Gene Summary

Gene:FBXW7; F-box and WD repeat domain containing 7
Aliases: AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10
Summary:This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene was previously referred to as FBX30, and belongs to the Fbws class; in addition to an F-box, this protein contains 7 tandem WD40 repeats. This protein binds directly to cyclin E and probably targets cyclin E for ubiquitin-mediated degradation. Mutations in this gene are detected in ovarian and breast cancer cell lines, implicating the gene's potential role in the pathogenesis of human cancers. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:F-box/WD repeat-containing protein 7
Source:NCBIAccessed: 01 September, 2019


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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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

Entity Topic PubMed Papers
Acute Lymphocytic Leukaemia (ALL)FBXW7 and Precursor T-Cell Lymphoblastic Leukemia-Lymphoma View Publications57
Colorectal CancerFBXW7 and Colorectal Cancer View Publications83
Breast CancerFBXW7 and Breast Cancer View Publications41
Acute Lymphocytic Leukemia (ALL), childFBXW7 and Childhood T-cell ALL View Publications35
Cervical CancerFBXW7 mutations in Cervical Cancer
Ojesina et al (2014) reported FBXW7 mutations in 15% of cervical carcinomas in a whole-exome sequencing analysis of 115 patients.
View Publications10
Chronic Lymphocytic LeukemiaFBXW7 mutations in CLL
In an analysis of 1160 untreated CLL patients Jeromin et al (2014) reported 2.5% of cases had FBXW7 mutations.
View Publications12
Wilms TumourFBXW7 mutations in Wilms Tumor
In a SIOP study of over 100 Wilms tumor patients, Williams et al (2010) found that FBXW7 was mutated or deleted in approximately 4% of cases including one patient with germline mutations in both FBXW7 and WT1. This study also reported MYCN amplification in 9% of cases and the authors note MYCN is a target of FBXW7-mediated ubiquitination and degradation - suggesting a common pathway is dysregulated by different mechanisms in various Wilms tumor subtypes.
View Publications2

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

Latest Publications: FBXW7 (cancer-related)

Liu F, Zou Y, Wang F, et al.
Genet Test Mol Biomarkers. 2019; 23(6):409-417 [PubMed] Related Publications

Peng Z, Chen Q
[Research progress in the role of FBXW7 in drug resistance against non-small cell lung cancer].
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2019; 44(4):444-448 [PubMed] Related Publications
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors in the world. NSCLC shows serious effect on prognosis for drug resistance, and it is necessary to study the molecular mechanism for drug resistance in NSCLC. Ubiquitin-proteasome system (UPS) can regulate some important cellular processes by degrading short-term protein, and the abnormal expression is closely related to the occurrence, development and prognosis of tumor. The F-box family protein is an important component of the ubiquitin proteasome, such as cycle regulation, transcriptional regulation, signal transduction, apoptosis and differentiation. F-box and WD-40 domain protein 7 (FBXW7) is just the classic protein components among F-box family protein. Studies have shown that FBXW7 is related to drug resistance in NSCLC. The main mechanism is that FBXW7 mutation leads to drug resistance by reducing ubiquitination and degradation of its downstream proteins, including Snail protein, myeloid cell leukemia sequence 1 (MCL-1), mammalian target of rapamycin (mTOR), and coiled-coil-domain containing 6 (CCDC6). Rapamycin, histone deacetylase inhibitor MS-275, and rabdosia are effective in drug-resistant NSCLC patients with FBXW7 mutation.

Xia Y, Ye B, Ding J, et al.
Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway.
Cancer Res. 2019; 79(15):3837-3850 [PubMed] Article available free on PMC after 01/08/2020 Related Publications

Qin Y, Hu Q, Xu J, et al.
PRMT5 enhances tumorigenicity and glycolysis in pancreatic cancer via the FBW7/cMyc axis.
Cell Commun Signal. 2019; 17(1):30 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. However, its role in pancreatic cancer remains unclear. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism.
METHODS: Real-time PCR, immunohistochemistry and analysis of a dataset from The Cancer Genome Atlas (TCGA) were performed to study the expression of PRMT5 at the mRNA and protein levels in pancreatic cancer. Cell proliferation assays, including cell viability, colony formation ability and subcutaneous mouse model assays, were utilized to confirm the role of PRMT5 in cell proliferation and tumorigenesis. A Seahorse extracellular flux analyzer, a glucose uptake kit, a lactate level measurement kit and the measurement of
RESULTS: PRMT5 expression was significantly upregulated in pancreatic cancer tissues compared with that in adjacent normal tissues. Clinically, elevated expression of PRMT5 was positively correlated with worse overall survival in pancreatic cancer patients. Silencing PRMT5 expression inhibited the proliferation of pancreatic cancer cells both in vitro and in vivo. Moreover, PRMT5 regulated aerobic glycolysis in vitro in cell lines, in vivo in pancreatic cancer patients and in a xenograft mouse model used to measure 18F-FDG uptake. We found that mechanistically, PRMT5 posttranslationally regulated cMyc stability via F-box/WD repeat-containing protein 7 (FBW7), an E3 ubiquitin ligase that controls cMyc degradation. Moreover, PRMT5 epigenetically regulated the expression of FBW7 in pancreatic cancer cells.
CONCLUSIONS: The present study demonstrated that PRMT5 epigenetically silenced the expression of the tumor suppressor FBW7, leading to increased cMyc levels and the subsequent enhancement of the proliferation of and aerobic glycolysis in pancreatic cancer cells. The PRMT5/FBW7/cMyc axis could be a potential therapeutic target for the treatment of pancreatic cancer.

Guo S, Yang J, Wu M, Xiao G
Clinical value screening, prognostic significance and key pathway identification of miR-204-5p in endometrial carcinoma: A study based on the Cancer Genome Atlas (TCGA), and bioinformatics analysis.
Pathol Res Pract. 2019; 215(5):1003-1011 [PubMed] Related Publications
BACKGROUND: Endometrial carcinoma is one of the common carcinomas in the female reproductive system. It is reported that miR-204-5p is down-regulated in endometrial carcinoma. However, the mechanism and key pathways of miR-204-5p in endometrial carcinoma have not been clarified.
MATERIAL/METHODS: We evaluated the expression profiles and prognostic value of miR-204-5p expression in endometrial carcinoma by using bioinformatics analysis of a public dataset from TCGA. Drug of endometrial carcinoma from DrugBank, GO analysis, KEGG analysis, PPI network, mutation, as well as assessment of the prognostic significance were performed to the overlapping target genes of miR-204-5p in endometrial carcinoma. The relative expression levels of miR-204-5p target genes in endometrial carcinoma, including SF3B1, FBXW7, SPOP, and BRD4, were assessed by real-time quantitative polymerase chain reaction (RT-qPCR).
RESULTS: First, through DrugBank website, we obtained target drugs for endometrial carcinoma. MiR-204-5p expression was found to be lower in the endometrial carcinoma tissues than in adjacent normal tissues from TCGA. Next, we identified 143 genes as potential targets of miR-204-5p. Then, through GO enrichment analysis, KEGG signaling pathway and PPI analysis, we revealed the key networks in endometrial carcinoma. Next, mutation and assessment of the prognostic significance of endometrial carcinoma were obtained. At last, in endometrial carcinoma, the relative expression of SF3B1 and BRD4 increased, and the relative expression of FBXW7 decreased.
CONCLUSIONS: MiR-204-5p is down-regulated in endometrial carcinoma and affects the prognostic significance of endometrial carcinoma, which might play an important role in the tumorigenesis of endometrial carcinoma.

Jiang L, Lv L, Liu X, et al.
MiR-223 promotes oral squamous cell carcinoma proliferation and migration by regulating FBXW7.
Cancer Biomark. 2019; 24(3):325-334 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Abnormally expressed microRNAs (miRNAs) contribute widely to human cancer, including oral squamous cell carcinoma (OSCC), by regulating their downstream targets. MiR-223 has been proved to be up-regulated in both gastric cancer and ovarian cancer. However, the effect of miR-223 on OSCC is still unclear. Here, we showed that miR-223 was over-expressed in OSCC tissues using qRT-PCR. Next, we investigated the biological mechanism of miR-223 in OSCC. The results demonstrated that miR-223 facilitated the cell proliferation and migration of OSCC using MTT assay and Transwell assay. Furthermore, we stated that the FBXW7 expression was decreased in OSCC and re-expression of FBXW7 inhibited the proliferation and migration of OSCC. In addition, FBXW7 mimic inversed the promotion effect of miR-223 in regulating of OSCC cells. In short, miR-223 promoted OSCC cell proliferation and migration by downregulating FBXW7, which provided a novel therapeutic strategy for OSCC.

Daniele G, L'Abbate A, Turchiano A, et al.
1q23.1 homozygous deletion and downregulation of Fc receptor-like family genes confer poor prognosis in chronic lymphocytic leukemia.
Clin Exp Med. 2019; 19(2):261-267 [PubMed] Related Publications
The identification of chromosome 1 translocations and deletions is a rare and poorly investigated event in chronic lymphocytic leukemia (CLL). Nevertheless, the identification of novel additional molecular alterations is of great interest, opening to new prognostic and therapeutic strategies for such heterogeneous hematological disease. We here describe a patient affected by CLL with a mutated IGHV status, showing a balanced t(1;3)(q23.1;q21.3) translocation and a der(18)t(1;18)(q24.2;p11.32), accompanying the recurrent 13q14 heterozygous deletion in all analyzed cells at onset. By combining whole-genome sequencing, SNP array, RNA sequencing, and FISH analyses, we defined a 1q23.1 biallelic minimally deleted region flanking translocations breakpoints at both derivative chromosome 1 homologues. The deletion resulted in the downregulation of the Fc receptor-like family genes FCRL1, FCRL2, and FCRL3 and in the lack of expression of FCRL5, observed by RT-qPCR. The mutational status of TP53, NOTCH1, SF3B1, MYD88, FBXW7, and XPO1 was investigated by targeted next-generation sequencing, detecting a frameshift deletion within NOTCH1 (c.7544_7545delCT). We hypothesize a loss of tumor suppressor function for FCRL genes, cooperating with NOTCH1 mutation and 13q14 genomic loss in our patient, both conferring a negative prognosis, independently from the known biological prognostic factors of CLL.

Bjerre MT, Strand SH, Nørgaard M, et al.
Int J Mol Sci. 2019; 20(5) [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in PCa tissue samples and not in blood cells or other cancer tissue types, we performed a systematic analysis of genome-wide DNA methylation data (Infinium 450K array) available in the Marmal-aid database for 4072 malignant/normal tissue samples of various types. We identified eight top candidate markers (cg12799885,

Cuevas D, Valls J, Gatius S, et al.
Targeted sequencing with a customized panel to assess histological typing in endometrial carcinoma.
Virchows Arch. 2019; 474(5):585-598 [PubMed] Related Publications
The two most frequent types of endometrial cancer (EC) are endometrioid (EEC) and serous carcinomas (SC). Differential diagnosis between them is not always easy. A subset of endometrial cancers shows misleading microscopical features, which cause problems in differential diagnosis, and may be a good scenario for next-generation sequencing. Previous studies have assessed the usefulness of targeted sequencing with panels of generic cancer-associated genes in EC histological typing. Based on the analysis of TCGA (The Cancer Genome Atlas), EEC and SC have different mutational profiles. In this proof of principle study, we have performed targeted sequencing analysis with a customized panel, based on the TCGA mutational profile of EEC and SC, in a series of 24 tumors (16 EEC and 8 SC). Our panel comprised coding and non-coding sequences of the following genes: ABCC9, ARID1A, ARID5B, ATR, BCOR, CCND1, CDH19, CHD4, COL11A1, CSDE1, CSMD3, CTCF, CTNNB1, EP300, ERBB2, FBXW7, FGFR2, FOXA2, KLLN, KMT2B, KRAS, MAP3K4, MKI67, NRAS, PGAP3, PIK3CA, PIK3R1, PPP2R1A, PRPF18, PTEN, RPL22, SCARNA11, SIN3A, SMARCA4, SPOP, TAF1, TP53, TSPYL2, USP36, and WRAP53. Targeted sequencing validation by Sanger sequencing and immunohistochemistry was performed in a group of genes. POLE mutation status was assessed by Sanger sequencing. The most mutated genes were PTEN (93.7%), ARID1A (68.7%), PIK3CA (50%), and KMT2B (43.7%) for EEC, and TP53 (87.5%), PIK3CA (50%), and PPP2R1A (25%) for SC. Our panel allowed correct classification of all tumors in the two categories (EEC, SC). Coexistence of mutations in PTEN, ARID1A, and KMT2B was diagnostic of EEC. On the other hand, absence of PTEN, ARID1A, and KMT2B mutations in the presence of TP53 mutation was diagnostic of SC. This proof of concept study demonstrates the suitability of targeted sequencing with a customized endometrial cancer gene panel as an additional tool for confirming histological typing.

Dye KN, Welcker M, Clurman BE, et al.
Merkel cell polyomavirus Tumor antigens expressed in Merkel cell carcinoma function independently of the ubiquitin ligases Fbw7 and β-TrCP.
PLoS Pathog. 2019; 15(1):e1007543 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Merkel cell polyomavirus (MCPyV) accounts for 80% of all Merkel cell carcinoma (MCC) cases through expression of two viral oncoproteins: the truncated large T antigen (LT-t) and small T antigen (ST). MCPyV ST is thought to be the main driver of cellular transformation and has also been shown to increase LT protein levels through the activity of its Large-T Stabilization Domain (LSD). The ST LSD was reported to bind and sequester several ubiquitin ligases, including Fbw7 and β-TrCP, and thereby stabilize LT-t and several other Fbw7 targets including c-Myc and cyclin E. Therefore, the ST LSD is thought to contribute to transformation by promoting the accumulation of these oncoproteins. Targets of Fbw7 and β-TrCP contain well-defined, conserved, phospho-degrons. However, as neither MCPyV LT, LT-t nor ST contain the canonical Fbw7 phospho-degron, we sought to further investigate the proposed model of ST stabilization of LT-t and transformation. In this study, we provide several lines of evidence that fail to support a specific interaction between MCPyV T antigens and Fbw7 or β-TrCP by co-immunoprecipitation or functional consequence. Although MCPyV ST does indeed increase LT protein levels through its Large-T Stabilization domain (LSD), this is accomplished independently of Fbw7. Therefore, our study indicates a need for further investigation into the role and mechanism(s) of MCPyV T antigens in viral replication, latency, transformation, and tumorigenesis.

Jang W, Park J, Kwon A, et al.
CDKN2B downregulation and other genetic characteristics in T-acute lymphoblastic leukemia.
Exp Mol Med. 2019; 51(1):4 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS, were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism.

Gao XH, Yu GY, Hong YG, et al.
Clinical significance of multiple gene detection with a 22-gene panel in formalin-fixed paraffin-embedded specimens of 207 colorectal cancer patients.
Int J Clin Oncol. 2019; 24(2):141-152 [PubMed] Related Publications
BACKGROUND: Simultaneous detection of multiple molecular biomarkers is helpful in the prediction of treatment response and prognosis for colorectal cancer (CRC) patients.
METHODS: A 22-gene panel consisting of 103 hotspot regions was utilized in the formalin-fixed paraffin-embedded (FFPE) tissue samples of 207 CRC patients, using the next-generation sequencing (NGS)-based multiplex PCR technique. Those 22 genes included AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, and TP53.
RESULTS: Of the 207 patients, 193 had one or more variants, with 170, 20, and 3 having one, two, and three mutated genes, respectively. Of the total 414 variants identified in this study, 384, 25, and 5 were single-nucleotide variants, deletion, and insertion. The top four frequently mutated genes were TP53, KRAS, PIK3CA, and FBXW7. There was high consistency between the results of NGS-PCR technique and routine ARMS-PCR in KRAS and BRAF mutation detection. Univariate and multivariate analyses demonstrated that advanced TNM stage, elevated serum CEA, total variants number ≥ 2, AKT1 and PTEN mutation were independent predictors of shorter DFS; poor differentiation, advanced TNM stage, total variants number ≥ 2, BRAF, CTNNB1 and NRAS mutation were independent predictors of shorter OS.
CONCLUSIONS: It is feasible to detect multiple gene mutations with a 22-gene panel in FFPE CRC specimens. TNM stage and total variants number ≥ 2 were independent predictors of DFS and OS. Detection of multiple gene mutations may provide additional prognostic information to TNM stage in CRC patients.

Li W, Qiu T, Guo L, et al.
NGS-based oncogenic mutations analysis in advanced colorectal cancer patients improves targeted therapy prediction.
Pathol Res Pract. 2019; 215(3):483-489 [PubMed] Related Publications
BACKGROUND: Characterization of genetic alterations has been revealed to be important to predict the outcomes of targeted therapy in cancer. We here aimed to assess the mutation profiling of 526 colorectal cancer (CRC) patients by next-generation sequencing (NGS) to enable a more personalized anti-EGFR treatment.
METHODS: Tumors were analyzed using NGS to determine hotspot mutations in 22 cancer-related genes.
RESULTS: Mutations were observed in 13 genes in 436 of 526 (82.9%) tumors, and the most common mutations occurred in TP53 and KRAS. PIK3CA mutations usually coexisted with KRAS, NRAS or BRAF mutations. A higher frequency of concomitant PIK3CA mutations was observed in tumors with KRAS outside codon 13 mutations, with NRAS codon 61 mutations and with BRAF kinase-activated mutations. Moreover, KRAS, PIK3CA, AKT1 and FBXW7 mutations were statistically associated with some clinicopathological features, including location, age or metastasis of CRC patients. For RAS wild-type patients treated with cetuximab, longer progression-free survival (PFS) was observed in patients identified as wild type in all 22 genes compared with patients with mutations in one or more genes.
CONCLUSIONS: A wild-type result in all 22 cancer-related genes detected by NGS is associated with a better outcome of cetuximab treatment. Determining mutation patterns by NGS may aid to understand the molecular mechanisms of CRC and improve targeted therapy prediction.

Maciel ALT, Poubel CP, Noronha EP, et al.
CRLF2 expression associates with ICN1 stabilization in T-cell acute lymphoblastic leukemia.
Genes Chromosomes Cancer. 2019; 58(6):396-401 [PubMed] Related Publications
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy with few molecular alterations showing a consensual prognostic value. CRLF2 overexpression was recently identified in high-risk T-ALL patients. For these cases, no genomic abnormality was found to be associated with CRLF2 overexpression. IKZF1 has been recently shown to be a direct transcriptional regulator of CRLF2 expression. Moreover, it is known that NOTCH1 antagonizes IKZF1 in T-ALL. In light of these pieces of evidence, we reasoned that IKZF1 binding perturbation and CRLF2 upregulation could be associated in T-ALL. We evaluated two independent series of pediatric T-ALL cases (PHOP, n = 57 and TARGET, n = 264) for the presence of common T-ALL molecular abnormalities, such as NOTCH1/FBXW7 mutations. We also assessed CRLF2 and IKZF1 gene expression. CRLF2 overexpression was observed in 14% (PHOP) and 16% (TARGET) of T-ALL patients. No correlation was found between mRNA expression of CRLF2 and IKZF1 in both cohorts. Interestingly, we show that patients with mutations affecting NOTCH1-PEST domain and/or FBXW7 had higher CRLF2 expression (P = .04). In summary, we demonstrate for the first time that only mutations resulting in ICN1 (intracellular domain of NOTCH1) stabilization are associated with CRLF2 overexpression.

Gillison ML, Akagi K, Xiao W, et al.
Human papillomavirus and the landscape of secondary genetic alterations in oral cancers.
Genome Res. 2019; 29(1):1-17 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5'-ATN-3' correlated with tobacco exposure. Universal expression of HPV

Hartman ML, Sztiller-Sikorska M, Czyz M
Whole-exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells.
Mol Carcinog. 2019; 58(4):588-602 [PubMed] Related Publications
We have extensively studied the phenotypic heterogeneity of patient-derived melanoma cells. Here, whole-exome sequencing revealed novel variants of genes associated with the MAPK, NOTCH, Hippo, cell-cycle, senescence, and ubiquitin-dependent pathways, which could contribute to the observed phenotypic diversity between cell lines. Focusing on mutations in the MAPK pathway-associated genes, we found BRAF (BRAF

Jung AR, Eun YG, Lee YC, et al.
Clinical Significance of CUB and Sushi Multiple Domains 1 Inactivation in Head and Neck Squamous Cell Carcinoma.
Int J Mol Sci. 2018; 19(12) [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Although the genetic alteration of CUB and Sushi multiple domains 1 (CSMD1) is known to be associated with poor prognosis in several cancers, there is a lack of clinical relevance in head and neck cancer. The aim of this study was to offer insight into the clinical significance of CSMD1, utilizing a multimodal approach that leverages publicly available independent genome-wide expression datasets. CSMD1-related genes were found and analyzed to examine the clinical significance of CSMD1 inactivation in the HNSCC cohort of publicly available databases. We analyzed the frequency of somatic mutations, clinicopathologic characteristics, association with immunotherapy-related gene signatures, and the pathways of gene signatures. We found 363 CSMD1-related genes. The prognosis of the CSMD1-inactivated subgroup was poor.

Ren W, Sun Q, Wu PY, et al.
Profiles of genomic alterations in primary esophageal follicular dendritic cell sarcoma: A case report.
Medicine (Baltimore). 2018; 97(48):e13413 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
RATIONALE: Follicular dendritic cell (FDC) sarcoma is a rare tumor with FDC differentiation that typically arises within lymph nodes but can also occur extranodally. To date, the primary esophageal FDC sarcoma has not been reported in the English literature.
PATIENT CONCERNS: We described a 67-year-old female who foremostly presented with dysphagia, and the patient was readmitted due to a dry cough and pain of his right shoulder 2 years after initial treatment.
DIAGNOSES: Primary esophageal FDC sarcoma with the right superior mediastinal lymph node metastasis.
INTERVENTIONS: The esophageal tumor was removed by endoscopic submucosal dissection at the first hospitalization. At the second hospitalization 2 years after the initial visit, the tracheal stent loaded with (125) iodine radioactive seeds was placed. The profiles of genetic variations and immunotherapeutic biomarkers were also explored by next-generation sequencing protocol from the patient's blood, esophageal primary, and mediastinal metastatic tumor samples.
OUTCOMES: The patient's symptom transitorily relieved, but she gave up further treatment and died 2 months after the tracheal stent was placed. As for the genomic alterations, we found 9 gene mutations in all the samples, including checkpoint kinase 2(CHEK2), FAT atypical cadherin 1 (FAT1), tumor protein 53 (TP53), DPYD, ERBB2 interacting protein (ERBB2IP), FBXW7, KMT2D, PPP2R1A, TSC2, whereas amplification of MYC was only in the metastatic example. The analysis of clonal evolution and phylogenetic tree showed the propagation and replay of polyclonal esophageal FDC sarcoma. At the same time, the detection of biomarkers for immunotherapy revealed microsatellite stable and mismatch repair-proficient (pMMR), which predicted a relatively poor anti-programmed death (PD-1)/programmed death ligand (PD-L1) immunotherapy outcome. On the contrary, the tumor mutational burdens were 10 mutations per 1 million bases in both the primary and metastatic tumor sample, which ranked the top 23.3% in solid tumors mutational burdens database of Geneseeq and might be a good predictor of the efficacy of anti-PD-1/PD-L1 immunotherapy.
LESSONS: To the best of our knowledge, this case report announced the first case of extranodal primary esophageal FDC sarcoma in the world, and firstly revealed its unique genetic alterations profiles, which might contribute to further in-depth study of this rare disease.

Murakami T, Akazawa Y, Yatagai N, et al.
Molecular characterization of sessile serrated adenoma/polyps with dysplasia/carcinoma based on immunohistochemistry, next-generation sequencing, and microsatellite instability testing: a case series study.
Diagn Pathol. 2018; 13(1):88 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway.
METHODS: We performed immunostaining for β-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma.
RESULTS: Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear β-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation.
CONCLUSIONS: SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/β-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.

Vaseva AV, Blake DR, Gilbert TSK, et al.
KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism.
Cancer Cell. 2018; 34(5):807-822.e7 [PubMed] Article available free on PMC after 12/11/2019 Related Publications
Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3β signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feedforward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth.

Kimura S, Seki M, Yoshida K, et al.
NOTCH1 pathway activating mutations and clonal evolution in pediatric T-cell acute lymphoblastic leukemia.
Cancer Sci. 2019; 110(2):784-794 [PubMed] Article available free on PMC after 12/11/2019 Related Publications
Molecular mechanisms involved in the relapse of T-cell acute lymphoblastic leukemia (T-ALL) are not fully understood, although activating NOTCH1 signaling due to NOTCH1/FBXW7 alterations is a major oncogenic driver. To unravel the relevance of NOTCH1/FBXW7 mutations associated with relapse, we performed whole-exome sequencing in 30 pediatric T-ALL cases, among which 11 diagnosis-relapse paired cases were further investigated to track the clonal evolution of relapse using amplicon-based deep sequencing. NOTCH1/FBXW7 alterations were detected in 73.3% (diagnosis) and 72.7% (relapse) of cases. Single nucleotide variations in the heterodimerization domain were the most frequent (40.0%) at diagnosis, whereas proline, glutamic acid, serine, threonine-rich (PEST) domain alterations were the most frequent at relapse (54.5%). Comparison between non-relapsed and relapsed cases at diagnosis showed a predominance of PEST alterations in relapsed cases (P = .045), although we failed to validate this in the TARGET cohort. Based on the clonal analysis of diagnosis-relapse samples, we identified NOTCH1 "switching" characterized by different NOTCH1 mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis-relapse paired cases analyzed. We found another NOTCH1 "switching" case in a previously reported Berlin-Frankfurt-Münster cohort (n = 13), indicating NOTCH1 importance in both the development and progression of T-ALL. Despite the limitations of having a small sample size and a non-minimal residual disease-based protocol, our results suggest that the presence of NOTCH1 mutations might contribute to the disease relapse of T-ALL.

Jiang G, Shi W, Fang H, Zhang X
miR‑27a promotes human breast cancer cell migration by inducing EMT in a FBXW7‑dependent manner.
Mol Med Rep. 2018; 18(6):5417-5426 [PubMed] Article available free on PMC after 12/11/2019 Related Publications
Increasingly, evidence has revealed that aberrant microRNA (miRNA) expression is involved in breast cancer carcinogenesis and further progression, including metastasis. miRNA (miR)‑27a was previously identified to be abnormally expressed and to serve pro‑oncogenic functions in multiple human cancer types, including breast cancer. However, its functions and underlying mechanisms in breast cancer remain poorly understood. In the present study, it was demonstrated that miR‑27a was significantly upregulated in breast cancer tissues and cell lines compared with their normal counterparts. Overexpression of miR‑27a resulted in enhanced cell migration by inducing epithelial‑to‑mesenchymal transition, while its knockdown effectively reversed these cellular events. The present study additionally confirmed for the first time, to the best of our knowledge, that F‑box and WD repeat domain containing 7 (FBXW7) is a downstream target gene of miR‑27a in human breast cancer cells. FBXW7 is underexpressed in breast cancer tissues and cell lines, and is an independent positive factor for the overall survival rate of patients with breast cancer. Notably, the ectopic expression of FBXW7 may effectively suppress the epithelial‑to‑mesenchymal transition and migratory activity of breast cancer cells, in addition to reversing the cell migration mediated by miR‑27a. Altogether, the results of the present study indicated the important function of miR‑27a in regulating the metastasis of breast cancer in a FBXW7‑dependent manner, and provide evidence for the potential application of miR‑27a in breast cancer therapy.

Mori A, Masuda K, Ohtsuka H, et al.
FBXW7 modulates malignant potential and cisplatin-induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1.
Cancer Sci. 2018; 109(12):3883-3895 [PubMed] Article available free on PMC after 12/11/2019 Related Publications
The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW7 in cholangiocarcinoma. We found that FBXW7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease-free and overall survival were significantly worse in the low-FBXW7 group than in the high-FBXW7 group (P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW7 was the most important independent prognostic factor for disease-free (P = .006) and overall (P = .0004) survival. We also showed that the two FBXW7 substrates, NOTCH1 and myeloid cell leukemia sequence 1 (MCL1), regulate cholangiocarcinoma progression. Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self-renewal. Interestingly, when cells were stimulated with cis-diamminedichloridoplatinum(II) (cisplatin), FBXW7 suppression induced MCL1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW7-mediated ubiquitylation is context-dependent. These results indicate that FBXW7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH1 and MCL1.

Liu H, Zhu L, Liu YH
[Effect of FBXW7 and NOTCH1 Mutations on Prognosis of Patients with Adult Acute T Lymphoblastic Leukemia].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2018; 26(5):1294-1300 [PubMed] Related Publications
OBJECTIVE: To investigate the mutation rate and mutation characteristics of FBXW7 and NOTCH1 in adult T-ALL, and to study the effect of these 2 mutations on the clinical features and prognosis of patients with adult T-ALL.
METHODS: The mutations of FBXW7 and NOTCH1 in 106 adult T-ALL patients were determined by gene sequencing of FBXW7 and NOTCH1 genes. and the clinical characteristics and prognosis were compared.
RESULTS: Among the 106 cases of adult T-ALL, there were 21 cases (19.8%) of FBXW7 mutation, 66 cases (62.3%) of NOTCH1 mutation and 18 cases (17.0%) of FBXW7 / NOTCH1 double mutations. The 2-year cumulative overall survival rate and event-free survival rate of the patiants in FBXW7 / NOTCH1 double mutant group were lower than those without mutations (27.8% vs 70.3%)(P<0.01) and (16.7% vs 48.6%) ( P<0.01) respectivly, but the FBXW7 or NOTCH1 mutations had a little effect on the prognosis. The recurrence rate at mutant group was higher than that of the non - mutant group (77.8% vs 43.2%) (P<0.05).
CONCLUSION: FBXW7 or NOTCH1 mutations can not be as the prognostic factors, but the FBXW7 / NOTCH1 double mutations may indicate poor prognosis.

Youssef O, Knuuttila A, Piirilä P, et al.
Hotspot Mutations Detectable by Next-generation Sequencing in Exhaled Breath Condensates from Patients with Lung Cancer.
Anticancer Res. 2018; 38(10):5627-5634 [PubMed] Related Publications
BACKGROUND: Genetic alterations occurring in lung cancer are the basis for defining molecular subtypes and essential for targeted therapies. Exhaled breath condensate (EBC) is a form of non-invasive sample that, amongst components, contains DNA from pulmonary tissue. Next-generation sequencing (NGS) was herein used to analyze mutations in EBC from patients with lung cancer.
MATERIALS AND METHODS: EBC was collected from 26 patients with cancer and 20 healthy controls. Amplicon-based sequencing using Ion Ampliseq Colon and Lung Cancer gene panel v2 was applied.
RESULTS: The sequencing was successful in 17 patients and 20 controls. EBC from patients revealed 39 hotspot mutations occurring in: adenomatous polyposis coli (APC), v-raf murine sarcoma viral oncogene homolog B (BRAF), discoidin domain receptor tyrosine kinase 2 (DDR2), epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 4 (ERBB4), F-box and WD repeat domain containing 7 (FBXW7), fibroblast growth factor receptor 1 (FGFR1), FGFR3 (fibroblast growth factor receptor 3), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1 (MAP2K1), met proto-oncogene (MET), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), ret proto-oncogene (RET), SMAD family member 4 (SMAD4), serine/threonine kinase 11 (STK11), and tumor protein p53 (TP53) genes. EBC from controls revealed 35 hotspot mutations. The average mutant allele fraction was higher in patients than controls.
CONCLUSION: NGS can identify mutations in EBCs from patients with lung cancer. This could provide a promising non-invasive method for the assessment of gene mutations in lung cancer.

Aziz D, Etemadmoghadam D, Caldon CE, et al.
19q12 amplified and non-amplified subsets of high grade serous ovarian cancer with overexpression of cyclin E1 differ in their molecular drivers and clinical outcomes.
Gynecol Oncol. 2018; 151(2):327-336 [PubMed] Related Publications
OBJECTIVES: Readily apparent cyclin E1 expression occurs in 50% of HGSOC, but only half are linked to 19q12 locus amplification. The amplified/cyclin E1
METHODS: 262 HGSOC cases were analyzed by in situ hybridization for 19q12 locus amplification and immunohistochemistry for cyclin E1, URI1 (another protein encoded by the 19q12 locus), FBXW7 and USP28 expression. Tumors were classified by 19q12 amplification status and correlated to cyclin E1 and URI1 expression, BRCA1/2 germline mutation, FBXW7 and USP28 expression, and clinical outcomes. Additionally, we assessed the relative genomic instability of amplified/cyclin E1
RESULTS: Of the 82 cyclin E1
CONCLUSIONS: Amplified/cyclin E1

Zhou R, Xu X, Liu M, et al.
Immunophenotypes of Ductal Epithelial Cells in Advanced Pancreatic Ductal Adenocarcinoma.
Digestion. 2019; 99(3):247-251 [PubMed] Related Publications
BACKGROUND/AIMS: In this report, we aimed to investigate the distribution and characterization of biomarker-immunolabeled ductal epithelium in advanced pancreatic ductal adenocarcinoma (PDAC).
DESIGN: Eighteen patients with PDAC were medically diagnosed prior to being treated periodically. All clinical records were collected and assayed. The PDAC samples were subjected to routine biochemical tests and immuno-stains of immunohistochemistry and immunofluorescence.
RESULTS: As results, immunohistochemical findings indicated pancreatic ductal cells in PDAC showed plenty of Ki-67, P53, RP, SAM positive cells expressed in nuclei. In addition, ductal epithelial cells exhibited numerous positive cells of CK7, 18, 19, 20 biomarkers, respectively. Interestingly, compared to non-PDAC controls, immunostaining results showed that endocrine hormones were positively expressed in pancreatic ducts of PDAC, characterized with increased insulin-, Ngn3-, PDX1-fluorescence-labeled cells, and reduced F-box and WD-40 domain protein 7 (Fbxw7)-labeled cells in ducts.
CONCLUSION: These clinicopathologic findings preliminarily disclose that there may be a potential for insulin-producing cells in PDAC, possibly through negatively inducing Fbxw7 ubiquitination in pancreatic ducts.

Liu Y, Weber Z, San Lucas FA, et al.
Assessing inter-component heterogeneity of biphasic uterine carcinosarcomas.
Gynecol Oncol. 2018; 151(2):243-249 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
OBJECTIVE: Uterine carcinosarcoma (UCS) is a rare and aggressive form of uterine cancer. It is bi-phasic, exhibiting histological features of both malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements, reflected in ambiguity in accepted treatment guidelines. We sought to study the genomic and transcriptomic profiles of these elements individually to gain further insights into the development of these tumors.
METHODS: We macro-dissected carcinomatous, sarcomatous, and normal tissues from formalin fixed paraffin embedded uterine samples of 10 UCS patients. Single nucleotide polymorphism microarrays, targeted DNA sequencing and whole-transcriptome RNA-sequencing were performed. Somatic chromosomal alterations (SCAs), point mutation and gene expression profiles were compared between carcinomatous and sarcomatous components.
RESULTS: In addition to TP53, other recurrently mutated genes harboring putative driver or loss-of-function mutations included PTEN, FBXW7, FGFR2, KRAS, PIK3CA and CTNNB1, genes known to be involved in UCS. Intra-patient somatic mutation and SCA profiles were highly similar between paired carcinoma and sarcoma samples. An epithelial-mesenchymal transition (EMT) signature tended to differentiate components, with EMT-like status more common in advanced-stage patients exhibiting higher inter-component SCA heterogeneity.
CONCLUSIONS: From DNA analysis, our results indicate a monoclonal disease origin for this cohort. Yet expression-derived EMT statuses of the carcinomatous and sarcomatous components were often discrepant, and advanced cases displayed greater genomic heterogeneity. Therefore, separately-profiled components of UCS tumors may better inform disease progression or potential.

Huang LY, Zhao J, Chen H, et al.
Nat Commun. 2018; 9(1):3569 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Brg1/SMARCA4 serves as the ATPase and the helicase catalytic subunit for the multi-component SWI/SNF chromatin remodeling complex, which plays a pivotal role in governing chromatin structure and gene transcription. However, the upstream signaling pathways regulating Brg1 protein stability and its physiological contribution to carcinogenesis remain largely elusive. Here we report that Brg1 is a bona fide ubiquitin substrate of SCF

Schulz GB, Grimm T, Buchner A, et al.
Surgical High-risk Patients With ASA ≥ 3 Undergoing Radical Cystectomy: Morbidity, Mortality, and Predictors for Major Complications in a High-volume Tertiary Center.
Clin Genitourin Cancer. 2018; 16(6):e1141-e1149 [PubMed] Related Publications
BACKGROUND: The purpose of this study was to investigate major complications and risk factors for adverse clinical outcome in surgical high-risk (American Society of Anesthesiologists [ASA] 3-4) patients undergoing radical cystectomy (RC) in a high-volume setting.
PATIENTS AND METHODS: A total of 1206 patients underwent RC between 2004 and 2017 in our institution and were included. We assessed complications graded by the Clavien-Dindo-Classification system (CDC) in addition to the 90-day mortality rate and stratified results by the ASA classification. In a multivariate analysis, risk factors for high-grade complications (CDC ≥ 3) were tested. Additionally, outcome parameters were compared between 2004 to 2010 and 2010 to 2017.
RESULTS: Patients with ASA ≥ 3 presented with more locally advanced tumors pT ≥ 3 (52.1% vs. 42.4%; P = .002) and positive lymphatic spread N1 (27.2% vs. 23.5%; P = .001) compared with patients with ASA ≤ 2. High-grade complications were significantly (P < .001) more prevalent in patients with ASA ≥ 3 compared with patients with ASA ≤ 2: CDC3 (14.6% vs. 9.4%), CDC4 (10.2% vs. 5.4%), and CDC5 (2.5% vs. 1.0%). The 90-day mortality rate (7.6% vs. 3.2%; P = .002) and perioperative reinterventions (23.5% vs. 13.1%; P < .001) were elevated in patients with ASA ≥ 3. ASA (odds ratio [OR], 2.701, 95% confidence interval [CI], 1.089-6.703; P = .032), previous abdominal operations (OR, 1.683; 95% CI, 1.188-2.384; P = .003), and body mass index ≥ 30 (OR, 1.533; 95% CI, 1.021-2.304; P = .039) proved to function as independent predictors for major complications. CDC ≥ 3 complications (31.7% vs. 24.3%; P = .029) and 90-day mortality (10.4% vs. 5.6%; P = .018) were significantly lower in the second half of the study period.
CONCLUSIONS: Mortality and morbidity in surgical high-risk patients with ASA 3 to 4 undergoing RC is about twice as high compared with patients with ASA 1 to 2. ASA, previous abdominal operations, and elevated body mass index independently predict adverse clinical outcome in patients with ASA 3 to 4. Our results may help to weigh the surgical risk of RC in multimorbid patients.

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