STMN1

Gene Summary

Gene:STMN1; stathmin 1
Aliases: Lag, SMN, OP18, PP17, PP19, PR22, LAP18, C1orf215
Location:1p36.11
Summary:This gene belongs to the stathmin family of genes. It encodes a ubiquitous cytosolic phosphoprotein proposed to function as an intracellular relay integrating regulatory signals of the cellular environment. The encoded protein is involved in the regulation of the microtubule filament system by destabilizing microtubules. It prevents assembly and promotes disassembly of microtubules. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:stathmin
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: STMN1 (cancer-related)

Saha A, Shree Padhi S, Roy S, Banerjee B
Method of detecting new cancer stem cell-like enrichment in development front assay (DFA).
J Stem Cells. 2014; 9(4):235-42 [PubMed] Related Publications
UNLABELLED: Wound healing is an inherent property of injured tissue or a group of cells. The healing front is always developed by new cells which are progenitor of differentiated parental cells. In cancer tissues we aim to study the healing front and observed an enriched population of stem cell like properties in the developing front when compared to the other areas of the cell matrix.
METHOD: In vitro scratch assays with special focus on stem cell expression was used to analyze metastatic potential of the tumor cell, epithelial to mesenchymal transition and rate of cell migration to get an insight into the genes and the proteins getting expressed at the developing front. In this protocol we describe a fluorescence dependent method to document stem cell like enrichment at the developing front of a given wound in drug treated and untreated control cells under the same culture conditions in a time lag manner. We have tried to compare the rate of cell migration and the expression levels of stem cell markers between the treated and untreated cells.
RESULTS: CD44 being a cell surface protein and being involved in cell migration and proliferation, higher intensity of CD44 was observed at the developing front with increasing time. The rate of cell migration differed with different treatments and so did the CD44 expression with expression being higher in 0.6mM concentration of bleomycin when compared to 0.4mM. Similar expression was observed for ALDH1 stem cell marker. This particular technique can not only be used for studying expression of CSC markers (like CD44, ALDH1) but also in assaying the expression profile of several proteins involved in cellular processes like EMT (Epithelial to Mesenchymal Transition), cell migration, tumorigeneisis and rate of proliferation.
CONCLUSION: Would healing is an integral property of solid tissues and in solid tumors properties of solid tissue wound are important characteristics of tumor development. Therefore combining the properties of stem cell like enrichment in the development front would be an important and fast assay to study migratory and metastatic properties of an invitro culture.

Zheng F, Liao YJ, Cai MY, et al.
Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets.
PLoS Genet. 2015; 11(2):e1004873 [PubMed] Free Access to Full Article Related Publications
Targeted therapy based on adjustment of microRNA (miRNA)s activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 replacement therapy to hepatocellular carcinoma (HCC) remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05). In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT) and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets.

Wang H, Yang B, Geng T, et al.
Tissue-specific selection of optimal reference genes for expression analysis of anti-cancer drug-related genes in tumor samples using quantitative real-time RT-PCR.
Exp Mol Pathol. 2015; 98(3):375-81 [PubMed] Related Publications
Gene transcription analysis in clinical tumor samples can help with diagnosis, prognosis, and treatment of cancers. We aimed to identify the optimal reference genes for reliable expression analysis in various tumor samples by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Using a one-step TaqMan-based qRT-PCR, 5 commonly used reference genes (ACTB, GAPDH, RPLPO, GUSB, and TFRC) and 10 anticancer drug-related genes (TYMS, RRM1, TUBB3, STMN1, TOP2A, EGFR, VEGFR2, HER2, ERCC1, and BRCA1) were analyzed in 327 tissue samples from lung, rectal, colon, gastric, esophageal, and breast tumors. According to the expression stability assessments obtained by using three programs (geNorm, NormFinder, and BestKeeper) and a comprehensive ranking method, the optimal reference genes for lung, gastric, esophageal, and breast tumors were RPLPO, GAPDH, ACTB, and ACTB, respectively. For rectal tumors, a combination of the 3 most stable genes (GUSB, ACTB, and RPLPO) was suitable for qRT-PCR, whereas for colon tumors, a combination of the 4 most stable genes (GAPDH, ACTB, GUSB, and RPLPO) was optimal for qRT-PCR. Based on the expression data of target genes normalized against selected reference genes, the principal component analysis revealed 4 expression patterns in 6 different tissues. One pattern was observed in gastric, rectal, and colon tumor tissues, which are gastrointestinal tumors. Expressions in the breast, lung, and esophageal tissues were separately represented as one pattern. Our results could facilitate the practice of personalized cancer medicine based on the gene expression profile of the patients.

Tinholt M, Viken MK, Dahm AE, et al.
Increased coagulation activity and genetic polymorphisms in the F5, F10 and EPCR genes are associated with breast cancer: a case-control study.
BMC Cancer. 2014; 14:845 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The procoagulant state in cancer increases the thrombotic risk, but also supports tumor progression. To investigate the molecular mechanisms controlling cancer and hemostasis, we conducted a case-control study of genotypic and phenotypic variables of the tissue factor (TF) pathway of coagulation in breast cancer.
METHODS: 366 breast cancer patients and 307 controls were genotyped for SNPs (n = 41) in the F2, F3 (TF), F5, F7, F10, TFPI and EPCR genes, and assayed for plasma coagulation markers (thrombin generation, activated protein C (APC) resistance, D-dimer, antithrombin, protein C, protein S, and TF pathway inhibitor (TFPI)). Associations with breast cancer were evaluated using logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs), or the chi-square test.
RESULTS: Four SNPs in F5 (rs12120605, rs6427202, rs9332542 and rs6427199), one in F10 (rs3093261), and one in EPCR (rs2069948) were associated with breast cancer. EPCR rs2069948 was associated with estrogen receptor (ER) and progesterone receptor (PR) positivity, while the SNPs in F5 appeared to follow hormone receptor negative and triple negative patients. The prothrombotic polymorphisms factor V Leiden (rs6025) and prothrombin G20210A (rs1799963) were not associated with breast cancer. High APC resistance was associated with breast cancer in both factor V Leiden non-carriers (OR 6.5, 95% CI 4.1-10.4) and carriers (OR 38.3, 95% CI 6.2-236.6). The thrombin parameters short lag times (OR 5.8, 95% CI 3.7-9.2), short times to peak thrombin (OR 7.1, 95% CI 4.4-11.3), and high thrombin peak (OR 6.1, 95% CI 3.9-9.5) predicted presence of breast cancer, and high D-dimer also associated with breast cancer (OR 2.0, 95% CI 1.3-3.3). Among the coagulation inhibitors, low levels of antithrombin associated with breast cancer (OR 5.7, 95% CI 3.6-9.0). The increased coagulability was not explained by the breast cancer associated SNPs, and was unaffected by ER, PR and triple negative status.
CONCLUSIONS: A procoagulant phenotype was found in the breast cancer patients. Novel associations with SNPs in F5, F10 and EPCR to breast cancer susceptibility were demonstrated, and the SNPs in F5 were confined to hormone receptor negative and triple negative patients. The study supports the importance of developing new therapeutic strategies targeting coagulation processes in cancer.

Han Y, Yu DP, Zhou SJ, et al.
Associations between clinical characteristics and oncogene expression in patients with non-small cell lung cancer.
Genet Mol Res. 2014; 13(4):8913-24 [PubMed] Related Publications
More than 40 oncogenes associated with non-small cell lung cancer (NSCLC) have been identified with varied gene expression. The correlations between specific clinical characteristics and oncogene expression in NSCLC patients were examined. From October 2011 to September 2012, a total of 60 patients with NSCLC (male:female, 34:24; mean age, 59.5 ± 10.6 years; age range, 31-81 years) were diagnosed and evaluated for treatment with radical resection at a single facility. Eligible patients exhibiting tumor node metastasis (TNM) stage I-III NSCLC confirmed by post-surgical pathology were included. mRNA expression was detected by branched DNA-liquidchip technology (bDNA-LCT) and mutations were detected at EGFR exons 18, 19, 20, and 21, KRAS exons 2 and 3, BRAF and PIK3CA exons 9 and 20. Correlations between gene expression at mutations and clinical characteristics of gender, age, histological type, degree of differentiation, smoking status, immunohistochemical (IHC) evaluation of TTF-1, TNM staging, and discrete age ("nage") were examined. Significant associations were observed between IHC staining for TTF-1 and histological type (P = 0.00001) and with BRAC1, TYMS, RRM1, and TUBB3 expression (P = 0.0187, 0.0051, 0.024, and 0.0238, respectively). Significant cross-correlations were observed between TYMS, BRAC1, TOP2A, STMN1, TUBB3, and RRM1 expression (P < 0.05), but not between EGFR exon 21, KRAS exon 2, and PIK3CA exon 9 expression and any other mutation expression (P > 0.05). Relationships between clinical characteristics and oncogene expression in NSCLC, particularly those of TTF-1 level and smoking status, may be useful indicators of prognosis and development of anti-cancer drug resistance.

Bhatia S
Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors.
Cancer. 2015; 121(5):648-63 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Subsequent malignant neoplasms (SMNs) are associated with significant morbidity and are a major cause of premature mortality among cancer survivors. Several large studies have demonstrated a strong association between the radiation and/or chemotherapy used to treat primary cancer and the risk of developing SMNs. However, for any given therapeutic exposure, the risk of developing an SMN varies between individuals. Genomic variation can potentially modify the association between therapeutic exposures and SMN risk and may explain the observed interindividual variability. In this review, the author provides a brief overview of the current knowledge regarding the role of genomic variation in the development of therapy-related SMNs and discusses the methodological challenges in undertaking an endeavor to develop a deeper understanding of the molecular underpinnings of therapy-related SMNs, such as an appropriate study design, the identification of an adequately sized study population together with a reliable plan for collecting and maintaining high-quality DNA, clinical validation of the phenotype, and the selection of an appropriate approach or platform for genotyping. Understanding the factors that can modify the risk of treatment-related SMNs is critical to developing targeted intervention strategies and optimizing risk-based health care for cancer survivors.

Lu X, Chen Y, Zeng T, et al.
Knockout of the HCC suppressor gene Lass2 downregulates the expression level of miR-694.
Oncol Rep. 2014; 32(6):2696-702 [PubMed] Related Publications
Homo sapiens longevity assurance homolog 2 of yeast LAG (Lass2) catalyzes the synthesis of long-chain ceramide which is an essential element of membranous structures. Deletion of Lass2 is associated with a high risk of spontaneous or DEN-induced hepatocellular carcinoma (HCC), yet the mechanism remains unclear. In the present study, we found extensive vesicles in hepatocytes of one-month-old Lass2-knockout (KO) mice. Hepatic biochemical indices were increased and expression of albumin was attenuated in the one‑month Lass2-KO liver. The results indicate that the injuries of the hepatocytes in young Lass2-KO mice, based on the results of Gene Ontology analysis of mRNA microarray of Lass2-KO liver vs. wild-type liver showed 'wounding response' was the mostly possible altered pathway in the Lass2-KO mice. miR-mRNA integrated analysis revealed that miR-694 was downregulated while its target gene tumor necrosis factor α-induced protein 3 (Tnfaip3) was upregulated, as confirmed by qPCR. The expression of NF-κB which is negatively controlled by Tnfaip3 was detected by qPCR and was found to be downregulated. Herein, we first report that Lass2 deficiency caused the downregulation of miR-694 and the upregulation of its target gene Tnfaip3 in vivo in mice, which may be related to a high risk of occurrence of HCC.

Schimmack S, Taylor A, Lawrence B, et al.
Stathmin in pancreatic neuroendocrine neoplasms: a marker of proliferation and PI3K signaling.
Tumour Biol. 2015; 36(1):399-408 [PubMed] Related Publications
Chromosome 1p35-36, which encodes tumor suppressors and mitotic checkpoint control genes, is commonly altered in human malignancies. One gene at this locus, stathmin 1 (STMN1), is involved in cell cycle progression and metastasis. We hypothesized that increased STMN1 expression may play a role in pancreatic neuroendocrine neoplasm (pNEN) malignancy. We investigated stathmin copy number variation, mRNA, and protein expression using PCR-Taqman Copy Number Assays, Q-PCR, Western blot, and immunohistochemistry. A mechanistic role for stathmin in proliferation was assessed in the BON cell line under growth-restrictive conditions and siRNA silencing. Furthermore, its role in PI3K signaling pathway activation was evaluated using pharmacological inhibitors. mRNA (p = 0.0001) and protein (p < 0.05) were overexpressed in pNENs. Expression was associated with pNEN tumor extension (p < 0.05), size (p < 0.01), and Ki67 expression (p < 0.01). Serum depletion decreased Ki67 expression (p < 0.01) as well as Ser38 phosphorylation (p < 0.05) in BON cells. STMN1 knockdown (siRNA) decreased proliferation (p < 0.05), and PI3K inhibitors directly inhibited proliferation via stathmin inactivation (dephosphorylation p < 0.01). We identified that stathmin was overexpressed and associated with pathological parameters in pancreatic NENs. We postulate that STMN1 overexpression and phosphorylation result in a loss of cell cycle mitotic checkpoint control and may render tumors amenable to PI3K inhibitory therapy.

Li J, Kong F, Wu K, et al.
miR-193b directly targets STMN1 and uPA genes and suppresses tumor growth and metastasis in pancreatic cancer.
Mol Med Rep. 2014; 10(5):2613-20 [PubMed] Related Publications
Pancreatic cancer has the poorest prognosis among all cancer types, due to its late diagnosis and the lack of effective therapies. Therefore, identification of novel gene targets, which are differentially expressed in pancreatic cancer and functionally involved in the malignant phenotype, is critical to achieve early diagnosis and develop effective therapeutic strategies. microRNAs (miRNAs) are small non-coding RNAs, which negatively regulate the expression of their targets. Due to their various targets, miRNAs play a key role in a number of physiological processes and in oncogenesis. Therefore, investigating the role of miRNAs in tumor may contribute to the development of new diagnostic and therapeutic tools for various types of cancer, including pancreatic cancer. Here, we investigated the role of miR-193b in pancreatic cancer. Our data showed that the expression of miR-193b is markedly decreased in pancreatic cancer tissues compared to adjacent healthy tissues. The Panc-1 cell line transfected with the miR‑193b exhibited significantly decreased proliferative, migratory, and invasive ability compared to untransfected cells. Moreover, miR-193b inhibited the expression of stathmin 1 (STMN1) and urokinase-type plasminogen activator (uPA) in Panc-1 cells. These data suggest that miR-193b acts as a tumor suppressor in pancreatic cancer. Therefore, miR-193b may constitute a promising therapeutic agent for the suppression of pancreatic cancer cell growth and metastasis.

Taleb S, Abbaszadegan MR, Moghbeli M, et al.
HES1 as an independent prognostic marker in esophageal squamous cell carcinoma.
J Gastrointest Cancer. 2014; 45(4):466-71 [PubMed] Related Publications
BACKGROUND: Notch signaling is one of the main involved pathways in cell differentiation and organogenesis, and its deregulation may lead to tumorigenesis. In this pathway, targeted to the CSL (CBF1, Suppressor of Hairless or Lag-1) complex, notch intracellular domain (NICD) releases corepressors and recruits MAML1 as coactivator triggering the activation of notch signaling transcription complex. Hairy enhance of split-1 (HES1) is one of the notch signaling target genes which is a basic helix-loop-helix (bHLH) transcription factor acting as a proliferation stimulator through the suppression of cell cycle inhibitors such as p27 and p21.
AIMS: In this study, we aimed to analyze the role of HES1 in the progression of esophageal squamous cell carcinoma (ESCC).
METHODS: Messenger RNA (mRNA) expression of HES1 in fresh tumoral tissues and their margin normal samples were assessed in 50 ESCC patients by real-time polymerase chain reaction (RT-PCR).
RESULTS: Thirteen out of 50 cases (26 %) had HES1 underexpression, while HES1 overexpression was observed only in 4 (8 %) samples. HES1 underexpression was significantly correlated with tumor depth of invasion (P = 0.035).
CONCLUSION: Although we have not observed any significant correlation between the HES1 expression and notch activation in ESCC, this study is the first report that elucidated the HES1 underexpression in ESCC and revealed its correlation with the invasiveness of ESCC.

Batsaikhan BE, Yoshikawa K, Kurita N, et al.
Expression of Stathmin1 in gastric adenocarcinoma.
Anticancer Res. 2014; 34(8):4217-21 [PubMed] Related Publications
BACKGROUND: Over expression of Stathmin1 (STMN1), activation-induced cytidine deaminase (AID) and protein kinase C iota (PKCi) proteins participate in the regulation of carcinogenesis. In the present study, we investigated the expression of STMN1 in patients with gastric adenocarcinoma and also determined the correlation of STMN1 with AID and PKCi proteins.
MATERIALS AND METHODS: This study was conducted in the Tokushima University Hospital between September 2009 and September 2010 on a total of 59 patients with gastric adenocarcinoma. Stathmin1, AID and PKCi protein expressions were evaluated by immuno-histochemistry in gastric adenocarcinoma.
RESULTS: A strong expression of STMN1 was significantly associated with gender- and poorly differentiated gastric adenocarcinoma (p<0.05). A high mRNA level of STMN1 was found in the tumor tissue of gastric adenocarcinoma compared to non-tumor tissue (p<0.05). In addition, STMN1 expression was significantly correlated with AID and PKCi protein expressions in gastric adenocarcinoma (p<0.05).
CONCLUSION: High mRNA level of the Stathmin1 gene was significantly expressed in gastric tumor tissue than non-tumor and strong expression of STMN1 protein is correlated with poorly-differentiated gastric adenocarcinoma.

Hemdan T, Lindén M, Lind SB, et al.
The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer.
Br J Cancer. 2014; 111(6):1180-7 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
BACKGROUND: The oncoprotein-18/stathmin 1 (STMN1), involved in cell progression and migration, is associated with clinical outcome in breast cancer. Here we aim to investigate its clinical significance in urinary bladder cancer and its possibilities as a therapeutic target.
METHODS: Immunohistochemical analyses of STMN1 protein expression were performed in three patient cohorts: cohort I (n=115 Ta, n=115 T1, n=112 T2-4 stages), cohort II, based on randomised controlled trials (n=239 T1-T4), and cohort III of primary tumour/matched metastasis (n=90 T1-T4). The effects of STMN1 on cell proliferation and migration were evaluated in the urinary bladder cancer cell line, T24, by inhibiting STMN1-cellular expression using siRNA.
RESULTS: In cohort I, high STMN1 expression correlated to shorter disease-specific survival hazard ratio (HR)=2.04 (95% confidence interval (CI) 1.13-3.68; P=0.02), elevated p53- (P<0.001) and Ki67-protein levels (P<0.001). The survival result was validated in cohort II: HR=1.76 (95% CI 1.04-2.99; P=0.03). In the metastatic bladder cancer material, 70% of the patients were STMN1-positive in both the primary tumour and matched metastases. In vitro, the growth and migration of the T24 cells were significantly reduced (P<0.01, P<0.0001, respectively), when transfecting the cells with STMN1-siRNA.
CONCLUSIONS: STMN1 protein expression has prognostic significance but is primarily a potential treatment target in urinary bladder cancer.

Landsman-Blumberg PB, Carter GC, Johnson BH, et al.
Metastatic colorectal cancer treatment patterns according to kirsten rat sarcoma viral oncogene homolog genotype in U.S. Community-based oncology practices.
Clin Colorectal Cancer. 2014; 13(3):178-84 [PubMed] Related Publications
INTRODUCTION: In 2008, the National Comprehensive Cancer Network guidelines were revised in light of the identification of the Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene as a biomarker of nonresponse to epidermal growth factor receptor inhibitors. This study sought to describe and compare real-world treatment patterns of metastatic colorectal cancer (mCRC) according to KRAS genotype in community-based oncology practices in the United States.
MATERIALS AND METHODS: Data from the ACORN (ACORN LLC, Memphis, TN) electronic medical record data warehouse, containing data of approximately 180,000 patients from 12 oncology practices across the United States were used. Records of adult patients with mCRC who had undergone KRAS testing between January 2008 and December 2011 were evaluated. Patient demographic characteristics, KRAS genotype, and treatment patterns were identified and compared.
RESULTS: Six hundred forty-eight mCRC patients who were tested for KRAS were identified. Of these, 48.1% had wild type (WT), 42.3% mutant, and 9.6% unknown genotypes. Most patients (72.1%) were tested in 2009 or later, after the guideline revision. Bevacizumab-containing combinations were the most common first-line regimens in KRAS mutant and WT patients. Approximately 90% of patients received at least 1 line of therapy, however, WT patients received significantly more lines of therapy than KRAS mutant patients (2.6 ± 1.5 vs. 2.1 ± 1.2; P < .001).
CONCLUSIONS: KRAS WT and mutant genotypes had similar first-line regimens; however, WT patients received more lines of therapy. Although there does not appear to be a lag between changes in guidelines and treatment practice, professional and government organizations must keep up with the changing science and disseminate this information to oncologists in a timely manner.

Wu W, Tan XF, Tan HT, et al.
Unbiased proteomic and transcript analyses reveal that stathmin-1 silencing inhibits colorectal cancer metastasis and sensitizes to 5-fluorouracil treatment.
Mol Cancer Res. 2014; 12(12):1717-28 [PubMed] Related Publications
UNLABELLED: Colorectal cancer metastasis is a major cause of mortality worldwide, which may only be controlled with novel methods limiting tumor dissemination and chemoresistance. High stathmin-1 (STMN1) expression was previously established as a hallmark of colorectal cancer progression and predictor of poor survival; however, the mechanism of action is less clear. This work demonstrates that STMN1 silencing arrests tumor-disseminative cascades by inhibiting multiple metastatic drivers, and repressing oncogenic and mesenchymal transcription. Using a sensitive iTRAQ labeling proteomic approach that quantified differential abundance of 4562 proteins, targeting STMN1 expression was shown to reinstate the default cellular program of metastatic inhibition, and promote cellular adhesion via amplification of hemidesmosomal junctions and intermediate filament tethering. Silencing STMN1 also significantly improved chemoresponse to the classical colorectal cancer therapeutic agent, 5FU, via a novel caspase-6 (CASP6)-dependent mechanism. Interestingly, the prometastatic function of STMN1 was independent of p53 but required phosphorylations at S25 or S38; abrogating phosphorylative events may constitute an alternative route to achieving metastatic inhibition. These findings establish STMN1 as a potential target in antimetastatic therapy, and demonstrate the power of an approach coupling proteomics and transcript analyses in the global assessment of treatment benefits and potential side-effects.
IMPLICATIONS: Stathmin-1 is a potential candidate in colorectal cancer therapy that targets simultaneously the twin problems of metastatic spread and chemoresistance.

Asad M, Wong MK, Tan TZ, et al.
FZD7 drives in vitro aggressiveness in Stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway.
Cell Death Dis. 2014; 5:e1346 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
Ovarian cancer (OC) can be classified into five biologically distinct molecular subgroups: epithelial-A (Epi-A), Epi-B, mesenchymal (Mes), Stem-A and Stem-B. Among them, Stem-A expresses genes relating to stemness and is correlated with poor clinical prognosis. In this study, we show that frizzled family receptor 7 (FZD7), a receptor for Wnt signalling, is overexpressed in the Stem-A subgroup. To elucidate the functional roles of FZD7, we used an RNA interference gene knockdown approach in three Stem-A cell lines: CH1, PA1 and OV-17R. Si-FZD7 OC cells showed reduced cell proliferation with an increase in the G0/G1 sub-population, with no effect on apoptosis. The cells also displayed a distinctive morphologic change by colony compaction to become more epithelial-like and polarised with smaller internuclear distances and increased z-axis height. Immunofluorescence (IF) staining patterns of pan-cadherin and β-catenin suggested an increase in cadherin-based cell-cell adhesion in si-FZD7 cells. We also observed a significant rearrangement in the actin cytoskeleton and an increase in tensile contractility in si-FZD7 OC cells, as evident by the loss of stress fibres and the redistribution of phospho-myosin light chain (pMLC) from the sites of cell-cell contacts to the periphery of cell colonies. Furthermore, there was reciprocal regulation of RhoA (Ras homolog family member A) and Rac1 (Ras-related C3 botulinum toxin substrate 1 (Rho family, small GTP-binding protein Rac1)) activities upon FZD7 knockdown, with a significant reduction in RhoA activity and a concomitant upregulation in Rac1 activity. These changes in pMLC and RhoA, as well as the increased TopFlash reporter activities in si-FZD7 cells, suggested involvement of the non-canonical Wnt/planar cell polarity (PCP) pathway. Selected PCP pathway genes (cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3), prickle homolog 4 (Drosophila) (PRICKLE4), dishevelled-associated activator of morphogenesis 1 (DAAM1), profilin 2 (PFN2), protocadherin 9 (PCDH9), protocadherin α1 (PCDHA1), protocadherin β17 pseudogene (PCDHB17), protocadherin β3 (PCDHB3), sprouty homolog 1 (SPRY1) and protein tyrosine kinase 7 (PTK7)) were found to be more highly expressed in Stem-A than non Stem-A subgroup of OC. Taken together, our results suggest that FZD7 might drive aggressiveness in Stem-A OC by regulating cell proliferation, cell cycle progression, maintenance of the Mes phenotype and cell migration via casein kinase 1ɛ-mediated non-canonical Wnt/PCP pathway.

Ferrero S, Ladetto M, Drandi D, et al.
Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival.
Leukemia. 2015; 29(3):689-95 [PubMed] Related Publications
Polymerase chain reaction (PCR)-based minimal residual disease (MRD) analysis is a useful prognostic tool in multiple myeloma (MM), although its long-term impact still needs to be addressed. This report presents the updated results of the GIMEMA-VEL-03-096 trial. Thirty-nine MM patients receiving bortezomib-thalidomide-dexamethasone after autologous transplantation were monitored for MRD by both nested and real-time quantitative-PCR until relapse. Our data confirm the strong impact of MRD on survival: overall survival was 72% at 8 years median follow-up for patients in major MRD response versus 48% for those experiencing MRD persistence (P=0.041). In addition, MRD kinetics resulted predictive for relapse: indeed median remission duration was not reached for patients in major MRD response, 38 months for those experiencing MRD reappearance and 9 months for patients with MRD persistence (P<0.001). Moreover: (1) 26 patients achieving major MRD response (67%) benefit of excellent disease control (median TNT: 42 months); (2) MRD reappearance heralds relapse, with a TNT comparable to that of MRD persistence (9 versus 10 months, P=0.706); (3) the median lag between MRD reappearance and need for salvage treatment is 9 months. These results suggest the usefulness of a long-term MRD monitoring in MM patients and the need for maintenance or pre-emptive treatments ensuring durable responses.

Wang HX, Yang XZ, Sun CY, et al.
Matrix metalloproteinase 2-responsive micelle for siRNA delivery.
Biomaterials. 2014; 35(26):7622-34 [PubMed] Related Publications
Systemic delivery of small interfering RNA (siRNA) into cancer cells remains the major obstacle to siRNA drug development. An ideal siRNA delivery vehicle for systemic administration should have long circulation time in blood, accumulate at tumor site, and sufficiently internalize into cancer cells for high-efficiency of gene silence. Herein, we report a core-shell Micelleplex delivery system that made from block copolymer bearing poly(ethylene glycol) (PEG), matrix metalloproteinase 2 (MMP-2)-degradable peptide PLG*LAG, cationic cell penetrating peptide polyarginine r9 and poly(ε-caprolactone) (PCL) for siRNA delivery. We show clear evidences in vitro and in vivo to prove that the micelle carrying siRNA can circulate enough time in blood, enrich accumulation at tumor sites, shed the PEG layer when triggered by tumor overexpressing MMP-2, and then the exposing cell penetrating peptide r9 enhanced cellular uptake of siRNA. Accordingly, this design strategy enhances the inhibition of breast tumor growth following systemic injection of this system carrying siRNA against Polo-like kinase 1, which demonstrating this Micelleplex can be a potential delivery system for systemic siRNA delivery in cancer therapy.

Mirabella F, Murison A, Aronson LI, et al.
A novel functional role for MMSET in RNA processing based on the link between the REIIBP isoform and its interaction with the SMN complex.
PLoS One. 2014; 9(6):e99493 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
The chromosomal translocation t(4;14) deregulates MMSET (WHSC1/NSD2) expression and is a poor prognostic factor in multiple myeloma (MM). MMSET encodes two major protein isoforms. We have characterized the role of the shorter isoform (REIIBP) in myeloma cells and identified a clear and novel interaction of REIIBP with members of the SMN (survival of motor neuron) complex that directly affects the assembly of the spliceosomal ribonucleic particles. Using RNA-seq we show that REIIBP influences the RNA splicing pattern of the cell. This new discovery provides novel insights into the understanding of MM pathology, and potential new leads for therapeutic targeting.

Kettner NM, Katchy CA, Fu L
Circadian gene variants in cancer.
Ann Med. 2014; 46(4):208-20 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment.

Akhtar J, Wang Z, Yu C, Zhang ZP
Effectiveness of local injection of lentivirus-delivered stathmin1 and stathmin1 shRNA in human gastric cancer xenograft mouse.
J Gastroenterol Hepatol. 2014; 29(9):1685-91 [PubMed] Related Publications
BACKGROUND AND AIM: We have reported previously that RNA interference targeting stathmin1 (STMN1) gene in human gastric cancer cells inhibits proliferation in vitro and tumor growth in vivo. Based on these observations, in the present study, the possibility that local injection of lentivirus-delivered stathmin shRNA would induce regression of the established human gastric cancer xenograft in animal model was investigated.
METHODS: BALB/c nude mice were inoculated subcutaneously into the right armpit with human gastric cancer cells SGC-7901(2 × 10(6) cells in 200 μL phosphate-buffered saline) to develop a xenograft model of human gastric cancer. When tumor reached suitable size, mice were randomly divided into two groups. STMN1 shRNA group (n = 6) were given local injection of lentivirus-delivered STMN1 shRNA, and the non-silencing shRNA group (n = 6) were administered with local injection of lentivirus-delivered non-silencing shRNA. Quantitative reverse transcription-polymerase chain reaction and Western blot were used to verify the knockdown of the gene expression in dissected tumor at mRNA and protein level, respectively.
RESULTS: Experimental therapy on the nude mice model bearing subcutaneous tumor of SGC-7901 cells showed that local administration of STMN1 shRNA effectively regressed the pre-established tumors. Stathmin shRNA-treated tumors were significantly regressed as compared with that of the tumor injected with non-silencing shRNA (P < 0.05). Tumor weight was significantly decreased in STMN1-treated group as compared with non-silencing shRNA group (P < 0.05). Quantitative reverse transcription-polymerase chain reaction and Western blot showed downregulation of STMN1 gene expression in STMN1 shRNA group as compared with non-silencing shRNA group (P < 0.05).
CONCLUSION: These findings highlight the potential use of local injection of lentivirus-delivered shRNA for the treatment of early localized human gastric carcinoma.

Watanabe A, Suzuki H, Yokobori T, et al.
Stathmin1 regulates p27 expression, proliferation and drug resistance, resulting in poor clinical prognosis in cholangiocarcinoma.
Cancer Sci. 2014; 105(6):690-6 [PubMed] Related Publications
Patients with extrahepatic cholangiocarcinoma (EHCC) have a poor prognosis; postoperative survival depends on cancer progression and therapeutic resistance. The mechanism of EHCC progression needs to be clarified to identify ways to improve disease prognosis. Stathmin1 (STMN1) is a major cytosolic phosphoprotein that regulates microtubule dynamics and is associated with malignant phenotypes and chemoresistance in various cancers. Recently, STMN1 was reported to interact with p27, an inhibitor of cyclin-dependent kinase complexes. Eighty EHCC cases were studied using immunohistochemistry and clinical pathology to determine the correlation between STMN1 and p27 expression; RNA interference to analyze the function of STMN1 in an EHCC cell line was also used. Cytoplasmic STMN1 expression correlated with venous invasion (P = 0.0021) and nuclear p27 underexpression (P = 0.0011). Patients in the high-STMN1-expression group were associated with shorter recurrence-free survival and overall survival than those in the low-expression group. An in vitro protein-binding assay revealed that cytoplasmic STMN1 bound to p27 in the cytoplasm, but not in the nucleus of EHCC cells. Moreover, p27 accumulated in EHCC cells after STMN1 suppression. STMN1 knockdown inhibited proliferation and increased the sensitivity of EHCC cells to paclitaxel. STMN1 contributes to a poor prognosis and cancer progression in EHCC patients. Understanding the regulation of p27 by STMN1 could provide new insights for overcoming therapeutic resistance in EHCC.

Chen X, Shen J, Li X, et al.
Rlim, an E3 ubiquitin ligase, influences the stability of Stathmin protein in human osteosarcoma cells.
Cell Signal. 2014; 26(7):1532-8 [PubMed] Related Publications
Stathmin is an oncoprotein and is expressed at high levels in a wide variety of human malignancies, which plays important roles in maintenance of malignant phenotypes. The regulation of Stathmin gene overexpression has been wildly explored, but the exact mechanism still needs to be elucidated. It is believed that regulation of an oncogene protein abundance through post-translational modifications is essential for maintenance of malignant phenotypes. Here we identified the Rlim, a Ring H2 zinc finger protein with intrinsic ubiquitin ligase activity, as a Stathmin-interacting protein that could increase Stathmin turnover through binding with this targeted protein and then induce its degradation by proteasome in a ubiquitin-dependent manner. Inhibition of endogenous Rlim expression by siRNA could increase the level of Stathmin protein, which further led to cell proliferation and cell cycle changes in human osteosarcoma cell lines. On the other hand, forced overexpression of Rlim could decrease the level of Stathmin protein. These results demonstrate that Rlim is involved in the negative regulation of Stathmin protein level through physical interaction and ubiquitin-mediated proteolysis. Hence, Rlim is a novel regulator of Stathmin protein in a ubiquitin-dependent manner, and represents a new pathway for malignant phenotype turnover by modulating the level of Stathmin protein in human osteosarcomas.

Gros A, Robbins PF, Yao X, et al.
PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors.
J Clin Invest. 2014; 124(5):2246-59 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression of metastatic melanoma; however, TILs are a heterogeneous population, and there are no effective markers to specifically identify and select the repertoire of tumor-reactive and mutation-specific CD8⁺ lymphocytes. The lack of biomarkers limits the ability to study these cells and develop strategies to enhance clinical efficacy and extend this therapy to other malignancies. Here, we evaluated unique phenotypic traits of CD8⁺ TILs and TCR β chain (TCRβ) clonotypic frequency in melanoma tumors to identify patient-specific repertoires of tumor-reactive CD8⁺ lymphocytes. In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8⁺ TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8⁺ lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137). TCRβ deep sequencing revealed oligoclonal expansion of specific TCRβ clonotypes in CD8⁺PD-1⁺ compared with CD8⁺PD-1- TIL populations. Furthermore, the most highly expanded TCRβ clonotypes in the CD8⁺ and the CD8⁺PD-1⁺ populations recognized the autologous tumor and included clonotypes targeting mutated antigens. Thus, in addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on CD8⁺ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.

Cho S, Moon H, Loh TJ, et al.
PSF contacts exon 7 of SMN2 pre-mRNA to promote exon 7 inclusion.
Biochim Biophys Acta. 2014; 1839(6):517-25 [PubMed] Related Publications
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease and a leading cause of infant mortality. Deletions or mutations of SMN1 cause SMA, a gene that encodes a SMN protein. SMN is important for the assembly of Sm proteins onto UsnRNA to UsnRNP. SMN has also been suggested to direct axonal transport of β-actin mRNA in neurons. Humans contain a second SMN gene called SMN2 thus SMA patients produce some SMN but not with sufficient levels. The majority of SMN2 mRNA does not include exon 7. Here we show that increased expression of PSF promotes inclusion of exon 7 in the SMN2 whereas reduced expression of PSF promotes exon 7 skipping. In addition, we present evidence showing that PSF interacts with the GAAGGA enhancer in exon 7. We also demonstrate that a mutation in this enhancer abolishes the effects of PSF on exon 7 splicing. Furthermore we show that the RNA target sequences of PSF and tra2β in exon 7 are partially overlapped. These results lead us to conclude that PSF interacts with an enhancer in exon 7 to promote exon 7 splicing of SMN2 pre-mRNA.

Camisaschi C, De Filippo A, Beretta V, et al.
Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3.
J Invest Dermatol. 2014; 134(7):1893-902 [PubMed] Related Publications
Plasmacytoid dendritic cells (pDCs) at tumor sites are often tolerogenic. Although pDCs initiate innate and adaptive immunity upon Toll-like receptor (TLR) triggering by pathogens, TLR-independent signals may be responsible for pDC activation and immune suppression in the tumor inflammatory environment. To identify molecules that are potentially involved in alternative pDC activation, we explored the expression and function of lymphocyte activation gene 3 (LAG-3) in human pDCs. In this report, we showed the expression of LAG-3 on the cell surface of a subset of circulating human pDCs. LAG-3+ pDCs exhibited a partially mature phenotype and were enriched at tumor sites in samples from melanoma patients. We found that LAG-3 interacted with major histocompatibility complex class II (MHC-II) to induce TLR-independent activation of pDCs with limited IFNα and enhanced IL-6 production. This in vitro cytokine profile of LAG-3-activated pDCs paralleled that of tumor-associated pDCs analyzed ex vivo. By confocal microscopy, LAG-3+ pDCs detected in melanoma-invaded lymph nodes (LNs) stained positive for IL-6 and preferentially localized near melanoma cells. These results suggest that LAG-3-mediated activation of pDCs takes place in vivo at tumor sites, and it is in part responsible for directing an immune-suppressive environment.

Tremblay I, Paré E, Arsenault D, et al.
The MEK/ERK pathway promotes NOTCH signalling in pancreatic cancer cells.
PLoS One. 2013; 8(12):e85502 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
Activation of the NOTCH receptors relies on their intracellular proteolysis by the gamma-secretase complex. This cleavage liberates the NOTCH intracellular domain (NIC) thereby allowing the translocation of NIC towards the nucleus to assemble into a transcriptional platform. Little information is available regarding the regulatory steps operating on NIC following its release from the transmembrane receptor up to its association with transcriptional partners. Interfering with these regulatory steps might potentially influences the nuclear outcome of NOTCH signalling. Herein, we exploited a reliable model to study the molecular events occurring subsequent to NOTCH1 cleavage. In pancreatic cancer cells, pulse of NOTCH1 activation led to increased expression of NOTCH target genes namely HES1 and c-MYC. We uncovered that, upon its release, the NOTCH1 intracellular domain, NIC1, undergoes a series of post-translational modifications that include phosphorylation. Most interestingly, we found that activation of the MEK/ERK pathway promotes HES1 expression. Inhibition of the gamma-secretase complex prevented the MEK/ERK-induced HES1 expression suggesting a NOTCH-dependent mechanism. Finally, higher levels of NIC1 were found associated with its transcriptional partners [CBF1, Su(H) and LAG-1] (CSL) and MASTERMIND-LIKE 1 (MAML1) upon MEK/ERK activation providing a potential mechanism whereby the MEK/ERK pathway promotes expression of NOTCH target genes. For the first time, our data exposed a signalling pathway, namely the MEK/ERK pathway that positively impacts on NOTCH nuclear outcome.

Akhtar J, Wang Z, Jiang WP, et al.
Stathmin overexpression identifies high risk for lymphatic metastatic recurrence in pN0 esophageal squamous cell carcinoma patients.
J Gastroenterol Hepatol. 2014; 29(5):944-50 [PubMed] Related Publications
BACKGROUND AND AIM: Common patterns of the operative failure after Ivor-Lewis esophagectomy in esophageal squamous cell carcinoma (ESCC) patients are locoregional lymph node metastasis. It is clinically significant to investigate the biological markers to predict the subset of patients who are at higher risk of lymphatic metastatic recurrence. Our research aimed to investigate the association between the Stathmin (STMN-1) gene expression and lymphatic metastatic recurrence in pN0 ESCC patients after surgery.
METHODS: One hundred seventy-four patients who suffered from mid-thoracic ESCC and completely resected with Ivor-Lewis esophagectomy were enrolled in our study. The entire patients were restricted to pN0 ESCC. Tissue specimens were examined for STMN-1 expression levels by immunohistochemistry and Western blotting methods. The correlation of STMN-1 levels with clinicopathological variables, prognosis, and metastatic potential was analyzed.
RESULTS: One hundred patients had STMN-1 protein overexpression (57.47%), and the patients with overexpression were accompanied by significantly higher rate of lymphatic metastatic recurrence as compared with patients who had low STMN-1 expression (P = 0.003). Multivariable Cox regression analysis revealed that the STMN-1 protein expression and T classification were independent factors to predict the lymphatic metastatic recurrence (P = 0.007, P = 0.000, respectively).
CONCLUSIONS: Even pN0 ESCC are a potential to lymphatic metastatic recurrence. Stathmin overexpression can be used as a marker to identify those patients who are at high risk for lymphatic metastatic recurrence in pN0 ESCC after an Ivor-Lewis esophagectomy.

Conner JR, Meserve E, Pizer E, et al.
Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations.
Gynecol Oncol. 2014; 132(2):280-6 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
OBJECTIVE: This study computed the risk of clinically silent adnexal neoplasia in women with germ-line BRCA1 or BRCA2 mutations (BRCA(m+)) and determined recurrence risk.
METHODS: We analyzed risk reduction salpingo-oophorectomies (RRSOs) from 349 BRCA(m+) women processed by the SEE-FIM protocol and addressed recurrence rates for 29 neoplasms from three institutions.
RESULTS: Nineteen neoplasms (5.4%) were identified at one institution, 9.2% of BRCA1 and 3.4% of BRCA2 mutation-positive women. Fourteen had a high-grade tubal intraepithelial neoplasm (HGTIN, 74%). Mean age (54.4) was higher than the BRCA(m+) cohort without neoplasia (47.8) and frequency increased with age (p < 0.001). Twenty-nine BRCA(m+) patients with neoplasia from three institutions were followed for a median of 5 years (1-8 years.). One of 11 with HGTIN alone (9%) recurred at 4 years, in contrast to 3 of 18 with invasion or involvement of other sites (16.7%). All but two are currently alive. Among the 29 patients in the three institution cohort, mean ages for HGTIN and advanced disease were 49.2 and 57.7 (p = 0.027).
CONCLUSIONS: Adnexal neoplasia is present in 5-6% of RRSOs, is more common in women with BRCA1 mutations, and recurs in 9% of women with HGTIN alone. The lag in time from diagnosis of the HGTIN to pelvic recurrence (4 years) and differences in mean age between HGTIN and advanced disease (8.5 years) suggest an interval of several years from the onset of HGTIN until pelvic cancer develops. However, some neoplasms occur in the absence of HGTIN.

Li J, Hu GH, Kong FJ, et al.
Reduced STMN1 expression induced by RNA interference inhibits the bioactivity of pancreatic cancer cell line Panc-1.
Neoplasma. 2014; 61(2):144-52 [PubMed] Related Publications
Increased expression of STMN1 has been observed in many tumor forms, but its expression and potential biological role in pancreatic cancer is still unknown. In this study, we demonstrated that STMN1 was expressed to a large extent in pancreatic cancer tissues and cell lines as compared to normal pancreatic tissues. Suppression of STMN1 expression via transfection with STMN1-specific siRNA could not only significantly inhibit the proliferation, migration and invasion ability of Panc-1 cells, but also enhance the apoptosis of Panc-1 cells. In addition, downregulation of STMN1 obviously enhanced the acetylation level of α-tubulin. All these results indicated that STMN1 plays an important role in pancreatic cancer development, and might serve as a potential therapeutic target for pancreatic cancer.

Gramatges MM, Liu Q, Yasui Y, et al.
Telomere content and risk of second malignant neoplasm in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.
Clin Cancer Res. 2014; 20(4):904-11 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
PURPOSE: Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine whether less telomere content was associated with treatment-related second malignant neoplasms (SMN) in childhood cancer survivors.
EXPERIMENTAL DESIGN: Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at the time of sample collection, years of follow-up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content as a continuous variable to estimate ORs with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma.
RESULTS: There was an inverse relationship between telomere content and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single-copy gene ratio (95% CI, 0.09-1.02; P = 0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR, 0.04; 95% CI, 0.00-0.55; P = 0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma.
CONCLUSIONS: A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.

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