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Chromosome 10q inversion in papillary thyroid carcinoma . (A) Two representative chromosome 10 homologs from tumor cells of patients 1 and 2 showing inv(10)(qll.2q21) (arrows). (B) Schematic view of the paracentric inversion of chromosome lOq generating the transforming sequence RET/PTC. The gene order on chromosome lOq has been previously determined (16). The indicated direction of gene transcription is one of the two possibilities (divergent vs. convergent).
Source publication
RET/PTC is a transforming sequence created by the fusion of the tyrosine kinase domain of the RET protooncogene with the 5' end of the locus D10S170 designated by probe H4 and is frequently found activated in human papillary thyroid carcinomas. RET and D10S170 have been mapped to contiguous regions of the long arm of chromosome 10: q11.2 and q21, r...
Citations
... CCDC6 is a coiled-coil domain-containing protein that is considered a tumor suppressor and was first identified due to its involvement in chromosomal rearrangements with the RET proto-oncogene in thyroid papillary carcinomas ( 41 ). It is a pro-apoptotic protein substrate of ATM that has been shown to be involved in the DNA damage response (42)(43)(44). ...
Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for the viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs and control human neural stem cells. Among top-scoring hits in a subset of GBM cells was the F-box-containing gene FBXO42, which was also predicted to be essential in ∼15% of cell lines derived from a broad range of cancers. Mechanistic studies revealed that, in sensitive cells, FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest and cell death. The cell cycle arrest, but not the cell death, triggered by FBXO42 inactivation could be suppressed by brief exposure to a chemical inhibitor of Mps1, a key spindle assembly checkpoint (SAC) kinase. FBXO42’s cancer-essential function requires its F-box and Kelch domains, which are necessary for FBXO42’s substrate recognition and targeting by SCF (SKP1–CUL1–F-box protein) ubiquitin ligase complex. However, none of FBXO42’s previously proposed targets, including ING4, p53 and RBPJ, were responsible for the observed phenotypes. Instead, our results suggest that FBOX42 alters the activity of one or more proteins that perturb chromosome–microtubule dynamics in cancer cells, which in turn leads to induction of the SAC and cell death.
... CCDC6 is a coiled-coil domain-containing protein that is considered a tumor suppressor and was first identified due to its involvement in chromosomal rearrangements with the RET proto-oncogene in thyroid papillary carcinomas [31]. It is a pro-apoptotic protein substrate of ATM that has been shown to be involved in the DNA damage response [32][33][34]. ...
Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for the viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs and control human neural stem cells. Among top scoring hits in a subset of GBM cells was the F-box-containing gene FBXO42, which was also essential in ~15% of cell lines derived from a broad range of cancers. Mechanistic studies revealed that, in sensitive cells, FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest, and cell death. The cell cycle arrest, but not the cell death, triggered by FBXO42 inactivation could be suppressed by brief exposure to a chemical inhibitor of Mps1, a key spindle assembly checkpoint (SAC) kinase. FBXO42s cancer-essential function requires its F-box and Kelch domains, which are necessary for FBXO42s substrate recognition and targeting by SCF ubiquitin ligase complex. However, none of FBXO42s previously proposed targets, including ING4, p53, and RBPJ, were responsible for the observed phenotypes. Instead, our results suggest that FBOX42 activity suppresses the accumulation of one or more proteins that perturb chromosome-microtubule dynamics in cancer cells, which, in turn, leads to induction of the SAC and cell death.
... CCDC6 (coiled-coil domain-containing protein 6) is a tumor suppressor gene in human chromosome 10q2l, its product is involved in apoptosis and the DNA damage response. It was originally detected while studying recombinant genes caused by chromosomal translocation involving the RET proto-oncogene in some thyroid tumors [9]. In primary tumors, an abnormal CCDC6 function could influence genome stability and contribute to carcinogenesis [10]. ...
... Immunoreactivity scores were calculated by multiplying the number representing the percentage of immunoreactive cells (1 for percentages < 1%; 2 for percentages between 1 and 10%; 3 for percentages between 11 and 50%; and 4 for percentages >50%) by the number representing the dyeing intensity (0 for absence of dye; 1 for weak dye detection; 2 for moderate detection; and 3 for strong detection). We classified the CCDC6 expression scores as negative (0-2), mildly positive (3)(4), moderately positive (5-8), or highly positive (9)(10)(11)(12). ...
Background: The diagnosis of hepatobiliary carcinoma includes both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the first and the second most common hepatobiliary malignancies, respectively. CCDC6 (coiled-coil domain-containing protein 6) is a protein that interacts with apoptosis and DNA damage response elements and is commonly detected in cells. The prognostic and biological roles of CCDC6 in hepatobiliary carcinoma remain unknown.
Methods: We used data from UALCAN, GEPIA, TIMER, GeneMANIA, STRING and HPA databases to determine the prognostic values and biological functions of CCDC6 in HCC and CCA. We downloaded the original online data from TCGA and GEO databases and analyzed them with R 3.2.2. We also gathered clinical records from patients with HCC (n = 94) and iCCA (n = 99) in our hospital to explore associations between CCDC6 expression and hepatobiliary carcinoma using immunohistochemistry detection. We used KEGG, GO and GESA analyses to explore relative pathways of CCDC6 in HCC and CCA. In addition, we assessed correlations between CCDC6 expression and tumor-infiltrating immune cells using data from the TIMER and GEPIA databases. Finally, we assessed associations between CCDC6 and marker genes of tumor-infiltrated immune cells in HCC to confirm some of our findings.
Results: The mRNA and protein expressions of CCDC6 were noticeably upregulated in HCC and CCA tissues as compared with the expressions in healthy control tissues. The high CCDC6 expression levels were significantly correlated with advanced tumor grades as well as poor prognosis in patients with HCC, but not in patients with CCA. Our functional enrichment analysis revealed that CCDC6 is mainly involved in cell cycle processes, gene transcription, and immune cell-related pathways. Moreover, we found that the CCDC6 levels were positively correlated with the presence of tumor-infiltrating immune cells, including macrophages, CD4+T cells and dendritic cells.
Conclusion: CCDC6 expression was increased in hepatobiliary carcinoma tissues. High expressions of CCDC6 were significantly associated with clinical severity variables (especially with advanced cancer stages and pathological tumor grades) and poor prognoses in patients with HCC. CCDC6 upregulation is associated with histone acetylation and immune infiltration in hepatobiliary carcinoma. In addition, CCDC6 has the potential to be used as a predictive biomarker during targeting therapy and immunotherapy.
... Fusion-mediated RET activation is induced by different mechanisms, including increased kinase expression due to replacement of the 5′-upstream RET promoter with that of fusion partners, 7,49 and dimerization/oligomerization of the RET kinase domain mediated by a C-terminal domain present in the fusion partners that leads to ligand-independent kinase activation. 40,45,48,50 Breakpoints in RET and its fusion partners mainly occur in the intronic regions, therefore, the ORF is retained after mRNA splicing. A RET in intron 11, the most common breakpoint in LC patients, allowed exon 12 to be retained in the fusion product. ...
Fusion of RET with different partner genes has been detected in papillary thyroid, lung, colorectal, pancreatic and breast cancer. Approval of Retevmo (Selpercatinib) for treatment of lung and thyroid cancer with RET gene mutations or fusions, calls for studies to explore RET fusion partners and their eligibility for RET based targeted therapy. In this study, RET fusion patterns in a large group of Chinese cancer patients covering several cancer types were identified using next‑generation sequencing. A total of 44 fusion patterns were identified in the study cohort with KIF5B, CCDC6 and ERC1 being the most common RET fusion partners. Notably, 17 novel fusions were first reported in this study. Prevalence of functional RET fusions was 1.05% in lung cancer, 6.03% in thyroid cancer, 0.39% in colorectal cancer, <0.1% in gastric cancer and hepatocellular carcinoma. Analysis showed a preference of fusion partners in different tumor types with KIF5B being the common type in lung cancer, CCDC6 in thyroid cancer and NCOA4 in colorectal cancer. Co-occurrence of EGFR mutations and RET fusions with rare partner genes (rather than KIF5B) in LC patients was correlated with EGFR-TKI resistance and may predict response to targeted therapies. Findings from this study provide a guide to clinicians in determining tumors with specific fusion patterns as candidates for RET targeted therapies.
... Many chromosomal rearrangements identified in radiation-induced tumors are known to be paracentric inversions. The most common is the RET fusion in papillary thyroid carcinoma, which is present in up to 80% of radiation-related tumors [78]. As another example, in 2007, EML4-ALK was identified as a novel fusion oncogenic driver of non-small cell lung cancer (NSCLC) [79]. ...
Fusion RNAs are a hallmark of some cancers. They result either from chromosomal rearrangements or from splicing mechanisms that are non-chromosomal rearrangements. Chromosomal rearrangements that result in gene fusions are particularly prevalent in sarcomas and hematopoietic malignancies; they are also common in solid tumors. The splicing process can also give rise to more complex RNA patterns in cells. Gene fusions frequently affect tyrosine kinases, chromatin regulators, or transcription factors, and can cause constitutive activation, enhancement of downstream signaling, and tumor development, as major drivers of oncogenesis. In addition, some fusion RNAs have been shown to function as noncoding RNAs and to affect cancer progression. Fusion genes and RNAs will therefore become increasingly important as diagnostic and therapeutic targets for cancer development. Here, we discuss the function, biogenesis, detection, clinical relevance, and therapeutic implications of oncogenic fusion genes and RNAs in cancer development. Further understanding the molecular mechanisms that regulate how fusion RNAs form in cancers is critical to the development of therapeutic strategies against tumorigenesis.
... The RET protein, encoded by the RET (REarranged during Transfection) gene, is activated by neurotrophic factors that induce receptor dimerization, phosphorylation of the kinase domain, and signal transduction of downstream pathways in physiologic conditions (2,3). In tumors with activating RET fusions, a partner gene, most commonly KIF5B, CCDC6, or NCOA4, is fused to the distal portion of the RET gene including the kinase domain (4)(5)(6)(7)(8)(9). This chromosomal rearrangement or structural variant (SV) can generate a constitutively active chimeric protein composed of a C-terminal coil-coiled domain and an N-terminal kinase domain. ...
Purpose:
Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced RET fusion-positive lung and thyroid cancer. RET fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort.
Experimental design:
Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a RET structural variant of unknown significance (SVUS) were present. Canonical DNA-level RET fusions and RNA-confirmed RET fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups.
Results:
A total of 171 of 41,869 patients with DNA NGS harbored RET structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic RET fusions. The most common RET fusion-positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were KIF5B (45%), CCDC6 (29.1%), and NCOA4 (13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for NCOA4-RET (66.7%, 8/12). A total of 87.5% (7/8) of RET SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: KIF5B sensitivity was highest (100%, 31/31), followed by CCDC6 (88.9%, 16/18) and NCOA4 (50%, 6/12). Specificity of RET IHC was 82% (73/89).
Conclusions:
Although DNA sequencing has high sensitivity and specificity, RNA sequencing of RET SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for NCOA4-RET fusions.
... RET (that maps at 10q11.21) is transcribed in an opposite orientation with respect to CCDC6 and NCOA4. Thus, a 10q paracentric (not including the centromere, e.g., with both breakpoints in the same chromosome arm) inversion is the plausible genomic mechanism underlying CCDC6-RET and NCOA4-RET fusions [94]. Instead, KIF5B maps at 10p11.22; therefore, a pericentric (including the centromere, e.g., with a breakpoint in each chromosome arm) inversion of chromosome 10 is the mechanism of KIF5B-RET fusion (Table 1) [29,50,51,95]. ...
Following the identification of the BCR-ABL1 (Breakpoint Cluster Region-ABelson murine Leukemia) fusion in chronic myelogenous leukemia, gene fusions generating chimeric oncoproteins have been recognized as common genomic structural variations in human malignancies. This is, in particular, a frequent mechanism in the oncogenic conversion of protein kinases. Gene fusion was the first mechanism identified for the oncogenic activation of the receptor tyrosine kinase RET (REarranged during Transfection), initially discovered in papillary thyroid carcinoma (PTC). More recently, the advent of highly sensitive massive parallel (next generation sequencing, NGS) sequencing of tumor DNA or cell-free (cfDNA) circulating tumor DNA, allowed for the detection of RET fusions in many other solid and hematopoietic malignancies. This review summarizes the role of RET fusions in the pathogenesis of human cancer.
... Одна из наиболее распространенных генетических аномалий при ВДРЩЖ, выявляемых в 16-25 % случаев, включает протоонкоген RET, ведущий посредством перестроек к слиянию домена тирозинкиназы с концом других генов, активных в фолликулярных клетках ЩЖ [18,19]. Это приводит к генерализации гибридных онкогенов и белков отмеченных RET/PTC, экспрессия которых контролируется агентами, обеспечиваемыми слившимися генами, что ведет к лиганд-независимой активации RET в ВДРЩЖ. ...
... Это приводит к генерализации гибридных онкогенов и белков отмеченных RET/PTC, экспрессия которых контролируется агентами, обеспечиваемыми слившимися генами, что ведет к лиганд-независимой активации RET в ВДРЩЖ. На сегодняшний день описано несколько десятков таких гибридных белков [19,20]. Специфичность подобных перестроек RET/PTC при злокачественных новообразованиях ЩЖ уже была продемонстрирована в нескольких научных работах [21][22][23][24]. ...
Highly differentiated thyroid cancer refers to the non-aggressive tumors due to the fact, that it can grow slowly and does not metastasize into surrounding tissues and organs. Modern medicine has the ability to cope with this disease, identify it in the early stages and begin timely treatment, which includes surgery and subsequent radioiodine therapy according to the indications. At the same time, the resistance of distant metastases to radioiodine therapy in patients with highly differentiated thyroid cancer significantly worsens the survival prognosis. Results of the use of chemotherapy do not allow recommend it as a therapy of choice. Today the achievements of antitumoral drug treatment are mainly related to the development of targeted therapy, namely, using individual tyrosine kinase inhibitors, in particular Sorafenib, which became the first registered in Russia drug, proved its therapeutic effectiveness in patients with this pathology, whose treatment options are currently extremely limited or absent.
... The first gene fusion found in malignant epithelial tumors was reported in 1987, when the DNA isolated from a primary papillary thyroid carcinoma (PTC) was successfully delivered to NIH3T3 cells through transfection (3). Cytogenetic and molecular findings demonstrated that the gene fusion occurred due to a paracentric inversion of chromosome 10, which juxtaposes the intracellular tyrosine kinase domain of the RET to the 5′ sequence of the CCDC6, which is expressed in thyroid follicular cells (3,4,5). This novel fusion transcript was named RET/PTC, as it encompasses the RET gene and was exclusively found in PTC (3). ...
Objective:
PTC-specific analysis identified novel fusions involving RET, BRAF, NTRK1, NTRK3, AGK and ALK genes in adults and pediatric PTC. Although many novel fusions are PTC-specific event and, therefore, are ideal for diagnosis purposes, validation across additional and larger cohorts is essential for introducing these potential diagnostic or prognostic biomarkers into the clinical practice. As most of the BRAF, NTRK3 and ALK fusions were initially found in pediatric PTC or in more aggressive thyroid carcinomas, and there is a great disparity across population, in this study, we screened a large set of adult sporadic PTC cases for the most prevalent kinases fusion lately described in the TCGA.
Design and methods:
The prevalence of the fusions was determined by RT-PCR in 71 classical PTC, 45 follicular variant of PTC (FVPTC), 19 follicular thyroid adenomas (FTA) and 22 follicular thyroid carcinomas (FTC).
Results:
ETV6-NTRK3 was exclusively found in FVPTC, in both encapsulated and infiltrative variants, but was not found in FTAs and FTCs. STRN-ALK was found in both classical PTC and FVPTC. No AGK-BRAF fusion was identified in this series, endorsing that AGK-BRAF is a genetic event mainly associated with pediatric PTCs.
Conclusions:
The identification of kinases fusions in thyroid carcinomas helps to expand our knowledge about the landscape of oncogenic alterations in PTC. As ETV6-NTRK3 and STRN-ALK are recurrent and not identified in benign lesions, they can certainly help with diagnosis of thyroid nodules. Further analysis is needed to define if they can also be useful for prognosis and guiding therapy.
... 2q21)>), leading to the chimeric oncogene PTC1, from Papillary Thyroid Carcinoma. 4 For a long time, CCDC6 was considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the Tyrosine Kinase (TK) domain of RET, localized at carboxy-terminus. ...
Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types. CCDC6 gene product has a proper role in sustaining the DNA damage checkpoints in response to DNA damage. The inactivation of CCDC6 secondary to chromosomal rearrangements or gene mutations could enhance tumor progression by impairing the apoptotic response upon the DNA damage exposure, contributing to the generation of radio- and chemo-resistance. Preclinical studies indicate that the attenuation of CCDC6 in cancer, while conferring a resistance to cisplatinum, sensitizes the cancer cells to the small molecule inhibitors of Poly (ADP-ribose) polymerase (PARP1/2) with a synthetic lethal effect. Several CCDC6 mutations and gene rearrangements have been described so far in different types of cancer and CCDC6 may represent a possible predictive biomarker of tumor resistance to the conventional anticancer treatments. Nevertheless, the detection of a CCDC6 impairment in cancer patients may help to select, in future clinical trials, those patients who could benefit of PARP-inhibitors treatment alone or in combination with other treatments. This article is protected by copyright. All rights reserved.
