Research IndicatorsGraph generated 13 March 2017 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 13 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
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: STAG2 (cancer-related)
Ibáñez M, Carbonell-Caballero J, García-Alonso L, et al.The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.
PLoS One. 2016; 11(2):e0148346 [PubMed
] Free Access to Full Article Related Publications
Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.
Somatic mutations of the cohesin complex subunit STAG2 are present in diverse tumor types. We and others have shown that STAG2 inactivation can lead to loss of sister chromatid cohesion and alterations in chromosome copy number in experimental systems. However, studies of naturally occurring human tumors have demonstrated little, if any, correlation between STAG2 mutational status and aneuploidy, and have further shown that STAG2-deficient tumors are often euploid. In an effort to provide insight into these discrepancies, here we analyze the effect of tumor-derived STAG2 mutations on the protein composition of cohesin and the expected mitotic phenotypes of STAG2 mutation. We find that many mutant STAG2 proteins retain their ability to interact with cohesin; however, the presence of mutant STAG2 resulted in a reduction in the ability of regulatory subunits WAPL, PDS5A, and PDS5B to interact with the core cohesin ring. Using AAV-mediated gene targeting, we then introduced nine tumor-derived mutations into the endogenous allele of STAG2 in cultured human cells. While all nonsense mutations led to defects in sister chromatid cohesion and a subset induced anaphase defects, missense mutations behaved like wild-type in these assays. Furthermore, only one of nine tumor-derived mutations tested induced overt alterations in chromosome counts. These data indicate that not all tumor-derived STAG2 mutations confer defects in cohesion, chromosome segregation, and ploidy, suggesting that there are likely to be other functional effects of STAG2 inactivation in human cancer cells that are relevant to cancer pathogenesis.
BACKGROUND: Testicular embryonal carcinoma (EC) is a major subtype of non-seminomatous germ cell tumours in males. Embryonal carcinomas are pluripotent, undifferentiated germ cell tumours believed to originate from primordial germ cells. Epigenetic changes during testicular EC tumorigenesis require better elucidation.
METHODS: To identify epigenetic changes during testicular neoplastic transformation, we profiled DNA methylation of six ECs. These samples represent different stages (stage I and stage III) of divergent invasiveness. Non-cancerous testicular tissues were included. Expression of a number of hypermethylated genes were examined by quantitative RT-PCR and immunohistochemistry (IHC).
RESULTS: A total of 1167 tumour-hypermethylated differentially methylated regions (DMRs) were identified across the genome. Among them, 40 genes/ncRNAs were found to have hypermethylated promoters. Quantitative RT-PCR confirmed downregulation of 8 out of 9 of the genes. Among the confirmed genes, five were sex-linked genes, including X-linked genes STAG2, SPANXD/E and MIR1184, and Y-linked genes RBMY1A1/1B/1D and FAM197Y2P. RBMY1A is a testis-specific gene for spermatogenesis. RNF168 and USP13 are potential tumour suppressors. Expression of RBMY1A was lost in EC and seminoma as documented in the Protein Atlas. We confirmed downregulation of USP13 in EC by IHC.
CONCLUSIONS: Our genome-wide analysis of testicular EC identified methylation changes in several previously unknown genes. This may provide insight of crosstalk between normal germ cell development and carcinogenesis.
Menzies GE, Reed SH, Brancale A, Lewis PDBase damage, local sequence context and TP53 mutation hotspots: a molecular dynamics study of benzo[a]pyrene induced DNA distortion and mutability.
Nucleic Acids Res. 2015; 43(19):9133-46 [PubMed
] Free Access to Full Article Related Publications
The mutational pattern for the TP53 tumour suppressor gene in lung tumours differs to other cancer types by having a higher frequency of G:C>T:A transversions. The aetiology of this differing mutation pattern is still unknown. Benzo[a]pyrene,diol epoxide (BPDE) is a potent cigarette smoke carcinogen that forms guanine adducts at TP53 CpG mutation hotspot sites including codons 157, 158, 245, 248 and 273. We performed molecular modelling of BPDE-adducted TP53 duplex sequences to determine the degree of local distortion caused by adducts which could influence the ability of nucleotide excision repair. We show that BPDE adducted codon 157 has greater structural distortion than other TP53 G:C>T:A hotspot sites and that sequence context more distal to adjacent bases must influence local distortion. Using TP53 trinucleotide mutation signatures for lung cancer in smokers and non-smokers we further show that codons 157 and 273 have the highest mutation probability in smokers. Combining this information with adduct structural data we predict that G:C>T:A mutations at codon 157 in lung tumours of smokers are predominantly caused by BPDE. Our results provide insight into how different DNA sequence contexts show variability in DNA distortion at mutagen adduct sites that could compromise DNA repair at well characterized cancer related mutation hotspots.
Cancer development and progression result from somatic evolution by an accumulation of genomic alterations. The effects of those alterations on the fitness of somatic cells lead to evolutionary adaptations such as increased cell proliferation, angiogenesis, and altered anticancer drug responses. However, there are few general mathematical models to quantitatively examine how perturbations of a single gene shape subsequent evolution of the cancer genome. In this study, we proposed the gene gravity model to study the evolution of cancer genomes by incorporating the genome-wide transcription and somatic mutation profiles of ~3,000 tumors across 9 cancer types from The Cancer Genome Atlas into a broad gene network. We found that somatic mutations of a cancer driver gene may drive cancer genome evolution by inducing mutations in other genes. This functional consequence is often generated by the combined effect of genetic and epigenetic (e.g., chromatin regulation) alterations. By quantifying cancer genome evolution using the gene gravity model, we identified six putative cancer genes (AHNAK, COL11A1, DDX3X, FAT4, STAG2, and SYNE1). The tumor genomes harboring the nonsynonymous somatic mutations in these genes had a higher mutation density at the genome level compared to the wild-type groups. Furthermore, we provided statistical evidence that hypermutation of cancer driver genes on inactive X chromosomes is a general feature in female cancer genomes. In summary, this study sheds light on the functional consequences and evolutionary characteristics of somatic mutations during tumorigenesis by propelling adaptive cancer genome evolution, which would provide new perspectives for cancer research and therapeutics.
Agelopoulos K, Richter GH, Schmidt E, et al.Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma.
Clin Cancer Res. 2015; 21(21):4935-46 [PubMed
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PURPOSE: A low mutation rate seems to be a general feature of pediatric cancers, in particular in oncofusion gene-driven tumors. Genetically, Ewing sarcoma is defined by balanced chromosomal EWS/ETS translocations, which give rise to oncogenic chimeric proteins (EWS-ETS). Other contributing somatic mutations involved in disease development have only been observed at low frequency.
EXPERIMENTAL DESIGN: Tumor samples of 116 Ewing sarcoma patients were analyzed here. Whole-genome sequencing was performed on two patients with normal, primary, and relapsed tissue. Whole-exome sequencing was performed on 50 Ewing sarcoma and 22 matched normal tissues. A discovery dataset of 14 of these tumor/normal pairs identified 232 somatic mutations. Recurrent nonsynonymous mutations were validated in the 36 remaining exomes. Transcriptome analysis was performed in a subset of 14 of 50 Ewing sarcomas and DNA copy number gain and expression of FGFR1 in 63 of 116 Ewing sarcomas.
RESULTS: Relapsed tumors consistently showed a 2- to 3-fold increased number of mutations. We identified several recurrently mutated genes at low frequency (ANKRD30A, CCDC19, KIAA0319, KIAA1522, LAMB4, SLFN11, STAG2, TP53, UNC80, ZNF98). An oncogenic fibroblast growth factor receptor 1 (FGFR1) mutation (N546K) was detected, and the FGFR1 locus frequently showed copy number gain (31.7%) in primary tumors. Furthermore, high-level FGFR1 expression was noted as a characteristic feature of Ewing sarcoma. RNA interference of FGFR1 expression in Ewing sarcoma lines blocked proliferation and completely suppressed xenograft tumor growth. FGFR1 tyrosine kinase inhibitor (TKI) therapy in a patient with Ewing sarcoma relapse significantly reduced 18-FDG-PET activity.
CONCLUSIONS: FGFR1 may constitute a promising target for novel therapeutic approaches in Ewing sarcoma.
Stoepker C, Ameziane N, van der Lelij P, et al.Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer.
Cancer Res. 2015; 75(17):3543-53 [PubMed
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Failure to repair DNA damage or defective sister chromatid cohesion, a process essential for correct chromosome segregation, can be causative of chromosomal instability (CIN), which is a hallmark of many types of cancers. We investigated how frequent this occurs in head and neck squamous cell carcinoma (HNSCC) and whether specific mechanisms or genes could be linked to these phenotypes. The genomic instability syndrome Fanconi anemia is caused by mutations in any of at least 16 genes regulating DNA interstrand crosslink (ICL) repair. Since patients with Fanconi anemia have a high risk to develop HNSCC, we investigated whether and to which extent Fanconi anemia pathway inactivation underlies CIN in HNSCC of non-Fanconi anemia individuals. We observed ICL-induced chromosomal breakage in 9 of 17 (53%) HNSCC cell lines derived from patients without Fanconi anemia. In addition, defective sister chromatid cohesion was observed in five HNSCC cell lines. Inactivation of FANCM was responsible for chromosomal breakage in one cell line, whereas in two other cell lines, somatic mutations in PDS5A or STAG2 resulted in inadequate sister chromatid cohesion. In addition, FANCF methylation was found in one cell line by screening an additional panel of 39 HNSCC cell lines. Our data demonstrate that CIN in terms of ICL-induced chromosomal breakage and defective chromatid cohesion is frequently observed in HNSCC. Inactivation of known Fanconi anemia and chromatid cohesion genes does explain CIN in the minority of cases. These findings point to phenotypes that may be highly relevant in treatment response of HNSCC.
Li X, Zhang TW, Tang JL, et al.Loss of STAG2 causes aneuploidy in normal human bladder cells.
Genet Mol Res. 2015; 14(1):2638-46 [PubMed
] Related Publications
The aim of this study was to determine how the function of human stromal antigen 2 (STAG2) plays an important role in proper chromosome separation. STAG2 mRNA in normal bladder cells and bladder tumor cells was evaluated by RT-PCR. The protein levels of STAG2 in normal bladder cells and bladder tumor cells were determined by western blot. A cell proliferation assay was used to measure the growth of tumor cells and STAG2-inhibited normal cells, and STAG2- inhibited normal cells were subjected to karyotype analysis. Both STAG-2 mRNA and protein expression levels were lower in bladder cancer cells compared to the controls. Knockdown of STAG2 caused aneuploidy in normal bladder cells, leading to a decreased expression of the cohesin complex components SMC1, SMC3 and RAD21, but there was no obvious effect of STAG2 knockdown on cell proliferation. Our study indicated that abnormal expression of STAG2 could cause aneuploidy in normal bladder cells.
Kuroda K, Asakuma J, Asano T, et al.Clinical significance of p21-activated kinase 1 expression level in patients with upper urinary tract urothelial carcinoma.
Jpn J Clin Oncol. 2015; 45(1):103-10 [PubMed
] Related Publications
OBJECTIVE: The p21-activated kinase serine/threonine kinases have been outlined as the main cytoskeletal remolding regulators. The same holds true for cell proliferation and motility. They additionally have a part in cellular invasion and carcinogenesis, but the effect of p21-activated kinase 1 expression on the progression of upper urinary tract urothelial carcinoma remains unclear. Therefore, we assessed the relation of p21-activated kinase 1 positivity level to clinicopathological features in patients with upper urinary tract urothelial carcinoma.
METHODS: Immunohistochemical staining was performed using formalin-fixed and paraffin-embedded specimens, which were all from 124 patients with upper urinary tract urothelial carcinoma. The determination of staining level was based on the intensity of the staining along with portion of cells stained. Correlation of p21-activated kinase 1 positivity with clinicopathological parameters, including disease-specific or extravesical-recurrence-free survival, was evaluated.
RESULTS: Statistically significant association was observed between moderate or more than moderate p21-activated kinase 1 positivity and higher tumor grade, pathological T stage, lymphovascular invasion, history of adjuvant chemotherapy and extravesical recurrence. Positivity for p21-activated kinase 1 had a significant association with shortened disease-specific survival in a multivariate analysis among clinicopathological parameters. Strongly positive p21-activated kinase 1 expression was also one of the independent factors for shortened extravesical-recurrence-free survival time in N0M0 upper urinary tract urothelial carcinoma patients in another multivariate analysis as well as histology and lymphovascular invasion (P = 0.0304, hazard ratio = 4.425).
CONCLUSIONS: We conclude that our findings can help us continue a careful follow-up for upper urinary tract urothelial carcinoma patients with high p21-activated kinase 1 expression in surgical specimens.
Whiteland H, Spencer-Harty S, Morgan C, et al.A role for STEAP2 in prostate cancer progression.
Clin Exp Metastasis. 2014; 31(8):909-20 [PubMed
] Related Publications
Prostate adenocarcinoma is the second most frequent cancer worldwide and is one of the leading causes of male cancer-related deaths. However, it varies greatly in its behaviour, from indolent non-progressive disease to metastatic cancers with high associated mortality. The aim of this study was to identify predictive biomarkers for patients with localised prostate tumours most likely to progress to aggressive disease, to facilitate future tailored clinical treatment and identify novel therapeutic targets. The expression of 602 genes was profiled using oligoarrays, across three prostate cancer cell lines: CA-HPV-10, LNCaP and PC3, qualitatively identifying several potential prognostic biomarkers. Of particular interest was six transmembrane epithelial antigen of the prostate (STEAP) 1 and STEAP 2 which was subsequently analysed further in prostate cancer tissue samples following optimisation of an RNA extraction method from laser captured cells isolated from formalin-fixed paraffin-embedded biopsy samples. Quantitative analysis of STEAP1 and 2 gene expression were statistically significantly associated with the metastatic cell lines DU145 and PC3 as compared to the normal prostate epithelial cell line, PNT2. This expression pattern was also mirrored at the protein level in the cells. Furthermore, STEAP2 up-regulation was observed within a small patient cohort and was associated with those that had locally advanced disease. Subsequent mechanistic studies in the PNT2 cell line demonstrated that an over-expression of STEAP2 resulted in these normal prostate cells gaining an ability to migrate and invade, suggesting that STEAP2 expression may be a crucial molecule in driving the invasive ability of prostate cancer cells.
UNLABELLED: Ewing sarcoma is a primary bone tumor initiated by EWSR1-ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants, and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2-immunonegative cells in relapsed tumors as compared with matched diagnostic samples.
SIGNIFICANCE: Whole-genome sequencing reveals that the somatic mutation rate in Ewing sarcoma is low. Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies. Novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers.
Crompton BD, Stewart C, Taylor-Weiner A, et al.The genomic landscape of pediatric Ewing sarcoma.
Cancer Discov. 2014; 4(11):1326-41 [PubMed
] Related Publications
UNLABELLED: Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. In this study, we describe the somatic landscape of pediatric Ewing sarcoma. These tumors are among the most genetically normal cancers characterized to date, with only EWS-ETS rearrangements identified in the majority of tumors. STAG2 loss, however, is present in more than 15% of Ewing sarcoma tumors; occurs by point mutation, rearrangement, and likely nongenetic mechanisms; and is associated with disease dissemination. Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways, highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease.
SIGNIFICANCE: We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS-ETS fusions. We found remarkably few mutations. However, we discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing sarcoma.
The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.
Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n = 386), myeloproliferative neoplasms (MPNs) (n = 55), MDS/MPNs (n = 169), and AML (n = 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deep-sequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P = .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P = .017).
Cohesin is a multi-protein complex composed of four core subunits (SMC1A, SMC3, RAD21, and either STAG1 or STAG2) that is responsible for the cohesion of sister chromatids following DNA replication until its cleavage during mitosis thereby enabling faithful segregation of sister chromatids into two daughter cells. Recent cancer genomics analyses have discovered a high frequency of somatic mutations in the genes encoding the core cohesin subunits as well as cohesin regulatory factors (e.g. NIPBL, PDS5B, ESPL1) in a select subset of human tumors including glioblastoma, Ewing sarcoma, urothelial carcinoma, acute myeloid leukemia, and acute megakaryoblastic leukemia. Herein we review these studies including discussion of the functional significance of cohesin inactivation in tumorigenesis and potential therapeutic mechanisms to selectively target cancers harboring cohesin mutations.
Gomes CC, Bernardes VF, Odell EW, Gomez RSSTAG2 loss of expression is rare in aneuploid malignant salivary gland neoplasms.
J Oral Pathol Med. 2014; 43(4):273-5 [PubMed
] Related Publications
BACKGROUND: STAG2 depletion leads to loss of centromere cohesion in vitro, and some human neoplasms have been shown to lose expression of this protein. As a result, STAG2 loss has been shown to cause chromosomal instability and aneuploidy in human cancer cell lines.
METHODS: We tested the hypothesis that aneuploid salivary gland tumours lose immunoexpression of STAG2 compared with diploid tumours using image cytometry to determine DNA ploidy and immunohistochemistry to assess STAG2 protein expression in 30 malignant salivary gland neoplasms.
RESULTS: There was no difference in the immunoexpression of STAG2 between aneuploid (n = 9) and diploid (n = 21) samples. In all but two samples, more than 50% of cells stained for STAG2.
CONCLUSION: Aneuploidy in human salivary gland carcinomas is not driven by loss of expression of STAG2.
Recent data have identified STAG2, a core subunit of the multifunctional cohesin complex, as a highly recurrently mutated gene in several types of cancer. We sought to identify a therapeutic strategy to selectively target cancer cells harboring inactivating mutations of STAG2 using two independent pairs of isogenic glioblastoma cell lines containing either an endogenous mutant STAG2 allele or a wild-type STAG2 allele restored by homologous recombination. We find that mutations in STAG2 are associated with significantly increased sensitivity to inhibitors of the DNA repair enzyme PARP. STAG2-mutated, PARP-inhibited cells accumulated in G2 phase and had a higher percentage of micronuclei, fragmented nuclei, and chromatin bridges compared with wild-type STAG2 cells. We also observed more 53BP1 foci in STAG2-mutated glioblastoma cells, suggesting that these cells have defects in DNA repair. Furthermore, cells with mutations in STAG2 were more sensitive than cells with wild-type STAG2 when PARP inhibitors were used in combination with DNA-damaging agents. These data suggest that PARP is a potential target for tumors harboring inactivating mutations in STAG2, and strongly recommend that STAG2 status be determined and correlated with therapeutic response to PARP inhibitors, both prospectively and retrospectively, in clinical trials.
Thol F, Bollin R, Gehlhaar M, et al.Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications.
Blood. 2014; 123(6):914-20 [PubMed
] Related Publications
Mutations in the cohesin complex are novel, genetic lesions in acute myeloid leukemia (AML) that are not well characterized. In this study, we analyzed the frequency, clinical, and prognostic implications of mutations in STAG1, STAG2, SMC1A, SMC3, and RAD21, all members of the cohesin complex, in a cohort of 389 uniformly treated AML patients by next generation sequencing. We identified a total of 23 patients (5.9%) with somatic mutations in 1 of the cohesin genes. All gene mutations were mutually exclusive, and STAG1 (1.8%), STAG2 (1.3%), and SMC3 (1.3%) were most frequently mutated. Patients with any cohesin complex mutation had lower BAALC expression levels. We found a strong association between mutations affecting the cohesin complex and NPM1. Mutated allele frequencies were similar between NPM1 and cohesin gene mutations. Overall survival (OS), relapse-free survival (RFS), and complete remission rates (CR) were not influenced by the presence of cohesin mutations (OS: hazard ratio [HR] 0.98; 95% confidence interval [CI], 0.56-1.72 [P = .94]; RFS: HR 0.7; 95% CI, 0.36-1.38 [P = .3]; CR: mutated 83% vs wild-type 76% [P = .45]). The cohesin complex presents a novel pathway affected by recurrent mutations in AML. This study is registered at www.clinicaltrials.gov as #NCT00209833.
Myelodysplasia is a diagnostic feature of myelodysplastic syndromes (MDSs) but is also found in other myeloid neoplasms. Its molecular basis has been recently elucidated by means of massive parallel sequencing studies. About 90% of MDS patients carry ≥1 oncogenic mutations, and two thirds of them are found in individuals with a normal karyotype. Driver mutant genes include those of RNA splicing (SF3B1, SRSF2, U2AF1, and ZRSR2), DNA methylation (TET2, DNMT3A, and IDH1/2), chromatin modification (ASXL1 and EZH2), transcription regulation (RUNX1), DNA repair (TP53), signal transduction (CBL, NRAS, and KRAS), and cohesin complex (STAG2). Only 4 to 6 genes are consistently mutated in ≥10% MDS patients, whereas a long tail of ∼50 genes are mutated less frequently. At presentation, most patients typically have 2 or 3 driver oncogenic mutations and hundreds of background mutations. MDS driver genes are also frequently mutated in other myeloid neoplasms. Reliable genotype/phenotype relationships include the association of the SF3B1 mutation with refractory anemia with ring sideroblasts, TET2/SRSF2 comutation with chronic myelomonocytic leukemia, and activating CSF3R mutation with chronic neutrophilic leukemia. Although both founding and subclonal driver mutations have been shown to have prognostic significance, prospective clinical trials that include the molecular characterization of the patient's genome are now needed.
Guo G, Sun X, Chen C, et al.Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation.
Nat Genet. 2013; 45(12):1459-63 [PubMed
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Bladder cancer is one of the most common cancers worldwide, with transitional cell carcinoma (TCC) being the predominant form. Here we report a genomic analysis of TCC by both whole-genome and whole-exome sequencing of 99 individuals with TCC. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, we identified additional altered genes and pathways that were implicated in TCC. Notably, we discovered frequent alterations in STAG2 and ESPL1, two genes involved in the sister chromatid cohesion and segregation (SCCS) process. Furthermore, we also detected a recurrent fusion involving FGFR3 and TACC3, another component of SCCS, by transcriptome sequencing of 42 DNA-sequenced tumors. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the SCCS process. Our analysis provides evidence that genetic alterations affecting the SCCS process may be involved in bladder tumorigenesis and identifies a new therapeutic possibility for bladder cancer.
Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological and genetic levels. Tumor invasiveness (T) and grade (G) are the main factors associated with outcome and determine patient management. A discovery exome sequencing screen (n = 17), followed by a prevalence screen (n = 60), identified new genes mutated in this tumor coding for proteins involved in chromatin modification (MLL2, ASXL2 and BPTF), cell division (STAG2, SMC1A and SMC1B) and DNA repair (ATM, ERCC2 and FANCA). STAG2, a subunit of cohesin, was significantly and commonly mutated or lost in UBC, mainly in tumors of low stage or grade, and its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in non-expressing cells led to reduced colony formation. Our findings indicate that STAG2 is a new UBC tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy.
Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. These findings identify STAG2 as one of the most commonly mutated genes in bladder cancer.
BACKGROUND: Chromosomal instability is a hallmark of human cancer caused by errors in mitotic control and chromosome segregation. STAG2 encodes a subunit of the cohesion complex that participates in mitotic chromatid separation and was recently found to show low expression and inactivating mutations in Ewing's sarcoma, melanoma and glioblastoma.In the childhood tumor neuroblastoma (NB) segmental chromosomal alterations are associated with poor prognosis whereas tumors displaying whole chromosome gains and losses have a much better prognosis.
METHOD: As the genetic contribution to aneuploidy is unknown in NB, we investigated the presence of STAG2 mutations through sequence analysis of all 33 coding exons in 37 primary NB tumors.
RESULTS AND CONCLUSION: As no STAG2 mutation was detected in this study, we conclude that inactivating mutation of STAG2 is not likely causative to neuroblastoma aneuploidy.
Lung cancer has become the top killer among malignant tumors in China and is significantly associated with somatic genetic alterations. We performed exome sequencing of 14 non-small cell lung carcinomas (NSCLCs) with matched adjacent normal lung tissues extracted from Chinese patients. In addition to the lung cancer-related genes (TP53, EGFR, KRAS, PIK3CA, and ROS1), this study revealed "novel" genes not previously implicated in NSCLC. Especially, matrix-remodeling associated 5 was the second most frequently mutated gene in NSCLC (first is TP53). Subsequent Sanger sequencing of matrix-remodeling associated 5 in an additional sample set consisting of 52 paired tumor-normal DNA samples revealed that 15% of Chinese NSCLCs contained somatic mutations in matrix-remodeling associated 5. These findings, together with the results from pathway analysis, strongly indicate that altered extracellular matrix-remodeling may be involved in the etiology of NSCLC.
Kim MS, Kim SS, Je EM, et al.Mutational and expressional analyses of STAG2 gene in solid cancers.
Neoplasma. 2012; 59(5):524-9 [PubMed
] Related Publications
Aneuploidy is frequently observed in cancers and is considered a crucial mechanism in cancer development. STAG2 is a gene that encodes a component of cohesion complex required for normal chromosomal segregation. Recently, somatic mutation of STAG2 gene and loss of STAG2 protein have been reported in glioblastoma, Ewing's sarcoma and melanoma. The aim of this study was to see whether such alterations of STAG2 are also common in other cancers. In this study, we analyzed STAG2 somatic mutation in 45 colorectal carcinomas (CRC), 45 gastric carcinomas (GC), 45 breast carcinomas, 45 non-small cell lung cancers and 45 prostate carcinomas (PCA) by single-strand conformation polymorphism. We analyzed also STAG2 protein expression in 100 GC, 103 CRC and 107 PCA by immunohistochemistry. STAG2 protein was well expressed in normal stomach, colon and prostate epithelial cells, while it was lost in 27% of GC, 23% of CRC and 30% of PCA. The loss of STAG2 was observed irrespective of subtypes, stages and grades of the cancers. However, we could not find any STAG2 mutations in these cancers. The loss of expression of STAG2 in GC, CRC and PCA tissues compared to their corresponding normal cells indicates that STAG2 loss is common in carcinomas as well. The data suggest also that loss of expression of STAG2, but not somatic mutation, might be responsible to STAG2 inactivation and is common in studied types of carcinomas.
Cuadrado A, Remeseiro S, Gómez-López G, et al.The specific contributions of cohesin-SA1 to cohesion and gene expression: implications for cancer and development.
Cell Cycle. 2012; 11(12):2233-8 [PubMed
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Besides its well-established role in sister chromatid cohesion, cohesin has recently emerged as major player in the organization of interphase chromatin. Such important function is related to its ability to entrap two DNA segments also in cis, thereby facilitating long-range DNA looping which is crucial for transcriptional regulation, organization of replication factories and V(D)J recombination. Vertebrate somatic cells have two different versions of cohesin, containing Smc1, Smc3, Rad21/Scc1 and either SA1 or SA2, but their functional specificity has been largely ignored. We recently generated a knockout mouse model for the gene encoding SA1, and found that this protein is essential to complete embryonic development. Cohesin-SA1 mediates cohesion at telomeres, which is required for their replication. Telomere defects in SA1- deficient cells provoke chromosome segregation errors resulting in aneuploidy despite robust centromere cohesion. This aneuploidy could explain why heterozygous animals have an earlier onset of tumorigenesis. In addition, the genome-wide distribution of cohesin changes dramatically in the absence of SA1, and the complex shows reduced accumulation at promoters and CTCF sites. As a consequence, gene expression is altered, leading to downregulation of biological processes related to a developmental disorder linked to cohesin function, the Cornelia de Lange Syndrome (CdLS). These results point out a prominent role of cohesin-SA1 in transcriptional regulation, with clear implications in the etiology of CdLS.
Gonzalez D, Thackeray H, Lewis PD, et al.Loss of WT1 expression in the endometrium of infertile PCOS patients: a hyperandrogenic effect?
J Clin Endocrinol Metab. 2012; 97(3):957-66 [PubMed
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CONTEXT: In fertile patients the endometrial Wilms tumor suppressor gene (WT1) is expressed during the window of implantation. Polycystic ovary syndrome (PCOS) patients suffer from hyperandrogenemia and infertility and have elevated endometrial androgen receptor (AR) expression. WT1 is known to be down-regulated by AR. Therefore, the expression of WT1 and its targets may be altered in PCOS endometrium.
OBJECTIVE: The objective of the study was to assess the expression and regulation of WT1 and selected downstream targets in secretory endometrium from ovulatory PCOS (ovPCOS) and fertile women.
DESIGN AND PATIENTS: Endometrial samples were obtained from 25 ovPCOS and 25 fertile patients.
MAIN OUTCOME MEASURE: Endometrial expression of WT1 and selected downstream targets were assessed by immunohistochemistry and RT-PCR. The androgen effect on WT1 expression was determined in vitro by immunoblots and RT-PCR. The expression of WT1 and its targets was quantified in fertile and ovPCOS stromal cells in the presence of androgens by RT-PCR. Caspase-3/7 activity was measured to evaluate sensitivity to drug-induced apoptosis.
RESULTS: WT1 expression was down-regulated in secretory-phase ovPCOS endometrium. Stromal expression of Bcl-2 and p27 was higher, and epidermal growth factor receptor was lower in ovPCOS than in fertile patients. Endometrial stromal expression of WT1, Bcl-2, Bcl-2-associated X protein, and β-catenin was regulated by androgens. Apoptosis levels were reduced in ovPCOS samples and androgen-treated fertile samples.
CONCLUSION: WT1 expression is down-regulated in ovPCOS endometrium during the window of implantation. Androgens regulate the expression of WT1 and its targets during endometrial decidualization. The altered balance between WT1 and AR in the endometrium of PCOS patients may jeopardize the success of decidualization and endometrial receptivity.
Most cancer cells are characterized by aneuploidy, an abnormal number of chromosomes. We have identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors. A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer.
Margarit L, Taylor A, Roberts MH, et al.MUC1 as a discriminator between endometrium from fertile and infertile patients with PCOS and endometriosis.
J Clin Endocrinol Metab. 2010; 95(12):5320-9 [PubMed
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CONTEXT: Endometrium of fertile women expresses progesterone-regulated Mucin 1 (MUC1) that carries selectin ligands recognized by the human blastocyst. Altered MUC1 expression at the time of implantation may contribute to endometrial infertility.
OBJECTIVE: The aim was to assess the expression of MUC1 in the endometrium from polycystic ovary syndrome (PCOS), endometriosis, and fertile women in comparison with other hormone-regulated proteins [hydroxysteroid dehydrogenase (HSD) 1, HSD2, estrogen receptor (ER) and progesterone receptor (PR)].
DESIGN AND PATIENTS: Endometrial samples were obtained from 33 fertile patients, 26 ovulatory PCOS patients, 15 anovulatory PCOS patients, and 25 endometriosis patients.
MAIN OUTCOME MEASURE: Immunohistochemistry assessed the expression of MUC1 subunits ER, PR, HSD1, and HSD2 in endometrial epithelium. Endometrial MUC1 expression was quantified by immunoblots and RT-PCR. HSD1 and HSD2 expression was assayed by RT-PCR.
RESULTS: MUC1ND expression was significantly higher in ovulatory PCOS than in fertile and anovulatory PCOS patients, even after progesterone stimulation. MUC1ND and -CD expression was lower in anovulatory PCOS than in fertile patients. Only MUC1CD expression was lower in endometriosis patients. Endometrial ER expression was significantly higher in PCOS and endometriosis patients, whereas PR expression was significantly higher in PCOS than in fertile patients. The expression of HSD1 was significantly higher in anovulatory PCOS than in fertile patients. Expression of HSD2 was significantly higher in PCOS patients and lower in endometriosis patients.
CONCLUSION: Expression of MUC1 subunits in the infertile endometrium is significantly different from fertile and appears to be a component of altered gene expression that potentially contributes to endometrial insufficiency.
Rocquain J, Gelsi-Boyer V, Adélaïde J, et al.Alteration of cohesin genes in myeloid diseases.
Am J Hematol. 2010; 85(9):717-9 [PubMed
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New genes involved in leukemogenesis, such as ASXL1 and TET2, have been identified recently using genomic analyses of DNA from patient samples. We have studied by array-comparative genomic hybridization (aCGH) a series of 167 samples including myelodysplastic syndromes, chronic myelomonocytic leukemias, and acute myeloid leukemias. We found a deletion of the RAD21 and STAG2 genes, which encode two components of the cohesin complex. We propose that these alterations may compromise the cohesin complex and its regulation of the transcription of genes.