Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: FEV (cancer-related)
Liu TH, Tang YJ, Huang Y, et al.Expression of the fetal hematopoiesis regulator FEV indicates leukemias of prenatal origin.
Leukemia. 2017; 31(5):1079-1086 [PubMed
] Related Publications
The origin of cancers is associated with etiology as well as therapeutics. Several studies reveal that malignancies in children can originate in utero. However, a diagnostic approach to distinguish between cancers initiated pre- or postnatally is absent. Here we identified a transcriptional factor FEV (fifth Ewing variant) that was expressed in fetal hematopoietic cells and became silent after birth. We characterized that FEV was essential for the self-renewal of hematopoietic stem cells (HSCs). We next found that FEV was expressed in most infant leukemia samples, but seldom in adult samples, in accord with the known prenatal origins of the former. We further determined the majority of pediatric acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) were FEV positive. Moreover, FEV knockdown markedly impaired the leukemia-propagating ability of leukemic stem cells. We therefore identified FEV is unique to fetal HSCs and stably expressed in leukemic cells of prenatal origin. It may also provide a tractable therapeutic target.
Chen S, Deniz K, Sung YS, et al.Ewing sarcoma with ERG gene rearrangements: A molecular study focusing on the prevalence of FUS-ERG and common pitfalls in detecting EWSR1-ERG fusions by FISH.
Genes Chromosomes Cancer. 2016; 55(4):340-9 [PubMed
] Free Access to Full Article Related Publications
The genetics of Ewing sarcoma (ES) are characterized by a canonical fusion involving EWSR1 gene and a member of the ETS family of transcription factors, such as FLI1 and ERG. In fact, ERG gene rearrangements represent the second most common molecular alteration, with EWSR1-ERG being identified in 5-10% of cases, while only a handful of reports document a FUS-ERG fusion. In this study, we focus on ES with ERG gene abnormalities, specifically to investigate the prevalence and clinicopathologic features of FUS-ERG fusions in a large cohort of small blue round cell tumors (SBRCTs) and compare to the eight reported FUS-positive ES. Among the 85 SBRCTs tested, seven (8.2%) cases harbored FUS gene rearrangements; six fused to ERG and one with FEV. During this investigation we came across a number of ERG-rearranged ES lacking both EWSR1 and FUS abnormalities by FISH. In one case, RNA sequencing identified an EWSR1-ERG transcript despite the negative EWSR1 rearrangements by FISH. Additional 3-color FISH fusion assay demonstrated the fusion of EWSR1 and ERG signals in all four cases negative for break-apart EWSR1 FISH. These results emphasize a potential pitfall of relying on EWSR1 FISH assay alone for diagnosis of ES. In cases with classic morphology and/or strong CD99 and ERG immunoreactivity, additional molecular testing should be applied, such as ERG FISH or RT-PCR/next generation sequencing, for a more definitive diagnosis. Although our study group is small, there were no differences noted between the clinical, morphologic features and immunoprofile of the different subsets of ERG-rearranged SBRCTs.
Cooper CD, Newman JA, Aitkenhead H, et al.Structures of the Ets Protein DNA-binding Domains of Transcription Factors Etv1, Etv4, Etv5, and Fev: DETERMINANTS OF DNA BINDING AND REDOX REGULATION BY DISULFIDE BOND FORMATION.
J Biol Chem. 2015; 290(22):13692-709 [PubMed
] Free Access to Full Article Related Publications
Ets transcription factors, which share the conserved Ets DNA-binding domain, number nearly 30 members in humans and are particularly involved in developmental processes. Their deregulation following changes in expression, transcriptional activity, or by chromosomal translocation plays a critical role in carcinogenesis. Ets DNA binding, selectivity, and regulation have been extensively studied; however, questions still arise regarding binding specificity outside the core GGA recognition sequence and the mode of action of Ets post-translational modifications. Here, we report the crystal structures of Etv1, Etv4, Etv5, and Fev, alone and in complex with DNA. We identify previously unrecognized features of the protein-DNA interface. Interactions with the DNA backbone account for most of the binding affinity. We describe a highly coordinated network of water molecules acting in base selection upstream of the GGAA core and the structural features that may account for discrimination against methylated cytidine residues. Unexpectedly, all proteins crystallized as disulfide-linked dimers, exhibiting a novel interface (distant to the DNA recognition helix). Homodimers of Etv1, Etv4, and Etv5 could be reduced to monomers, leading to a 40-200-fold increase in DNA binding affinity. Hence, we present the first indication of a redox-dependent regulatory mechanism that may control the activity of this subset of oncogenic Ets transcription factors.
Milione M, Gasparini P, Sozzi G, et al.Ewing sarcoma of the small bowel: a study of seven cases, including one with the uncommonly reported EWSR1-FEV translocation.
Histopathology. 2014; 64(7):1014-26 [PubMed
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AIMS: Primary Ewing sarcoma of the ileum has rarely been documented. Little is known about its pathogenesis and clinical implications, and it would be helpful to identify novel molecular markers. EWSR1-FEV translocation is exceedingly rare in Ewing sarcoma, as FEV expression is restricted to prostate, brain and serotonin neuroendocrine cells (NE) and related tumours.
METHODS AND RESULTS: Paraffin sections or snap-frozen material were used in this investigation. Tumours were investigated by means of immunohistochemistry, RT-PCR (EWSR1-FLI1, EWSR1-ERG and EWSR1-FEV transcripts), FISH analysis (EWSR1 break-apart and specific EWSR1-FEV translocation) and spectral karyotyping (SKY). Ten ileal neuroendocrine tumours (INET) made up the control group for EWSR1-FEV translocation. Among 445 Ewing sarcomas cases spanning a period of 20 years, seven (1.6%) arose in the ileum. All tumours were immunoreactive for synaptophysin, CD99, FLI1 and vimentin. FISH identified EWSR1 rearrangement in all cases, with EWSR1-FLI1 transcripts being detected in all but one tumour showing the uncommon EWSR1-FEV rearrangement, with SKY, RT-PCR and FISH confirmation. The mean survival of EWSR1-FLI1 patients was 14 months, whereas the EWSR1-FEV patient was alive after 15 years despite several recurrences controlled by surgery alone. No INET showed EWSR1 translocation.
CONCLUSIONS: Most primary Ewing sarcomas of the ileum show the common EWSR1-FLI1 translocation, but EWSR1-FEV could be specific for tumours arising in the ileum and showing better prognosis.
Vera-Badillo FE, Templeton AJ, de Gouveia P, et al.Androgen receptor expression and outcomes in early breast cancer: a systematic review and meta-analysis.
J Natl Cancer Inst. 2014; 106(1):djt319 [PubMed
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BACKGROUND: The androgen receptor (AR) is expressed frequently in breast cancer, but its prognostic significance is unclear. Preclinical data suggest that expression of AR may modify clinical outcomes in early breast cancer with improved prognosis in estrogen receptor (ER)-positive disease and poorer prognosis in ER-negative disease.
METHODS: A systematic review of electronic databases was conducted to identify studies published between 1946 and July 2012 and to explore the association between AR expression and overall survival (OS) and disease-free survival (DFS) in women diagnosed with early breast cancer. The odds ratios (OR) for OS and DFS at 3 and 5 years were calculated and then weighted and pooled in a meta-analysis with Mantel-Haenszel random-effect modeling. All statistical tests were two-sided.
RESULTS: Nineteen studies with a total of 7693 women were included. AR expression was documented in 60.5% of patients. ER-positive tumors were more likely to express AR- than ER-negative tumors (74.8% vs 31.8%, χ(2) P < .001). Compared with tumors without AR expression, those expressing AR were associated with improved OS at both 3 and 5 years (OR = 0.47, 95% confidence interval [CI] = 0.39 to 0.58, P < .001; and OR = 0.40, 95% CI = 0.29 to 0.56, P < .001). The absolute differences in the probability of OS at 3 and 5 years were 6.7% (95% CI = 3.5% to 9.8%) and 13.5% (95% CI = 7.5% to 19.6%), respectively. Results for 3- and 5-year DFS were similar. Coexpression of the ER did not influence OS at 3 or at 5 years.
CONCLUSIONS: Expression of AR in women with breast cancer is associated with better OS and DFS irrespective of coexpression of ER.
Shulman SC, Katzenstein H, Bridge J, et al.Ewing sarcoma with 7;22 translocation: three new cases and clinicopathological characterization.
Fetal Pediatr Pathol. 2012; 31(6):341-8 [PubMed
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Ewing sarcoma (ES) is the second most common primary bone malignancy in children and is typically characterized by a translocation involving the EWS gene on chromosome 22 and a member of the ETS family of genes: FLI1 (90%), ERG1 (5%), ETV1 (1%), ETV4 (1%), and FEV (1%). We identified three new cases of t(7;22) (p22;q12) (EWS-ETV1) ES and a literature search revealed an additional six cases. In comparison to conventional ES with t(11;22) (q24;q12) (EWS-FLI1), the t(7;22) ES variant has a higher propensity for females and children in a younger age group and it occurs more commonly in extraosseous locations.
Shaikhibrahim Z, Lindstrot A, Ellinger J, et al.The peripheral zone of the prostate is more prone to tumor development than the transitional zone: is the ETS family the key?
Mol Med Rep. 2012; 5(2):313-6 [PubMed
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Predisposition to develop prostate cancer (PCA) varies among the prostate zones, with the peripheral zone (PZ) more prone to tumor development than the transitional zone (TZ). In view of the fact that molecular differences between the zones may explain this difference, combined with the findings that translocations between TMPRSS2 and several ETS members are frequently observed in PCA, we hypothesized that the ETS family may be crucial to explaining this difference. Normal tissues from the PZ and the TZ of 20 PCA patients were laser microdissected to separate glands from stroma. Two oligo microarrays were performed in order to investigate the variation in ETS family gene expression between the glands and the stroma of the two zones. The ETS members, ELF-3, ELF-5, ERG, ETV-1, ETV-4, ETV-5, ETV-7 and FEV, were found to be differentially expressed. A striking observation was that ERG and ETV-1 were found to be up-regulated in the glands of the PZ compared to the TZ, particularly when considering that ERG and ETV-1 fusions account for 50-80% and 20% of PCA occurrences, respectively. These results indicate that the glands and stroma of the two zones display distinct molecular differences and zonal-specific expression of ETS members. Furthermore, ETS members up-regulated in PCA are already overexpressed in the normal PZ, suggesting that these members play a role in the development and progression of PCA.
The Ewing's family of tumors (EFTs) are characterized by chimeric transcripts generated by specific chromosomal rearrangements. The most common fusions are between the EWSR1 gene on chromosome 22 and the ETS family of transcription factors; rarely, FUS (on chromosome 16) substitutes for EWSR1. The detection of specific translocations using molecular analysis is now a routine part of the pathological examination of EFT. Here, we report our experience with molecular diagnosis of EFT during the 4 years (2006-2009) at the Rizzoli Institute. We analyzed 222 consecutive tumors with a presumptive diagnosis of EFT using molecular techniques and IHC. We found five distinct types of EWSR1-FLI1 fusion transcripts resulting from translocation t(11;22), three types of EWSR1-ERG transcripts resulting from t(21;22), and one type of t(2;22) resulting in EWSR1-FEV fusion. Molecular investigation validated 92% of cases ultimately diagnosed as EFT; IHC validated 76% of the cases. Thus, despite the difficulties and limitations associated with both molecular and IHC analysis on fresh and formalin-fixed, paraffin-embedded tissue, a combination of these techniques is the best approach to enhancing the accuracy of EFT diagnosis. We also present our method for choosing which molecular techniques to apply. Finally, we collected the most prevalent breakpoints reported in the literature, indicating which exons are involved, the sequence breakpoints, and the NCBI reference sequences.
Epidemiological studies show that approximately 20-30% of chronic smokers develop chronic obstructive pulmonary disease (COPD) while 10-15% develop lung cancer. COPD pre-exists lung cancer in 50-90% of cases and has a heritability of 40-77%, much greater than for lung cancer with heritability of 15-25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400) subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV(1), appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV(1) is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the "risk genotypes" derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70). We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.
Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is negatively regulated by 5-HT1A autoreceptors on raphe neurons, and is implicated in mood disorders. Pet-1/FEV is an ETS transcription factor expressed exclusively in serotonergic neurons and is essential for serotonergic differentiation, although its regulation of 5-HT receptors has not yet been studied. Here, we show by electrophoretic mobility shift assay that recombinant human Pet-1/FEV binds directly to multiple Pet-1 elements of the human 5-HT1A receptor promoter to enhance its transcriptional activity. In luciferase reporter assays, mutational analysis indicated that while several sites contribute, the Pet-1 site at -1406 bp had the greatest effect on 5-HT1A promoter activity. To address the effect of Pet-1 on 5-HT1A receptor regulation in vivo, we compared the expression of 5-HT1A receptor RNA and protein in Pet-1 null and wild-type littermate mice. In the raphe nuclei of Pet-1-/- mice tryptophan hydroxylase 2 (TPH2) RNA, and 5-HT and TPH immunostaining were greatly reduced, indicating a deficit in 5-HT production. Raphe 5-HT1A RNA and protein levels were also reduced in Pet-1-deficient mice, consistent with an absence of Pet-1-mediated transcriptional enhancement of 5-HT1A autoreceptors in serotonergic neurons. Interestingly, 5-HT1A receptor expression was up-regulated in the hippocampus, but down-regulated in the striatum and cortex. These data indicate that, in addition to transcriptional regulation by Pet-1 in raphe neurons, 5-HT1A receptor expression is regulated indirectly by alterations in 5-HT neurotransmission in a region-specific manner that together may contribute to the aggressive/anxiety phenotype observed in Pet-1 null mice.
RATIONALE: Lymphangioleiomyomatosis, a cystic lung disease of women, is characterized by proliferation of smooth muscle-like lymphangioleiomyomatosis cells, which possess mutations in the tuberous sclerosis complex genes, TSC1/TSC2. Growth factors involved in lymphangioleiomyomatosis cell proliferation are unknown. Prolactin, an important reproductive hormone in women, is known to promote cell proliferation and survival in other tissues.
OBJECTIVES: To determine the role of prolactin in signaling and proliferation in lymphangioleiomyomatosis.
METHODS: Prolactin levels in the sera of patients with lymphangioleiomyomatosis were correlated with clinical status. Components of prolactin signal transduction pathways were assessed in lymphangioleiomyomatosis lesions from human lung explants by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Prolactin effects on proliferation and signaling were quantified in tuberin-deficient and tuberin-expressing rat cells in vitro.
MEASUREMENTS AND MAIN RESULTS: Higher prolactin levels in the sera of patients with lymphangioleiomyomatosis were associated with a faster rate of decline in FEV(1) and an increased history of pneumothorax (P < 0.01). Higher levels of prolactin and prolactin receptor mRNA and immunoreactivity were found in lymphangioleiomyomatosis lesions when compared with vascular smooth muscle cells in the same region of tissue. This was accompanied by evidence of activation of signal transducer and activator of transcription-1 (STAT1), STAT3, p44/42, and p38 mitogen-activated protein kinase. Tsc2(-/-) Eker rat embryonic fibroblasts expressed more prolactin receptor than did Tsc2(+/+) cells, and responded to prolactin with increased proliferation and activation of the same signaling pathways seen in vivo.
CONCLUSIONS: Prolactin may be an important growth factor in the pathogenesis of lymphangioleiomyomatosis.
Berg T, Kalsaas AH, Buechner J, Busund LTEwing sarcoma-peripheral neuroectodermal tumor of the kidney with a FUS-ERG fusion transcript.
Cancer Genet Cytogenet. 2009; 194(1):53-7 [PubMed
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The Ewing family of tumors (EFTs) represents a neoplastic entity characterized by specific chromosomal rearrangements. The most commonly detected translocation involves fusion of EWSR1 to one of the genes encoding ETS family of transcription factors, usually FLI1 or ERG. In rare cases, FUS or FEV has been shown to substitute for EWSR1. The detection of specific translocations by fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), or both has become a diagnostic hallmark for the EFTs. We report here a case of small round blue cell tumor detected in the kidney of a 3-year-old girl. The use of FISH in combination with RT-PCR led to identification of a novel FUS-ERG fusion transcript in the tumor, with FUS exons 1-5 fused in-frame to ERG exons 6-9. The results from the molecular analyses were critical for reaching a final diagnostic conclusion of Ewing tumor-peripheral neuroectodermal tumor and hence had important therapeutic implications for the patient.
Asami S, Chin M, Shichino H, et al.Treatment of Ewing's sarcoma using an antisense oligodeoxynucleotide to regulate the cell cycle.
Biol Pharm Bull. 2008; 31(3):391-4 [PubMed
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Ewing's sarcoma (ES) is one of the most malignant tumors of bone and soft tissue in children and young adults. ES belongs to a group of small round cell tumors (SRCTs) that also includes neuroblastoma, rhabdomyosarcoma, and malignant lymphoma. However, ES exhibits several specific chimeric genes (EWS-FLI1, EWS-ERG, EWS-ETV1, EWS-E1AF, and EWS-FEV) caused by chromosomal translocations that are not shared by other SRCTs. These chimeric genes regulate the expression of various other genes; that is, they activate inhibitors of DNA binding 2 (Id2) gene expression or they suppress transforming growth factor beta II (TbetaRII) receptor gene expression. The regulation of these chimeric genes may affect critical cell signal transductions, such as signals involved in cell cycle and apoptosis in ES tumor cells. Using an antisense oligodeoxynucleotide against a sequence containing the ATG initiation codon of the EWS-FLI1 chimeric gene that specifically reacts with the EWS-FLI1 and EWS-ERG chimeric genes, we were able to regulate the cell cycle through the down-regulation of Id2. Here, we report that treatment with an antisense oligodeoxynucleotide against this chimeric gene was very useful for inducing the regression of ES tumor growth; thus, this chimeric gene may be an important target for the treatment of ES patients.
Duerr EM, Mizukami Y, Ng A, et al.Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis.
Endocr Relat Cancer. 2008; 15(1):243-56 [PubMed
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Current classifications of human gastroenteropancreatic neuroendocrine tumors (NETs) are inconsistent and based upon histopathologic but not molecular features. We sought to compare a molecular classification with the World Health Organization (WHO) histologic classification, identify genes that may be important for tumor progression, and determine whether gastrointestinal NETs (GI-NETs) differ in their molecular profile from pancreatic NETs (PNETs). DNA microarray analysis was performed to identify differentially expressed genes in PNETs and GI-NETs. Confirmation of expression levels was obtained by quantitative real-time PCR. Immunoblotting and mutational analysis were performed for selected genes. Hierarchical clustering of 19 PNETs revealed a 'benign' and 'malignant' cluster that corresponded well with the WHO categories of well-differentiated endocrine tumor (WDET) and well-differentiated endocrine carcinoma (WDEC) respectively. FEV, adenylate cyclase 2 (ADCY2), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and growth arrest and DNA-damage-inducible, beta (GADD45b) were the most highly up-regulated genes in the malignant group of PNETs. Platelet-derived growth factor receptor (PDGFR) was expressed in both WDETs and WDECs, and phosphorylation of PDGFR-beta was observed in 83% of all PNETs. Malignant ileal GI-NETs exhibited a distinctive gene expression profile, and extracellular matrix protein 1 (ECM), vesicular monoamine member 1 (VMAT1), galectin 4 (LGALS4), and RET Proto-oncogene (RET) were highly up-regulated genes. Gene expression profiles reflect the current WHO classification and can distinguish benign from malignant PNETs and also PNETs from GI-NETs. This suggests that molecular profiling may enhance tumor classification schemes. Potential gene targets have also been identified, and PDGFR and RET are candidates that may represent novel therapeutic targets.
Colice GL, Shafazand S, Griffin JP, et al.Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition).
Chest. 2007; 132(3 Suppl):161S-77S [PubMed
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BACKGROUND: This section of the guidelines is intended to provide an evidence-based approach to the preoperative physiologic assessment of a patient being considered for surgical resection of lung cancer.
METHODS: Current guidelines and medical literature applicable to this issue were identified by computerized search and evaluated using standardized methods. Recommendations were framed using the approach described by the Health and Science Policy Committee.
RESULTS: The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV(1). If diffuse parenchymal lung disease is evident on radiographic studies or if there is dyspnea on exertion that is clinically out of proportion to the FEV(1), the diffusing capacity of the lung for carbon monoxide (Dlco) should also be measured. In patients with either an FEV(1) or Dlco < 80% predicted, the likely postoperative pulmonary reserve should be estimated by either the perfusion scan method for pneumonectomy or the anatomic method, based on counting the number of segments to be removed, for lobectomy. An estimated postoperative FEV(1) or Dlco < 40% predicted indicates an increased risk for perioperative complications, including death, from a standard lung cancer resection (lobectomy or greater removal of lung tissue). Cardiopulmonary exercise testing (CPET) to measure maximal oxygen consumption (Vo(2)max) should be performed to further define the perioperative risk of surgery; a Vo(2)max of < 15 mL/kg/min indicates an increased risk of perioperative complications. Alternative types of exercise testing, such as stair climbing, the shuttle walk, and the 6-min walk, should be considered if CPET is not available. Although often not performed in a standardized manner, patients who cannot climb one flight of stairs are expected to have a Vo(2)max of < 10 mL/kg/min. Data on the shuttle walk and 6-min walk are limited, but patients who cannot complete 25 shuttles on two occasions will likely have a Vo(2)max of < 10 mL/kg/min. Desaturation during an exercise test has not clearly been associated with an increased risk for perioperative complications. Lung volume reduction surgery (LVRS) improves survival in selected patients with severe emphysema. Accumulating experience suggests that patients with extremely poor lung function who are deemed inoperable by conventional criteria might tolerate combined LVRS and curative-intent resection of lung cancer with an acceptable mortality rate and good postoperative outcomes. Combining LVRS and lung cancer resection should be considered in patients with a cancer in an area of upper lobe emphysema, an FEV(1) of > 20% predicted, and a Dlco of > 20% predicted.
CONCLUSIONS: A careful preoperative physiologic assessment will be useful to identify those patients who are at increased risk with standard lung cancer resection and to enable an informed decision by the patient about the appropriate therapeutic approach to treating their lung cancer. This preoperative risk assessment must be placed in the context that surgery for early-stage lung cancer is the most effective currently available treatment for this disease.
Severe alpha(1)-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV(1)) and the ratio of FEV(1)/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV(1) = 50 percent predicted. Six of 11 single-nucleotide polymorphisms (SNPs) in IL10 (P = 0.0005-0.05) and 3 of 5 SNPs in TNF (P = 0.01-0.05) were associated with FEV(1) and/or FEV(1)/FVC. IL10 SNPs also demonstrated association with the qualitative COPD phenotype. When phenotypes of individuals with a physician's diagnosis of asthma were excluded, IL10 SNPs remained significantly associated, suggesting that the association with airflow obstruction was independent of an association with asthma. Haplotype analysis of IL10 SNPs suggested the strongest association with IL10 promoter SNPs. IL10 is likely an important modifier gene for the development of COPD in individuals with severe AAT deficiency.
Wang L, Bhargava R, Zheng T, et al.Undifferentiated small round cell sarcomas with rare EWS gene fusions: identification of a novel EWS-SP3 fusion and of additional cases with the EWS-ETV1 and EWS-FEV fusions.
J Mol Diagn. 2007; 9(4):498-509 [PubMed
] Free Access to Full Article Related Publications
Ewing family tumors (EFTs) are prototypical primitive small round blue cell sarcomas arising in bone or extraskeletal soft tissues in children or adolescents. EFTs show fusions of EWS with a gene of the ETS family of transcription factors, either EWS-FLI1 (90 to 95%) or EWS-ERG (5 to 10%). Rare cases with fusions of EWS to other ETS family genes, such as ETV1, E1AF, and FEV, have been identified, but their clinicopathological similarity to classic EFTs remains unclear. We report four new cases of EFT-like tumors with rare EWS fusions, including two with EWS-ETV1, one with EWS-FEV, and a fourth case in which we cloned a novel EWS-SP3 fusion, the first known cancer gene fusion involving a gene of the Sp zinc finger family. Analysis of these three new cases along with data on nine previously reported cases with fusions of EWS to ETV1, E1AF, or FEV suggest a strong predilection for extraskeletal primary sites. EFT-like cases with fusions of EWS to non-ETS translocation partners are also uncommon but involve the same amino-terminal portion of EWS, which in our novel EWS-SP3 fusion is joined to the SP3 zinc-finger DNA-binding domain. As these data further support, these types of EWS fusions are associated with primitive extraskeletal small round cell sarcomas of uncertain lineage arising mainly in the pediatric population.
Bria E, Cuppone F, Fornier M, et al.Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: the dark side of the moon? A meta-analysis of the randomized trials.
Breast Cancer Res Treat. 2008; 109(2):231-9 [PubMed
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BACKGROUND: In five randomized clinical trials (RCTs), adjuvant trastuzumab (T) for early stage breast cancer with human epidermal growth-factor receptor-2 over-expression/gene-amplification has shown to decrease the risk of both recurrence and death. The issue regarding the long-term safety profile of such drug is still open; in particular, questions remain about long-term cardiotoxicity, and specific patterns of relapse such as brain metastases (BM). In order to quantify the magnitude of these two risks, and then balance those with the survival outcome, a literature-based meta-analysis was performed.
METHODS: All phase III trials were considered eligible. A literature-based meta-analysis was accomplished, and event-based relative risk ratios with 95% confidence interval were derived. A fixed- and a random-effect model according to the inverse variance and the Mantel-Haenzel method were applied. Heterogeneity test was applied as well. Absolute differences (AD) and the Number of patients Needed to Treat or to Harm (NNT/NNH) were calculated. Safety end-points were: (1) Chronic Heart Failure (CHF) grade III-IV rate, (2) Significant reduction of left-ventricular-ejection-fraction (L-FEV) rate and (3) BM rate. In order to quantify the magnitude of the significant benefit already found in the original RCTs, Efficacy end-points were: (1) disease-free survival (DFS) and (2) overall survival (OS).
RESULTS: Five RCTs were gathered (11,187 patients); at an average 2-years follow-up, all data was available for the safety and efficacy end-points, while three RCTs reported results for BM analysis (6,738 patients). When considering RCTs with trastuzumab administered for 1 year, a significant increased risk of grade III-IV Congestive Heart Failure (CHF) was found in the T-arm, with an AD of 1.61% (p < 0.00001), which translates into 62 treated patients required to harm one (NNH). When considering the asymptomatic L-FEV reduction, a significant increased risk of grade significant L-FEV reduction was found in the T-arm, although significantly heterogeneous, with an AD of 7.20% (p < 0.00001), which translates into 14 NNH. The incidence of BM was significantly higher in the T-arm, without significant heterogeneity, with an AD of 0.62 (p = 0.033), which translates into 161 NNH. The DFS, DDFS, and OS were significantly better in the T-arm, with an AD of 6.00, 4.80 and 1.96%, which translates into 16, 21 and 51 NNT, respectively.
CONCLUSIONS: The overall outcome results show that trastuzumab is one of the most important discoveries in oncology. Nevertheless, the biological activity of trastuzumab needs to be investigated more extensively to explore both long-term safety and specific relapse patterns.
Ewing family tumors are molecularly characterized by expression of chimeric transcripts generated by specific chromosomal translocations, most commonly involving fusion of the EWS gene to a member of the ETS family of transcription factors (including FLI1, ERG, ETV1, E1AF, and FEV). Approximately 85% of reported cases of Ewing sarcoma bear an EWS-FLI1 fusion. In rare cases, FUS can substitute for EWS, with translocation t(16;21)(p11;q24) producing a FUS-ERG fusion with no EWS rearrangement. We report a case of Ewing sarcoma, presenting as a pathological fracture of the distal clavicle in a 33-year-old male, in which cytogenetic analysis revealed a single t(2;16)(q35;p11) balanced translocation. Fluorescence in situ hybridization using a commercially available diagnostic probe was negative for an EWS gene rearrangement; instead, break-apart fluorescence in situ hybridization probes for FUS and FEV were positive for a translocation involving these genes. Cloning and sequencing of the breakpoint region demonstrated an in-frame fusion of FUS to FEV. In conclusion, this represents the first reported case of Ewing family tumors demonstrating a variant translocation involving FUS and FEV and highlights the need to consider alternative permutations of fusion partners for molecular diagnosis of sarcomas.
Steagall WK, Glasgow CG, Hathaway OM, et al.Genetic and morphologic determinants of pneumothorax in lymphangioleiomyomatosis.
Am J Physiol Lung Cell Mol Physiol. 2007; 293(3):L800-8 [PubMed
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Lymphangioleiomyomatosis, a multisystem disease affecting women, is characterized by proliferation of abnormal smooth muscle-like cells in the lungs, leading to cystic destruction of the parenchyma and recurrent pneumothoraces. Clinical characteristics of lymphangioleiomyomatosis patients were analyzed to determine the relationship of pneumothoraces to disease progression. Patients were genotyped for polymorphisms in genes of extracellular matrix proteins collagen, elastin, and matrix metalloproteinase-1 to assess their association with pneumothoraces. Clinical data and polymorphisms in the genes for types I and III collagen, elastin, and matrix metalloproteinase-1 were compared with the prevalence of pneumothorax. Of 227 patients, 57% reported having had at least one pneumothorax. Cyst size on high-resolution computed tomography scans was associated with pneumothorax; patients with a history of pneumothorax were more likely to have larger cysts than patients who had no pneumothoraces. In patients with mild disease, those with a history of pneumothorax had a faster rate of decline in forced expiratory volume in 1 s (FEV(1); P = 0.001, adjusted for age) than those without. Genotype frequencies differed between patients with and without pneumothorax for polymorphisms in the types I and III collagen and matrix metalloproteinase-1 genes. Larger cysts may predispose lymphangioleiomyomatosis patients to pneumothorax, which, in early stages of disease, correlates with a more rapid rate of decline in FEV(1). Polymorphisms in types I and III collagen and matrix metalloproteinase-1 genes may cause differences in lung extracellular matrix that result in greater susceptibility to pneumothorax.
Szuhai K, Ijszenga M, Tanke HJ, et al.Molecular cytogenetic characterization of four previously established and two newly established Ewing sarcoma cell lines.
Cancer Genet Cytogenet. 2006; 166(2):173-9 [PubMed
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Most Ewing family tumors are identified by the characteristic translocation t(11;22)(q24;q12), resulting in a fusion protein EWS/FLI1 that acts as an aberrant transcription factor. In a minority of cases, the EWS gene is fused to another member of the ETS gene (ERG, ETV1, E1AF, and FEV). Though the oncogenic transforming capability of the EWS/FLI1 protein is highly suggestive, the exact pathway behind remains to be elucidated. The availability of cell lines may help in the understanding of underlying cellular processes. In this study, we have established two new Ewing sarcoma cell lines and characterized them with molecular cytogenetic tools. This technology was also applied on four other previously published Ewing sarcoma cell lines. Our findings in relation to previous data on similar tumors are discussed.
Jacobs AH, Li H, Winkeler A, et al.PET-based molecular imaging in neuroscience.
Eur J Nucl Med Mol Imaging. 2003; 30(7):1051-65 [PubMed
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Positron emission tomography (PET) allows non-invasive assessment of physiological, metabolic and molecular processes in humans and animals in vivo. Advances in detector technology have led to a considerable improvement in the spatial resolution of PET (1-2 mm), enabling for the first time investigations in small experimental animals such as mice. With the developments in radiochemistry and tracer technology, a variety of endogenously expressed and exogenously introduced genes can be analysed by PET. This opens up the exciting and rapidly evolving field of molecular imaging, aiming at the non-invasive localisation of a biological process of interest in normal and diseased cells in animal models and humans in vivo. The main and most intriguing advantage of molecular imaging is the kinetic analysis of a given molecular event in the same experimental subject over time. This will allow non-invasive characterisation and "phenotyping" of animal models of human disease at various disease stages, under certain pathophysiological stimuli and after therapeutic intervention. The potential broad applications of imaging molecular events in vivo lie in the study of cell biology, biochemistry, gene/protein function and regulation, signal transduction, transcriptional regulation and characterisation of transgenic animals. Most importantly, molecular imaging will have great implications for the identification of potential molecular therapeutic targets, in the development of new treatment strategies, and in their successful implementation into clinical application. Here, the potential impact of molecular imaging by PET in applications in neuroscience research with a special focus on neurodegeneration and neuro-oncology is reviewed.
Yoshino N, Kojima T, Asami S, et al.Diagnostic significance and clinical applications of chimeric genes in Ewing's sarcoma.
Biol Pharm Bull. 2003; 26(5):585-8 [PubMed
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Ewing's sarcoma (ES) is one of the most malignant bone and soft tissue tumors in childhood. Morphologically, ES belongs to the small round cell tumors (SRCT). ES, peripheral primitive neuroectodermal tumor (PNET), and Askin's tumor are classified as ES family tumors (ESFT) because they share a common chromosomal translocation. The EWS-FLI1 chimeric gene is generated by t (11; 22). Other reciprocal translocations resulting in formation of chimeric genes between EWS and ETS family genes (ERG, ETV1, E1AF, and FEV) are t (21; 22), t (7; 22), t (17; 22), and t (2; 22), respectively. Although it is generally difficult to distinguish ES from SRCT, we could easily and quickly distinguish ES from other SRCT by using reverse transcription polymerase chain reaction (RT-PCR). We looked for specific chimeric genes in 23 tumor samples, including three ES clinical samples. We detected five chimeric genes in the three ES samples. Three chimeric genes, all EWS-FLI1, were detected in one ES sample. Different chimeric genes, EWS-ERG and EWS-ETV1, were detected in the other two ES samples. Moreover, because we could not detect specific chimeric genes in samples from non-ESFT, it may be possible to use this technique to diagnose ESFT and to detect tumor cell contamination before hematopoietic stem cell transplantation.
Kojima T, Asami S, Chin M, et al.Detection of chimeric genes in Ewing's sarcoma and its clinical applications.
Biol Pharm Bull. 2002; 25(8):991-4 [PubMed
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Ewing's sarcoma (ES), most commonly an undifferentiated tumor of bone, belongs to the enigmatic diagnostic category of small round cell tumors (SRCT) of childhood. The consistent presence of the translocation t (11; 22) in the vast majority of tumors provides evidence for a common histogenesis in ES and its family of tumors (ESFT), and also provides a unique diagnostic characteristic to discriminate this tumor family from SRCT. Molecular analysis of this translocation has revealed that it forms a chimeric gene between EWS on chromosome 22 and FLI-1 on chromosome 11. Similarly, the variant t (21; 22), t (7; 22), t (17; 22), and t (2; 22) rearrangements also form chimeric genes between regions of EWS and the ETS gene family (ERG, ETV1, E1AF, and FEV). Detection of these specific chimeric genes would provide a method for diagnosis of ESFT. We have developed a procedure for simultaneous detection of the chimeric genes by reverse transcription polymerase chain reaction (RT-PCR) with a mixture of primers. We conclude that the detecting those chimeric genes by this method can be easy and useful for diagnosis of ESFT. Moreover, by defining the specific chimeric gene it is possible to detect the tumor cell contamination in autologous blood stem cell transplantation.
Navarro S, Noguera R, Pellín A, et al.Atypical pleomorphic extraosseous ewing tumor/peripheral primitive neuroectodermal tumor with unusual phenotypic/genotypic profile.
Diagn Mol Pathol. 2002; 11(1):9-15 [PubMed
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A pleomorphic undifferentiated tumor primarily located in the retroperitoneum with a phenotype compatible with an extraosseous Ewing tumor/peripheral primitive neuroectodermal tumor (ET/pPNET) pattern and unusual molecular features is described. Immunohistochemically, HBA-71 (CD99/mic2) and several neural markers were intensively expressed together with scattered cells expressing carcinoembryonic antigen (CEA). Short-term culture showed biphasic neuroblastic and epithelioid cell populations, with the latter expressing germ cell markers (CEA, alpha-fetoprotein, and the beta-subunit of chorionic gonadotrophin). Conventional cytogenetics displayed several chromosomic rearrangements, especially a complex translocation t(17,2,22,13) (q21::q11-->q33::q12-->q13::q14). These structural abnormalities were confirmed using fluorescence in situ hybridization analysis. Molecular studies revealed EWS-FEV fusion transcripts (exon 7 of the EWS gene and exon 2 of the FEV gene). In addition, a new p53 mutation not previously reported in ET/pPNET involving exon 5 codon 138: GCC to GAC (Ala/Asp) was detected. In our case, we emphasize the presence of atypical features not only from the phenotypic point of view but also at the genetic level as well as the value of detecting such markers in the differential diagnosis with other abdominal pleomorphic tumors.
Llombart-Bosch A, Pellín A, Carda C, et al.Soft tissue Ewing sarcoma--peripheral primitive neuroectodermal tumor with atypical clear cell pattern shows a new type of EWS-FEV fusion transcript.
Diagn Mol Pathol. 2000; 9(3):137-44 [PubMed
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This study describes a new case of Ewing sarcoma (ES)-peripheral primitive neuroectodermal tumor (pPNET) with unusual phenotype and fusion gene structure. The tumor located in the inguinal area of a 15-year-old boy showed a highly aggressive behavior with hematogenous metastases after intensive chemotherapy and bone marrow transplant, causing death 28 months after diagnosis. The tumor displayed a clear cell pattern, and several neuroectodermal markers proved positive both in the original tumor and in xenografts. This neuroectodermal character was confirmed by electron microscopy. Moreover, cytogenetically the tumor has an unusual chromosomal rearrangement, t(2;22)(q13;q22,t(3;18)(p21;q23); representing a new EWS-FEV fusion type in which exon 7 of EWS gene is fused with exon 2 of FEV gene. This is the third published study of an ES-pPNET showing EWS-FEV fusion described, but it is the first study of a tumor with the aforementioned fusion points. These findings support the genetic and morphologic heterogeneity existing within the group of ES-pPNET tumors.
Mastrangelo T, Modena P, Tornielli S, et al.A novel zinc finger gene is fused to EWS in small round cell tumor.
Oncogene. 2000; 19(33):3799-804 [PubMed
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Ewing sarcoma family of tumors share recurrent translocations that fuse EWS from 22q12 to five different members of transcription factors namely FLI-1, ERG, ETV1, E1AF and FEV. Different classes of DNA binding proteins, ATF1, WT1 and CHOP are fused to EWS generating distinct tumor phenotypes: clear cell sarcoma, desmoplastic small round cell tumor, and myxoid liposarcoma, respectively. We have cloned a novel gene located at 22q12 fused to EWS by a submicroscopic inversion of 22q in a small round cell sarcoma showing a translocation (t(1;22)(p36.1;q12). The gene, designated ZSG (Zinc finger Sarcoma Gene), is a putative Cys2-His2 zinc finger protein which contains a POZ transcriptional repressor-like domain at the N-terminus. The rearrangement involves intron 8 of EWS and exon 1 of ZSG creating a chimeric sequence containing the transactivation domain of EWS fused to zinc finger domain of ZSG. This product lacks the transcriptional repressor domain at the N-terminus of ZSG. A rearrangement of the second ZSG allele was also found in tumor cells. This is the first example of an intra-chromosomal rearrangement of chromosome 22, undetectable by cytogenetics, activating EWS in soft tissue sarcoma.
Im YH, Kim HT, Lee C, et al.EWS-FLI1, EWS-ERG, and EWS-ETV1 oncoproteins of Ewing tumor family all suppress transcription of transforming growth factor beta type II receptor gene.
Cancer Res. 2000; 60(6):1536-40 [PubMed
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Ewing sarcoma-specific chromosomal translocations fuse the EWS gene to a subset of ets transcription factor family members, most commonly the FLI1 gene and less frequently ERG, ETV1, E1A-F, or FEV. These fusion proteins are thought to act as aberrant transcription factors that bind DNA through their ets DNA binding domain. Recently, we have shown (K-B. Hahm et al., Nat. Genet., 23: 222-227, 1999) that the transforming growth factor beta (TGF-beta) type II receptor (TGF-beta RII), a putative tumor suppressor gene, is a target of the EWS-FLI1 fusion protein. Here, we also examined effects of EWS-ETV1 and EWS-ERG on expression of the TGF-beta RII gene. We show that relative to the control, NIH-3T3 cell lines stably transfected with the EWS-FLI1, EWS-ERG, or EWS-ETV1 gene fusion express reduced levels of TGF-beta RII mRNA and protein, and that these cell lines have reduced TGF-beta sensitivity. Cotransfection of these fusion genes and the TGF-beta RII promoter suppresses TGF-beta RII promoter activity and also FLI1-, ERG-, or ETV1-induced promoter activity. These results indicate that transcriptional repression of TGF-beta RII is an important target of the EWS-FLI1, EWS-ERG, or EWS-ETV1 oncogene, and that EWS-ets fusion proteins may function as dominant negative forms of ets transcription factors.
Esthesioneuroblastoma (ENB) is a rare, site-specific, locally aggressive neuronal malignancy so far thought to belong to primitive peripheral neuroectodermal tumour-Ewing's tumour (pPNETs-ETs). Its anatomical location, in addition to morphologic, immunophenotypic and ultrastructural features, suggests its origin in the neuronal or neuroendocrine cells of the olfactory epithelium. However, the cytogenetic and molecular data currently available appear controversial on the presence of the typical translocation t(11;22)(q24;q12) and of trisomy 8, chromosomal changes that characterize the tumours belonging to the pPNETs-ETs. Herein we have analysed five ENB tumour specimens for trisomy 8 by fluorescence in situ hybridization (FISH), for the presence of EWS gene rearrangements by FISH, reverse transcription polymerase chain reaction and Southern blot analyses, as well as for the expression of the Ewing sarcoma-associated MIC2 antigen by immunohistochemistry. Neither EWS/FLI-I, EWS/ERG and EWS/FEV fusion genes nor MIC2 expression were found in any tumour, whereas trisomy 8 was found in one case only. Moreover, DNA from three cases analysed by Southern blot did not show EWS gene rearrangements. Our results support the evidence that ENB is not a member of the pPNETs-ETs.
Ewing's sarcoma, one of the most malignant tumors of children and young adults, expresses specific chimeric genes, e.g. EWS-FLI-1, EWS-ERG, EWS-ETV1 and EWS-FEV. In this paper, we extensively characterized a new fusion gene, EWS-EIAF by means of whole cDNA sequencing, RNA blot analysis, DNA blot analysis and chromosomal analysis, and showed it to be available for the diagnosis of Ewing's sarcoma and to participate in the oncogenesis of Ewing's sarcoma. Furthermore, we conducted a genetic analysis of Ewing family tumors in conjunction with immunohistochemical analysis and ultrastructural analysis. Our results demonstrate some limitations of both genetic analysis and histopathological analysis, and establish the relationship between neurogenic phenotypes and chimera genes.