Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response to treatment with tyrosine kinase inhibitors, the role of tumor genotype as a prognostic factor ...remains controversial. The ConticaGIST study sought to determine the pathologic and molecular factors associated with disease-free survival (DFS) in patients with operable, imatinib-naive GIST.
Clinicopathologic and molecular data from 1,056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European ConticaGIST database were prospectively obtained and reviewed. Risk of tumor recurrence was stratified using the modified NIH criteria. The median follow-up was 52 months.
On testing for potential prognostic parameters, the following were associated with inferior DFS on multivariable Cox model analysis: primary nongastric site, size >10 cm, mitotic index >10 mitoses per 50 high power field, and the KIT exon 9 duplication hazard ratio (HR), 1.47; 95% confidence interval (CI), 0.9-2.5; P = 0.037 and KIT exon 11 deletions involving codons 557 and/or 558 KITdel-inc557/558; HR, 1.45; 95% CI, 1.0-2.2; P = 0.004. Conversely, PDGFRA exon 18 mutations were indicators of better prognosis HR, 0.23; 95% CI, 0.1-0.6; P = 0.002. KITdel-inc557/558 were an adverse indicator only in GIST localized in the stomach (P < 0.001) but not in tumors with nongastric origin. In gastric GIST, all other mutations presented remarkably superior 5-year DFS.
In conclusion, tumor genotype is an independent molecular prognostic variable associated with gastric GIST and should be used for optimizing tailored adjuvant imatinib treatment.
SWI/SNF-type ATP-dependent chromatin remodeling complexes (CRCs) are evolutionarily conserved multiprotein machineries controlling DNA accessibility by regulating chromatin structure. We summarize ...here recent advances highlighting the role of SWI/SNF in the regulation of hormone signaling pathways and their crosstalk in Arabidopsis thaliana. We discuss the functional interdependences of SWI/SNF complexes and key elements regulating developmental and hormone signaling pathways by indicating intriguing similarities and differences in plants and humans, and summarize proposed mechanisms of SWI/SNF action on target loci. We postulate that, given their viability, several plant SWI/SNF mutants may serve as an attractive model for searching for conserved functions of SWI/SNF CRCs in hormone signaling, cell cycle control, and other regulatory pathways.
SWI/SNF CRCs control various stages of development. Loss of SWI/SNF subunits results in severe aberrations of organ differentiation, altered regulation of flowering, sterility, and embryo lethality.
SWI/SNF CRCs are involved in hormonal regulation through physical interaction with various components of hormone signaling pathways and transcriptional regulators of genes involved in hormone biosynthesis and hormone perception.
Hormone treatments partially compensate for some secondary growth defects that result from inhibition of hormone biosynthesis by inactivation of SWI/SNF CRCs.
We present the assay based on multimarker analysis of mRNA transcripts associated with melanocytic cells detected in lymphatic fluid collected after lymph node dissection. Positive results of reverse ...transcriptase polymerase chain reaction (RT-PCR) test have a strong relationship with melanoma recurrence and disease-specific survival time in stage III melanoma.
BRM (BRAHMA) is a core, SWI2/SNF2-type ATPase subunit of SWI/SNF chromatin-remodelling complex (CRC) involved in various important regulatory processes including development. Mutations in SMARCA2, a ...BRM-encoding gene as well as overexpression or epigenetic silencing were found in various human diseases including cancer. Missense mutations in SMARCA2 gene were recently connected with occurrence of Nicolaides-Baraitser genetics syndrome. By contrast, SMARCA2 duplication rather than mutations is characteristic for Coffin-Siris syndrome. It is believed that BRM usually acts as a tumour suppressor or a tumour susceptibility gene. However, other studies provided evidence that BRM function may differ depending on the cancer type and the disease stage, where BRM may play a role in the disease progression. The existence of alternative splicing forms of SMARCA2 gene, leading to appearance of truncated functional, loss of function or gain-of-function forms of BRM protein suggest a far more complicated mode of BRM-containing SWI/SNF CRCs actions. Therefore, the summary of recent knowledge regarding BRM alteration in various types of cancer and highlighting of differences and commonalities between BRM and BRG1, another SWI2/SNF2 type ATPase, will lead to better understanding of SWI/SNF CRCs function in cancer development/progression. BRM has been recently proposed as an attractive target for various anticancer therapies including the use of small molecule inhibitors, synthetic lethality induction or proteolysis-targeting chimera (PROTAC). However, such attempts have some limitations and may lead to severe side effects given the homology of BRM ATPase domain to other ATPases, as well as due to the tissue-specific appearance of BRM- and BRG1-containing SWI/SNF CRC classes. Thus, a better insight into BRM-containing SWI/SNF CRCs function in human tissues and cancers is clearly required to provide a solid basis for establishment of new safe anticancer therapies.
Succinate dehydrogenase (SDH)‐deficient renal cancer is a rare renal cancer subtype recently accepted by the World Health Organization as a unique subtype of renal cell carcinoma (RCC). Here we ...report a case of 17‐year‐old man. The detailed evaluation indicated occurrence of the SDHB‐deficient RCC. The genetic testing revealed no germline mutation in SDH genes. Immunohistochemistry showed SDHB deficiency, overexpression of pyruvate kinase M2 and dramatic downregulation of fructose‐1,6‐bisphosphatase metabolic enzymes, and unaltered levels of phosphorylated AMP‐activated protein kinase and mammalian target of rapamycin. Strong upregulation of INI1 and BRG1 and overexpression of BAF180, subunits of SWI/SNF ATP‐dependent chromatin remodeling complex, were also found. The identified tumor pathologically did not resemble clear cell renal cell carcinoma (ccRCC), but some metabolic alterations are common for both cancer types. Thus, we postulate that the phenotypical differences between ccRCC and SDHB‐deficient RCC may be related to distinct molecular and metabolic alterations.
Implications for Practice
Succinate dehydrogenase (SDH)‐deficient renal cell carcinoma (RCC) is a rare renal tumor occurring even in young patients. Until now, in all described and genetically tested cases, mutations and deletions in SDH genes have been found. This article describes SDHB‐deficient RCC without any germline mutations in SDH genes. Therefore, genetic analysis for germline mutations in SDH genes in SDH‐deficient RCC, especially in young individuals, should be strongly recommended, although as of now it is not obligatory. This knowledge will allow improvement of patient monitoring including both disease recurrence and new cancer appearance.
SDH‐deficient renal cell cancer is a rare renal tumor that can occur at a young age. This brief communication describes the case of a 17‐year‐old man.
Growing tumors avoid recognition and destruction by the immune system. During continuous stimulation of tumor-infiltrating lymphocytes (TILs) by tumors, TILs become functionally exhausted; thus, they ...become unable to kill tumor cells and to produce certain cytokines and lose their ability to proliferate. This collectively results in the immune escape of cancer cells. Here, we show that breast cancer cells expressing PD-L1 can accelerate exhaustion of persistently activated human effector CD4+ T cells, manifesting in high PD-1 and PD-L1 expression level son T cell surfaces, decreased glucose metabolism genes, strong downregulation of SWI/SNF chromatin remodeling complex subunits, and p21 cell cycle inhibitor upregulation. This results in inhibition of T cell proliferation and reduction of T cell numbers. The RNAseq analysis on exhausted CD4+ T cells indicated strong overexpression of IDO1 and genes encoding pro-inflammatory cytokines and chemokines. Some interleukins were also detected in media from CD4+ T cells co-cultured with cancer cells. The PD-L1 overexpression was also observed in CD4+ T cells after co-cultivation with other cell lines overexpressing PD-L1, which suggested the existence of a general mechanism of CD4+ T cell exhaustion induced by cancer cells. The ChIP analysis on the PD-L1 promoter region indicated that the BRM recruitment in control CD4+ T cells was replaced by BRG1 and EZH2 in CD4+ T cells strongly exhausted by cancer cells. These findings suggest that epi-drugs such as EZH2 inhibitors may be used as immunomodulators in cancer treatment.
Objective Pituitary corticotroph adenomas commonly cause Cushing’s disease (CD) but part of these tumours are hormonally inactive (silent corticotroph adenomas, SCA). USP8 mutations are well-known ...driver mutations in corticotrophinomas. Differences in transcriptomic profiles between functioning and silent tumours or tumours with different USP8 status have not been investigated. Design and methods Forty-eight patients (28 CD, 20 SCA) were screened for USP8 mutations with Sanger sequencing. Twenty-four patients were included in transcriptomic profiling with Ampliseq Transcriptome Human Gene Expression Core Panel. The entire patients group was included in qRT-PCR analysis of selected genes expression. Immunohistochemistry was used for visualization of selected protein. Results We found USP8 mutation in 15 patients with CD and 4 SCAs. USP8 mutations determine molecular profile of the tumours as showed by hierarchical clustering and identification of 1648 genes differentially expressed in USP8-mutated and USP8-wild-type tumours. Mutations affect many molecular pathways as observed in Gene Set Enrichment analysis. USP8-mutated adenomas showed higher level of POMC, CDC25A, MAPK4 but lower level of CCND2, CDK6, CDKN1B than USP8-wt tumours. Eighty-seven genes differentially expressed between CD-related adenomas and SCAs were found, including those involved in cell signalling (GLI2, DLC1, TBX2, RASSF6), cell adhesion (GJA1, CDH6), ion transport (KCNN4, KCNJ5) and GABA signalling (GABBR2, GABRD). Conclusion USP8 mutations occur in functioning and silent corticotrophinomas. They have pleiotropic effect, not limited to EGFR signalling, and affect expression levels of many genes involved in different pathways. Expression of GABA-related genes GABBR2, GNAL, GABARD and KCNJ5 correspond to functional status of the tumours.
Synovial sarcoma (SynSa) is an aggressive mesenchymal tumor, comprising approximately 10% of all soft tissue sarcomas. Over half of SynSa patients develop metastasis or local recurrence, but the ...underlying molecular mechanisms of the aggressive clinical behavior remain poorly characterized.
Sixty-four frozen tumor specimens from 54 SynSa patients were subjected to array comparative genomic hybridization (aCGH) and gene expression profiling. The examined set of tumor specimens included 16 primary tumors from untreated patients who did not develop metastasis/local recurrence (SynSa1 group), 26 primary tumors from untreated patients who developed metastases or local recurrence during follow-up (SynSa2 group), and 22 metachronous metastatic/recurrent SynSa tumors (SynSa3 group).
AURKA and KIF18A, which play important roles in various mitotic events, were the two most up-regulated genes in SynSa2 and SynSa3 groups compared to the SynSa1 group. Expression profiles of SynSa2 and SynSa3 tumors did not show any significant differences. Analysis of genomic index (GI) based on aCGH profiles demonstrated that the SynSa1 group consisted of tumors with significantly less complex genomes compared to SynSa2 and SynSa3 groups. There was no significant difference in genome complexity between SynSa2 and SynSa3 tumors.
Primary SynSa tumors from patients who develop metastases or local recurrence share common molecular features with metastatic/recurrent tumors. Presented data suggest that the aggressive clinical SynSa behavior is determined early in tumorigenesis and might be related to impaired regulation of mitotic mechanisms.
This article is part of a Directed Issue entitled: Rare Cancers.
Cardiotoxicity danger in immunotherapy Jagielska, Beata; Ozdowska, Patrycja; Gepner, Katarzyna ...
IUBMB life,
June 2020, 2020-06-00, 20200601, Letnik:
72, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Immunotherapy based on immune checkpoint inhibitors (ICIs) is currently broadly used in the treatment of different types of cancer. The treatment targeting programmed cell death protein 1/programmed ...death‐ligand 1 axis is already approved by Food and Drug Administration for numerous cancers. These kinds of therapy brought spectacular results in the treatment of non‐small cell lung cancer where systemic therapy was ineffective. However, a wide range of applied therapies based on ICIs in the clinic have led to unexpected side effects, such as severe cardiotoxicity. It needs to be underlined that the molecular mechanism of myocarditis in response to ICIs is still not fully understood. Lack of sufficient knowledge, especially concerning the kind of risk factors increasing probability of myocarditis, poses currently a large clinical problem. Continuous cardiac monitoring of patients who undergo ICI treatment presents another problem as it is cost‐ineffective for the healthcare system. Herein, we highlight the risks of use of anticancer therapy based on ICIs. We also stress that detailed monitoring of any event of cardiotoxicity following ICIs treatment should be carefully investigated and registered to give a global overview of the frequency of myocarditis occurrence. Moreover, we propose that the extension of molecular and systemic knowledge of etiology of myocarditis as a side effect, including the role of protein kinases, will be highly beneficial for the medical field. Last but not least, better understanding of mechanisms of cardiotoxicity induction will improve the safety of cancer patients and will help clinicians in prediction of unexpected side effect occurrence.
Bladder cancer (BC) is a frequently diagnosed malignancy affecting predominantly adult and elderly populations. It is expected that due to the longer life time, BC will become even more frequent in ...the future; thus in consequence, it will represent serious health problem of older society part. The treatment of advanced BC is mostly ineffective due to its very aggressive behavior. So far, no effective targeted therapy is used for BC treatment. Here, we found that BC is characterized by lower protein levels of BRM, INI1, and BAF155 main subunits of SWI/SNF chromatin remodeling complex (CRC) which is involved in global control of gene expression and influences various important cellular processes like: cell cycle control, apoptosis, DNA repair, etc. Moreover, the expression of SMARCA2, a BRM encoding gene, strongly correlated with BC metastasis and expression of such metabolic genes as PKM2 and PRKAA1. Furthermore, the analysis of T24 and 5637 commonly used BC cell lines revealed different expression levels of metabolic genes including FBP1 gene encoding Frutose‐1,6‐Bisphosphatase, an enzyme controlling glycolysis flux and gluconeogenesis. The tested BC cell lines exhibited various molecular and metabolic alterations as well as differential glucose uptake, growth rate, and migration potential. We have shown that BRM subunit is involved in the transcriptional control of genes encoding metabolic enzymes. Moreover, we found that the FBP1 expression level and the SWI/SNF CRCs may serve as markers of molecular subtypes of BC. Collectively, this study may provide a new knowledge about the molecular and metabolic BC subtypes which likely will be of high importance for the clinic in the future.
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