSHOX2 = 1.14-1.85, HRmeanSEPT9/SHOX2 =1.19-1.89 ; testing cohort: HRSEPT9 =1.22-1.67, HRSHOX2 = 1.15-1.71, HRmeanSEPT9/SHOX2 = 1.12-1.77). Conclusion: The concordant clinical performance based on different quantification algorithms allows for the application of various diagnostic platforms for the analysis of ccfDNA methylation biomarkers. [ABSTRACT FROM AUTHOR]

Purpose of Review: This article serves as a critical review and summary of the role of stool- and blood-based molecular tests for colorectal cancer (CRC) screening indexed in PubMed between 2011 and early 2017. In particular, we focus on assays approved for clinical use and recent findings on novel biomarkers. The biological rationale, clinical performance characteristics, and limitations of these tools are discussed. Recent Findings: Novel miRNA markers and bacterial DNA markers have been reported and evaluated in case-controlled studies. The plasma-based SEPT9 test and the multi-target stool DNA test (mt-sDNA) have received approval for CRC screening and are available to patients. Mt-sDNA has demonstrated a high accuracy rate in detecting colorectal neoplasia. Summary: Despite the proven benefits of CRC screening, a large percentage of the eligible population remains unscreened due to suboptimal screening compliance and the limitations of current modalities. The opportunity to improve CRC screening rates has driven research to develop novel screening approaches. Stool- and blood-based molecular tests have demonstrated significant potential for improving access to CRC screening. [ABSTRACT FROM AUTHOR]

monitoring and prognosis prediction. Its performance in these areas has not been thoroughly examined. OBJECTIVE: We aim to evaluate the performance of the SEPT9 assay in CRC screening, diagnosis and therapy by reviewing the current data published in these aspects. METHODS: The Ovid MEDLINE ,EMBASE, CBMdisc (China Biology Medicine disc) and CJFD (Chinese Journal Full -- text Database) database were searched for potential reports on the assay performance. Letters, reviews, meta-analysis and guidelines, basic research studies and articles irrelevant to mSEPT9 detection assays were excluded. Finally, data from 19 studies was summarized and systematically reviewed to clarify the assay performance. RESULTS: 2/3 algorithm provided the best overall performance in diagnosis and screening, while the 1/3 algorithm exhibited the best sensitivity in screening. The combination of SEPT9 assay with FIT and/or CEA enhanced the CRC detection rate in screening. The SEPT9 assay appeared to be effective in monitoring the therapeutic effect and may potentially predict the CRC recurrence and survival. CONCLUSION: The SEPT9 assay exhibited satisfactory performance in CRC diagnosis and screening, while more evidence is needed for therapeutic effect monitoring and prognosis prediction. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to examine the influence of algorithm and subject-related factors, including cancer stage, age, sex, and cancer location, on the performance of the SEPT9 gene methylation test, an assay approved by the US FDA for colorectal cancer (CRC) screening. Methods: A total of 1225 subjects were recruited in this opportunistic screening study, including 388 CRC patients, 139 subjects with adenoma, 108 subjects with hyperplastic polyps, and 590 subjects with no evidence of disease (NED). Epi proColon 2.0 CE assay was used to examine the blood level of SEPT9 gene methylation. Results: It was found that tests using 1/3 algorithm exhibited higher detection rate than those using the 2/3 algorithm for CRC, adenoma, hyperplastic polyps, while the false positive rate in subjects with NED was also higher with 1/3 algorithm. The positive detection rate (PDR) of the assay for stage 0 and I CRC were lower than later stages (Stage II, III and IV). Interestingly, the normal subjects above 60 years old exhibited significantly higher PDR than subjects from younger groups, while no significant change in PDR was observed among age groups in CRC patients. Furthermore, no difference in the PDR for CRC was found between male and female, and the PDR for CRC at various colorectal locations were essentially identical. Conclusions: Algorithm, cancer stage and age are factors affecting the detection rate of the SEPT9 assay, while sex and cancer location appeared to have no influence on its performance. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignancies, and the third leading cause of cancer mortality worldwide. Timely detection of CRC in patients with earlier stages provides the highest rate of survival. Epigenetic alterations are important in the occurrence and progression of CRC, and represent the primary modifications of cancer cells. Therefore, detection of these alterations in CRC cases are thought to hold great promise as diagnostic biomarkers. It has been shown that the SEPT9 and NTRK3 genes are aberrantly methylated and their detection can be used as biomarkers for early diagnosis of CRC. The present study analyzed promoter methylation status of these genes in CRC patients. Genomic DNA was extracted from 45 CRC and paired adjacent healthy tissues and undergone bisulfite conversion, and the methylation status of NTRK3 and SEPT9 were defined using the MS-HRM assay. Our results showed that there are statistically significant differences in methylation status of NTRK3 and specially SEPT9 between CRC and adjacent normal tissues (P<0.001). High sensitivity and specificity for a specific location in SEPT9 gene promoter as a diagnostic biomarker was observed. SEPT9 promoter hypermethylation may serve as a promising biomarker for the detection of CRC development. However, to validate the biomarker potential of NTRK3 there is a requirement for further investigation. [ABSTRACT FROM AUTHOR]

Solid tumors shed DNA into circulation, and there is growing evidence that the detection of circulating tumor DNA (ctDNA) has broad clinical utility, including monitoring of disease, prognosis, response to chemotherapy and tracking tumor heterogeneity. The appearance of ctDNA in the circulating cell-free DNA (ccfDNA) isolated from plasma or serum is commonly detected by identifying tumor-specific features such as insertions, deletions, mutations and/or aberrant methylation. Methylation is a normal cell regulatory event, and since the majority of ccfDNA is derived from white blood cells (WBC), it is important that tumour-specific DNA methylation markers show rare to no methylation events in WBC DNA. We have used a novel approach for assessment of low levels of DNA methylation in WBC DNA. DNA methylation in 29 previously identified regions (residing in 17 genes) was analyzed in WBC DNA and eight differentially-methylated regions (DMRs) were taken through to testing in clinical samples using methylation specific PCR assays. DMRs residing in four genes, BCAT1, GRASP, IKZF1 and IRF4, exhibited low positivity, 3.5% to 7%, in the plasma of colonoscopy-confirmed healthy subjects, with the sensitivity for detection of ctDNA in colonoscopy-confirmed patients with colorectal cancer being 65%, 54.5%, 67.6% and 59% respectively. [ABSTRACT FROM AUTHOR]

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Stems cells of the colon crypt are the origin of colon mature cells. Colorectal cancer cells are also suggested to originate from crypt stem cells undergoing a series of epigenetic and genetic alterations. Aberrant methylation plays important roles in early carcinogenesis and lead to altered gene expression and regulation, resulting in accumulation of damages to cell function and ultimately, malignant transformation. Aberrances in hypermethylation and hypomethylation act in different mechanism through the regulation of various genes during CSC carcinogenesis, and both of them play crucial roles in stem cell differentiation towards cancer cells. A large majority of epigenetic and genetic abnormalities that work coordinately in colorectal carcinogenesis are related to cell growth and division, indicating that the intrinsic abnormalities of CRC lie in dysregulation of basic cellular processes. Detection of abnormal methylation can be used in cancer screening and early detection, while reversal of aberrant methylation using drugs may have potential in cancer therapy. This review will provide an overview on the roles of aberrant methylation and a summary of genes that are affected during CRC carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) appear to arise from precursor lesions in a well-characterized adenomacarcinoma sequence. Significant efforts have been invested to develop biomarkers that identify early adenocarcinomas and adenomas with high-grade dysplasia, since these are believed to harbor a particularly high risk for malignant transition and thus require resection. Promoter methylation of SEPT9 and SHOX2 has been suggested as a biomarker for various solid malignant tumors. Hence, the present study aimed to test their biomarker potential in CRC and precursor lesions. Results: Assessment of promoter methylation of SEPT9 distinguished adenomas and CRC from controls as well as advanced from non-advanced adenomas (all p < 0.001). Correspondingly, SHOX2 methylation levels in adenomas and colorectal carcinomas were significantly higher compared to those in normal control tissues (p < 0.001). Histologic transition from adenomas to CRC was paralleled by amplification of the SEPT9 gene locus. Conclusions: SEPT9/SHOX2 methylation assays may help to distinguish colorectal cancer and adenomas from normal and inflammatory colonic tissue, as well as advanced from non-advanced adenomas. Further studies need to validate these findings before introduction in clinical routine. [ABSTRACT FROM AUTHOR]

Background: Cytology remains the gold standard for the detection of malignant cells in ascites. However, its sensitivity is limited. The aim of this study was to evaluate DNA methylation biomarkers for the differential diagnosis of benign (ascites in patients without malignancy), malignant (ascites in cancer patients directly caused by malignancy), and paramalignant (ascites in cancer patients caused by comorbidities but not by malignancy) ascites. Methods: A cohort of 283 patients (134 cancer patients, 149 patients with benign diseases) presenting with ascites was prospectively enrolled. Ascites was evaluated by means of cytopathological investigation and DNA methylation of SHOX2 and SEPT9 in the cell-free and cellular fraction. DNA methylation in bisulfite-converted DNA was determined using quantitative methylation specific real-time PCR. Cytopathological and DNA methylation results were evaluated with regard to diagnosis and overall survival (OS). Results: Patients with positive DNA methylation had a poor overall survival compared to methylation-negative patients (hazard ratio: HR = 1.97, p = 0.001). In multivariate survival analysis, DNA methylation was an independent prognostic parameter (p = 0.003) together with age (HR = 1.03, p < 0.001) and the presence of malignant disease (HR = 1.87, p < 0.001). The combination of methylation with cytopathological analyses led to a 42% increase in the detection rate of malignant ascites, resulting in 37% positively diagnosed cancer patients and a specificity of 97%. Among cancer patients, patients with DNA methylation-positive ascites showed an adverse clinical course (HR = 1.63, p = 0.039). Conclusions: DNA methylation testing adds diagnostic and prognostic information and might constitute an effective ancillary method for the differential diagnosis of malignant, paramalignant, and benign ascites. [ABSTRACT FROM AUTHOR]

Background: About half of all prostate cancers harbor the TMPRSS2:ERG (T2E) gene fusion. While T2E-positive and T2E-negative tumors represent specific molecular subtypes of prostate cancer (PCa), previous studies have not yet comprehensively investigated how these tumor subtypes differ at the epigenetic level. We therefore investigated epigenome-wide DNA methylation profiles of PCa stratified by T2E status. Results: The study included 496 patients with clinically localized PCa who had a radical prostatectomy as primary treatment for PCa. Fluorescence in situ hybridization (FISH) "break-apart" assays were used to determine tumor T2E-fusion status, which showed that 266 patients (53.6 %) had T2E-positive PCa. The study showed global DNA methylation differences between tumor subtypes. A large number of differentially methylated CpG sites were identified (false-discovery rate [FDR] Q-value <0.00001; n = 27,876) and DNA methylation profiles accurately distinguished between tumor T2E subgroups. A number of top-ranked differentially methylated CpGs in genes (FDR Q-values ≤1.53E-29) were identified: C3orf14, CACNA1D, GREM1, KLK10, NT5C, PDE4D, RAB40C, SEPT9, and TRIB2, several of which had a corresponding alteration in mRNA expression. These genes may have various roles in the pathogenesis of PCa, and the calcium-channel gene CACNA1D is a known ERG-target. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings. Conclusions: This study identified substantial differences in DNA methylation profiles of T2E-positive and T2E-negative tumors, thereby providing further evidence that different underlying oncogenic pathways characterize these molecular subtypes. [ABSTRACT FROM AUTHOR]

Septins constitute a family of GTP-binding proteins that are involved in a variety of biological processes. Several isoforms have been implicated in disease, but the molecular mechanisms underlying pathogenesis are poorly understood. Here, we show that depletion of SEPT9 decreases surface levels of epidermal growth factor receptors (EGFRs) by enhancing receptor degradation. We identify a consensus motif within the SEPT9 N-terminal domain that supports its association with the adaptor protein CIN85 (also known as SH3KBP1). We further show CIN85-SEPT9 to be localized exclusively to the plasma membrane, where SEPT9 is recruited to EGF-engaged receptors in a CIN85-dependent manner. Finally, we demonstrate that SEPT9 negatively regulates EGFR degradation by preventing the association of the ubiquitin ligase Cbl with CIN85, resulting in reduced EGFR ubiquitylation. Taken together, these data provide a mechanistic explanation of how SEPT9, though acting exclusively at the plasma membrane, impairs the sorting of EGFRs into the degradative pathway. [ABSTRACT FROM AUTHOR]

SEPTIN9 (SEPT9) is a filament-forming protein involved in numerous cellular processes. We have used a conditional knock out allele of Sept9 to specifically delete Sept9 in T-cells. As shown by fluorescence-activated cell sorting, loss of Sept9 at an early thymocyte stage in the thymus results in increased numbers of double-negative cells indicating that SEPT9 is involved in the transition from the double-negative stage during T-cell development. Accordingly, the relative numbers of mature T-cells in the periphery are decreased in mice with a T-cell-specific deletion of Sept9. Proliferation of Sept9-deleted CD8 T-cells from the spleen is decreased upon stimulation in culture. The altered T-cell homeostasis caused by the loss of Sept9 results in an increase of CD8 central memory T-cells. [ABSTRACT FROM AUTHOR]

Background: The evolutionarily conserved septin family of genes encode GTP binding proteins involved in a variety of cellular functions including cytokinesis, apoptosis, membrane dynamics and vesicle trafficking. Septin proteins can form hetero-oligomeric complexes and interact with other proteins including actin and tubulin. The human SEPT9 gene on chromosome 17q25.3 has a complex genomic architecture with 18 different transcripts that can encode 15 distinct polypeptides. Two distinct transcripts with unique 5′ ends (SEPT9_v4 and SEPT9_v4*) encode the same protein. In tumours the ratio of these transcripts changes with elevated levels of SEPT9_v4* mRNA, a transcript that is translated with enhanced efficiency leading to increased SEPT9_i4 protein. Methods: We have examined the effect of over-expression of SEPT9_i4 on the dynamics of microtubule polymer mass in cultured cells. Results: We show that the microtubule network in SEPT9_i4 over-expressing cells resists disruption by paclitaxel or cold incubation but also repolymerises tubulin more slowly after microtubule depolymerisation. Finally we show that SEPT9_i4 over-expressing cells have enhanced survival in the presence of clinically relevant microtubule acting drugs but not after treatment with DNAinteracting agents. Conclusions: Given that SEPT9 over-expression is seen in diverse tumours and in particular ovarian and breast cancer, such data indicate that SEPT9_v4 expression may be clinically relevant and contribute to some forms of drug resistance. [ABSTRACT FROM AUTHOR]

Peterson EA and Petty EM. Conquering the complex world of human septins: implications for health and disease. Septins are highly conserved filamentous proteins first characterized in budding yeast and subsequently identified in must eukaryotes. Septins can bind and hydrolyze GTP, which is intrinsically related to their formation of septin hexamers and functional protein interactions. The human septin family is composed of 14 loci, SEPT1-SEPT14, which encode dozens of different septin proteins. Their central GTPase and polybasic domain regions are highly conserved but they diverge in their N-terminus and/or C-terminus. The mechanism by which the different isoforms are generated is not yet well understood, but one can hypothesize that the use of different promoters and/or alternative splicing could give rise to these variants. Septins perform diverse cellular functions according to tissue expression and their interacting partners. Functions identified to date include cell division, chromosome segregation, protein scaffolding, cellular polarity, motility, membrane dynamics, vesicle trafficking, exocytosis, apoptosis, and DNA damage response. Their expression is tightly regulated to maintain proper filament assembly and normal cellular functions. Alterations of these proteins, by mutation or expression changes, have been associated with a variety of cancers and neurological diseases. The association of septins with cancer results from alterations of expression in solid tumors or translocations in leukemias [mixed lineage leukemia (MLL)]. Expression changes in septins have also been associated with neurological conditions such as Alzheimer's and Parkinson's disease, as well as retinopathies, hepatitis C, spermatogenesis and Listeria infection. Pathogenic mutations of SEPT9 were identified in the autosomal dominant neurological disorder hereditary neuralgic amyotrophy (HNA). Human septin research over the past decade has established their importance in cell biology and human disease. Further functional characterization of septins is crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications. [ABSTRACT FROM AUTHOR]

As a result of recurrent chromosomal translocations in acute leukemias, the mixed-lineage-leukemia (MLL) gene fuses with a variety of partner genes, which include several members of the septin gene family. SEPT9 is a very rare but recurrent fusion partner of MLL, and has recently been implicated in the oncogenesis of various malignancies. Herein, we report a case of de novo acute monocytic leukemia (M5b) with t(11;17)(q23;q25). MLL involvement was revealed by fluorescent in situ hybridization (FISH) analysis, and an MLL/SEP9 fusion transcript was detected by RT-PCR. Sequencing analysis further showed that, in contrast to originally reported cases, MLL exon 8 was fused not with SEPT9 exon 3 but with exon 2, which codes for the unique N-terminal region of the SEPT9_v1 isoform, the region implicated in the regulation of gene expression and cell proliferation. We did not detect any mutation of FLT3, which was expressed at a relatively low level in the leukemic cells. Relapsing after a very short complete remission, the leukemia progressed rapidly and became fatal in spite of intensive therapies including hematopoietic stem cell transplantation. It is thus suggested that, in common with the original MLL/SEPT9 cases, monocytic differentiation and a poor prognosis may also be associated with acute myeloid leukemia with the variant MLL/SEPT9 fusion transcript. [ABSTRACT FROM AUTHOR]

There is growing evidence for crosstalk between septin filaments and actin cytoskeleton which is regulated by Rho family of GTPases. Here we show that active Rho disrupts septin filament structures in rat embryonic fibroblast REF52 cells. Among Rho effector molecules tested, Rhotekin induced morphological changes of septin filaments similar to those by activated Rho. The center region of Rhotekin was sufficient for the septin reorganization in the cells, and likely to interact indirectly with the C-terminal half of a septin Sept9b, where a GTPase domain is located. Rhotekin and Sept9b are colocalized mainly in perinuclear regions in serum-starved REF52 cells. Upon stimulation with lysophosphatidic acid, they translocated to actin stress fibers in 10 min and then redistributed again to cytoplasm after 90 min treatment. In neuroblastoma Neuro2a cells, Rhotekin and Sept9b were enriched in the tip of neurites, a location where cortical actin reorganization is induced upon stimulation with lysophosphatidic acid. Taken together, we propose that Rhotekin is a novel regulator organizing mammalian septin structures and provide a new link between the septin and Rho-signaling.Oncogene (2005) 24, 7064–7072. doi:10.1038/sj.onc.1208862; published online 27 June 2005 [ABSTRACT FROM AUTHOR]

Septins are an evolutionarily conserved family of GTPases with diverse functions including roles in cytokinesis that have been implicated in neoplasia. To address the potential role of SEPT9 in tumorigenesis, we assessed the expression of SEPT9 in 7287 fresh frozen human tissue samples and 292 human cell lines by microarray analysis. In addition, we used a sensitive RT–PCR strategy to define the expression of SEPT9 isoforms in archival formalin-fixed and paraffin-embedded normal human tissues. The mRNA data were further confirmed by immunohistological analyses of SEPT9 protein expression in normal human tissues using antisera that detect SEPT9 isoforms. Using these complementary approaches, we demonstrate that SEPT9 mRNA and protein are expressed ubiquitously, with the isoforms showing tissue-specific expression. The microarray analysis indicates that there is consistent overexpression of SEPT9 in diverse human tumours including breast, CNS, endometrium, kidney, liver, lung, lymphoid, oesophagus, ovary, pancreas, skin, soft tissue and thyroid. Since tumours are commonly associated with enhanced cell proliferation, we examined the possible correlation of Ki67 and SEPT9 expression in normal tissues and tumours. Our data indicate that the overexpression of SEPT9 in neoplasia is not simply a proliferation-associated phenomenon, despite its role in cytokinesis.Oncogene (2005) 24, 4688–4700. doi:10.1038/sj.onc.1208574 Published online 14 March 2005 [ABSTRACT FROM AUTHOR]

Small GTPase Rho and septin family proteins are thought to be related to tumorigenesis. We have identified a Rho-guanine nucleotide exchange factor (GEF) as a binding partner for a mammalian septin Sept9b using yeast two-hybrid screening. We termed this molecule septin-associated RhoGEF (SA-RhoGEF). Molecular dissection analyses indicated that the C-terminal area of SA-RhoGEF exhibited binding to the N-terminal variable region of Sept9b. SA-RhoGEF was found by immunoprecipitation analysis to associate with septin complexes in REF52 fibroblast cells, maybe through direct interaction with Sept9b. Immunofluorescence analyses revealed the colocalization of SA-RhoGEF and Sept9b along with actin stress fibers in REF52 cells, and their colocalization along stress fibers was most likely to depend on their mutual interaction. In transient expression analyses, Sept9b inhibited SA-RhoGEF-dependent Rho activation in COS7 and HeLa cells. SA-RhoGEF and its fragments expressed in REF52 cells altered endogenous septin filament structures. To our knowledge, SA-RhoGEF is the first molecule providing a link between septins and Rho signaling.Oncogene (2005) 24, 65-76. doi:10.1038/sj.onc.1208101 Published online 22 November 2004 [ABSTRACT FROM AUTHOR]

Simple Summary: High-performance, non-invasive screening is a requirement in colorectal cancer (CRC) as early detection is a key in reducing disease-related mortality in CRC patients. However, colonoscopy, the actual gold standard in CRC screening, is invasive and often avoided by patients. Conventional screening methods encounter several limitations; therefore, new testing strategies have been considered. DNA methylation is the most prevalent epigenetic alteration that occurs in all stages of carcinogenesis. Our research focused on identifying potential DNA methylation single biomarkers or panels as promising tools in the early detection of CRC; it evaluated methylated genes currently targeted by already approved diagnostic kits. A panel of five CTCF methylated binding sites holds the promise for early-stage specific detection of CRC. CRC screening compliance and accuracy can be enhanced by employing a stool mt-DNA methylation test. In CRC, screening compliance is decreased due to the experienced discomfort associated with colonoscopy, although this method is the gold standard in terms of sensitivity and specificity. Promoter DNA methylation (hypomethylation or hypermethylation) has been linked to all CRC stages. Study objectives: to systematically review the current knowledge on approved biomarkers, reveal new potential ones, and inspect tactics that can improve performance. This research was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines; the risk of bias was evaluated using the revised Quality Assessment of Diagnostic Accuracy Studies criteria (QUADAS-2). The Web of Science® Core Collection, MEDLINE® and Scopus® databases were searched for original articles published in peer-reviewed journals with the specific keywords "colorectal cancer", "early detection", "early-stage colorectal cancer", "epigenetics", "biomarkers", "DNA methylation biomarkers", "stool or blood or tissue or biopsy", "NDRG4", "BMP3", "SEPT9", and "SDC2". Based on eligibility criteria, 74 articles were accepted for analysis. mSDC2 and mSEPT9 were frequently assessed in studies, alone or together as part of the ColoDefense panel test—the latter with the greatest performance. mBMP3 may not be an appropriate marker for detecting CRC. A panel of five methylated binding sites of the CTCF gene holds the promise for early-stage specific detection of CRC. CRC screening compliance and accuracy can be enhanced by employing a stool mt-DNA methylation test. [ABSTRACT FROM AUTHOR]

Background: Cervical cancer screening by combined cytology and HPV test has reduced the incidence of cervical cancer, but cytological screening lacks a higher sensitivity while HPV testing possesses a lower specificity. Most patients with invasive cervical cancer are treated with radiotherapy. However, insensitivity to radiotherapy leads to poor efficacy. Methods: Illumina Methylation EPIC 850k Beadchip was used for genomic screening. We detected methylation of SEPT9 and mRNA expression in different cervical tissues by using methylation-specific PCR and qRT-PCR. Then using CCK8, migration assay, and flow cytometry to detect the biological function and irradiation resistance of SEPT9 in vitro and in vivo. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (CoIP) were used to find the interacting gene with SEPT9. Immunostaining of CD206 in cervical cancer and polarization of macrophages (M2) were evaluated by immunofluorescence and WB. The Cancer Genome Atlas (TCGA) database was used for screening the potential miRNAs induced by SEPT9. Results: Hyper-methylation of SEPT9 detects cervical cancer and normal tissues, normal+CIN1 and CIN2+CIN3+cancer with high sensitivity and specificity (AUC = 0.854 and 0.797, respectively, P < 0.001). The mRNA and protein expression of SEPT9 was upregulated in cervical cancer tissues when compared to para-carcinoma tissues. SEPT9 promotes proliferation, invasion, migration, and influences the cell cycle of cervical cancer. SEPT9 interacted with HMGB1-RB axis increases irradiation resistance. Furthermore, SEPT9 mediated miR-375 via the tumor-associated macrophages (TAMs) polarization, affecting the resistance to radiotherapy in cervical cancer. Conclusions: These findings give us the evidence that SEPT9 methylation could be a biomarker for cervical cancer diagnoses. It promotes tumorigenesis and radioresistance of cervical cancer by targeting HMGB1-RB axis and causes polarization of macrophages by mediating miR-375. We suggest SEPT9 could be a potential screening and therapeutic biomarker for cervical cancer. [ABSTRACT FROM AUTHOR]