FBXW7

Gene Summary

Gene:FBXW7; F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase
Aliases: AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10
Location:4q31.3
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, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:F-box/WD repeat-containing protein 7
HPRD
Source:NCBIAccessed: 28 February, 2015

Ontology:

What does this gene/protein do?
Show (28)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 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 28 February, 2015 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 Publications34
Colorectal CancerFBXW7 and Colorectal Cancer View Publications26
Acute Lymphocytic Leukemia (ALL), childFBXW7 and Childhood T-cell ALL View Publications23
Breast CancerFBXW7 and Breast Cancer View Publications20
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 Publications3
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 Publications3
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)

Natarajan V, Bandapalli OR, Rajkumar T, et al.
NOTCH1 and FBXW7 mutations favor better outcome in pediatric South Indian T-cell acute lymphoblastic leukemia.
J Pediatr Hematol Oncol. 2015; 37(1):e23-30 [PubMed] Related Publications
The NOTCH1 signaling pathway is essential for hematopoiesis and a critical regulatory step for T-cell proliferation and maturation. The E3 ubiquitin ligase FBXW7 controls NOTCH1 protein stability. Mutations in NOTCH1/FBXW7 activate NOTCH signaling and are of prognostic significance in patients with T-cell acute lymphoblastic leukemia (T-ALL). In this study we analyzed NOTCH1 and FBXW7 mutations in 50 South Indian T-ALL patients treated by a modified ALL BFM 95 regimen. The hot spot exons (HD-N, HD-C, TAD, and PEST) of NOTCH1 and exons 9 of the 10 of FBXW7 were polymerase chain reaction amplified and sequenced. In total, 20 of the 50 (40%) T-ALL patients revealed heterozygous mutations in the NOTCH1 domains, and a predominance of missense mutations in HD-N (70%) and PEST (15%) domains. FBXW7 mutations were detected in 5 of the 50 (10%) T-ALL patients. T-ALL patients with NOTCH1/FBXW7 mutations expressed higher protein level of NOTCH1 compared with patients without NOTCH1/FBXW7 mutations. Six of the mutations detected in NOTCH1 were not reported previously. When tested in a Dual Luciferase Renilla reporter assay some of these conferred increased NOTCH activity, suggesting that these are activating mutations. Importantly, 13 of the 20 (65%) NOTCH1/FBXW7-mutated T-ALL patients showed a good prednisone response (P=0.01) and a better clinical outcome compared with NOTCH1/FBXW7 nonmutated patients (P=0.03). These data suggest that NOTCH1/FBXW7 mutations are present in T-ALL patients from Southern India and may be useful biomarkers to predict prognosis in T-ALL.

Davis RJ, Welcker M, Clurman BE
Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities.
Cancer Cell. 2014; 26(4):455-64 [PubMed] Article available free on PMC after 13/10/2015 Related Publications
Tumor suppressors with widespread impact on carcinogenesis control broad spectra of oncogenic pathways. Protein degradation is an emerging mechanism by which tumor suppressors regulate a diversity of pathways and is exemplified by the SCF(Fbw7) ubiquitin ligase. Rapidly accumulating data indicate that SCF(Fbw7) regulates a network of crucial oncoproteins. Importantly, the FBXW7 gene, which encodes Fbw7, is one of the most frequently mutated genes in human cancers. These studies are yielding important new insights into tumorigenesis and may soon enable therapies targeting the Fbw7 pathway. Here, we focus on the mechanisms and consequences of Fbw7 deregulation in cancers and discuss possible therapeutic approaches.

Li L, Sarver AL, Khatri R, et al.
Sequential expression of miR-182 and miR-503 cooperatively targets FBXW7, contributing to the malignant transformation of colon adenoma to adenocarcinoma.
J Pathol. 2014; 234(4):488-501 [PubMed] Related Publications
Genetic changes in colon cancer are known to parallel the tissue abnormalities associated with the disease, namely adenoma and adenocarcinoma. The role of microRNA dysregulation in dysplastic progression, however, is not well understood. Here, we show that miR-182 and miR-503 undergo sequential up-regulation and drive the progression of colon adenoma to adenocarcinoma by cooperatively down-regulating the tumour suppressor FBXW7. We identified that increased expression of miR-182 is a feature of adenomas. A subsequent increase in miR-503 expression works cooperatively with miR-182 to induce transformation of an adenoma to adenocarcinoma. We show that introducing miR-503 into AAC1 cells, which are derived from a benign adenoma, confers tumourigenic potential. We also demonstrated that blocking both miR-182 and miR-503 in HCT116 colon cancer cells resulted in increased FBXW7 expression and significantly reduced tumour size in xenograft models. We confirmed relevance of these results in patients by examining the expression levels of miR-182 and miR-503 in over 200 colon cancer patients with 12 year survival outcome data. Decreased patient survival was correlated with elevated expression of both miRNAs, suggesting that elevated levels of both miR-182 and miR-503 define a novel prognostic biomarker for colon cancer patients. In conclusion, we show that a sequential expression of miR-182 and miR-503 in benign adenoma cooperatively regulates the tumour suppressor FBXW7, contributing to the malignant transformation of colon adenoma to adenocarcinoma and miR-182 and miR-503 may prove to be novel therapeutic targets. Array data are available at: http://www.oncomir.umn.edu/

Gao YB, Chen ZL, Li JG, et al.
Genetic landscape of esophageal squamous cell carcinoma.
Nat Genet. 2014; 46(10):1097-102 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

Trietsch MD, Spaans VM, ter Haar NT, et al.
CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma.
Gynecol Oncol. 2014; 135(1):149-55 [PubMed] Related Publications
BACKGROUND: Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs).
METHODS: A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry.
RESULTS: Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53=58, CDKN2A(p16)=14, HRAS=10, PIK3CA=7, PPP2R1A=3, KRAS=1, PTEN=1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P=.035), with a large effect from patients carrying HRAS-mutations.
CONCLUSION: Somatic mutations were detected in 62% of VSCCs. As expected, HPV infection and TP53-mutations play a key role in the development of VSCC, but CDKN2A(p16), HRAS, and PIK3CA-mutations were also frequently seen in HPV-negative patients. Patients with somatic mutations, especially HRAS-mutations, have a significantly worse prognosis than patients lacking these changes, which could be of importance for the development of targeted therapy.

Siu KT, Xu Y, Swartz KL, et al.
Chromosome instability underlies hematopoietic stem cell dysfunction and lymphoid neoplasia associated with impaired Fbw7-mediated cyclin E regulation.
Mol Cell Biol. 2014; 34(17):3244-58 [PubMed] Article available free on PMC after 13/10/2015 Related Publications
The Fbw7 ubiquitin ligase critically regulates hematopoietic stem cell (HSC) function, though the precise contribution of individual substrate ubiquitination pathways to HSC homeostasis is unknown. In the work reported here, we used a mouse model in which we introduced two knock-in mutations (T74A and T393A [changes of T to A at positions 74 and 393]) to disrupt Fbw7-dependent regulation of cyclin E, its prototypic substrate, and to examine the consequences of cyclin E dysregulation for HSC function. Serial transplantation revealed that cyclin E(T74A T393A) HSCs self-renewed normally; however, we identified defects in their multilineage reconstituting capacity. By inducing hematologic stress, we exposed an impaired self-renewal phenotype in cyclin E knock-in HSCs that was associated with defective cell cycle exit and the emergence of chromosome instability (CIN). Importantly, p53 deletion induced both defects in self-renewal and multilineage reconstitution in cyclin E knock-in HSCs with serial transplantation and CIN in hematopoietic stem and progenitor cells. Moreover, CIN was a feature of fatal T-cell malignancies that ultimately developed in recipients of cyclin E(T74A T393A); p53-null HSCs. Together, our findings demonstrate the importance of Fbw7-dependent cyclin E control to the hematopoietic system and highlight CIN as a characteristic feature of HSC dysfunction and malignancy induced by deregulated cyclin E.

Wang L, Ye X, Liu Y, et al.
Aberrant regulation of FBW7 in cancer.
Oncotarget. 2014; 5(8):2000-15 [PubMed] Article available free on PMC after 13/10/2015 Related Publications
FBW7 (F-box and WD repeat domain-containing 7) or Fbxw7 is a tumor suppressor, which promotes the ubiquitination and subsequent degradation of numerous oncoproteins including Mcl-1, Cyclin E, Notch, c- Jun, and c-Myc. In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-δ, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p. Given that the Fbw7 tumor suppressor is frequently inactivated or deleted in various human cancers, targeting FBW7 regulators is a promising anti-cancer therapeutic strategy.

Tu K, Yang W, Li C, et al.
Fbxw7 is an independent prognostic marker and induces apoptosis and growth arrest by regulating YAP abundance in hepatocellular carcinoma.
Mol Cancer. 2014; 13:110 [PubMed] Article available free on PMC after 13/10/2015 Related Publications
BACKGROUND: The E3 ubiquitin ligase Fbxw7 functions as a general tumor suppressor by targeting several well-known oncoproteins for ubiquitination and proteasomal degradation. However, the clinical significance of Fbxw7 and the mechanisms involved in the anti-cancer effect of Fbxw7 in HCC are not clear.
METHOD: The Fbxw7 and YAP expression in 60 samples of surgical resected HCC and matched normal tumor-adjacent tissues were assessed using IHC or immunoblotting. Flow cytometry, caspase 3/7 activity assay, BrdU cell proliferation assay and MTT assay were used to detect proliferation and apoptosis of HCC cells. The regulatory effect of Fbxw7 on YAP in HCC cells was confirmed by qRT-PCR, immunoblotting and immunofluorescence. Co-immunoprecipitation was used to analyze interaction between YAP and Fbxw7. Nude mice subcutaneous injection, Ki-67 staining and TUNEL assay were used to evaluate tumor growth and apoptosis in vivo.
RESULTS: In this study, we found that Fbxw7 expression was impaired in HCC tissues and loss of Fbxw7 expression was correlated with poor clinicopathological features including large tumor size, venous infiltration, high pathological grading and advanced TNM stage. Additionally, we demonstrated that patients with positive Fbxw7 expression had a better 5-year survival and Fbxw7 was an independent factor for predicting the prognosis of HCC patients. We confirmed that Fbxw7 inhibited HCC by inducing both apoptosis and growth arrest. Elevated YAP expression was observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated that Fbxw7 was inversely associated with YAP protein expression in HCC tissues. We also found that Fbxw7 regulated YAP protein abundance by targeting YAP for ubiquitination and proteasomal degradation in HCC. Furthermore, restoring YAP expression partially abrogated Fbxw7 induced HCC cell apoptosis and growth arrest in vitro and in vivo.
CONCLUSION: These results indicate that Fbxw7 may serve as a prognostic marker and that YAP may be a potential target of Fbxw7 in HCC.

Takeishi S, Nakayama KI
Role of Fbxw7 in the maintenance of normal stem cells and cancer-initiating cells.
Br J Cancer. 2014; 111(6):1054-9 [PubMed] Related Publications
In addition to the properties of self-renewal and multipotency, stem cells are characterised by their distinct cell cycle status. Somatic stem cells are maintained in a quiescent state but switch reversibly from quiescence to proliferation as needed. On the other hand, embryonic stem cells and induced pluripotent stem cells proliferate rapidly until the induction of differentiation results in inhibition of cell cycle progression. Uncovering the mechanisms underlying cell cycle control in stem cells should thus provide insight into regulation of the balance between self-renewal and differentiation, a key goal of stem cell biology. Recent research has shown that cancer-initiating cells (CICs), a cell population with stem cell-like properties in cancer, are also quiescent, with this characteristic conferring resistance to anticancer therapies that target dividing cells. Elucidation of the mechanisms of CIC quiescence might therefore be expected to provide a basis for the eradication of cancer. This review summarises our current understanding of the role of F-box and WD40 repeat domain-containing 7 (Fbxw7), a key regulator of the cell cycle, in the maintenance of normal stem cells and CICs, as well as attempts to define future challenges in this field.

Aydin IT, Melamed RD, Adams SJ, et al.
FBXW7 mutations in melanoma and a new therapeutic paradigm.
J Natl Cancer Inst. 2014; 106(6):dju107 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: Melanoma is a heterogeneous tumor with subgroups requiring distinct therapeutic strategies. Genetic dissection of melanoma subgroups and identification of therapeutic agents are of great interest in the field. These efforts will ultimately lead to treatment strategies, likely combinatorial, based on genetic information.
METHODS: To identify "driver" genes that can be targeted therapeutically, we screened metastatic melanomas for somatic mutations by exome sequencing followed by selecting those with available targeted therapies directed to the gene product or its functional partner. The FBXW7 gene and its substrate NOTCH1 were identified and further examined. Mutation profiling of FBXW7, biological relevance of these mutations and its inactivation, and pharmacological inhibition of NOTCH1 were examined using in vitro and in vivo assays.
RESULTS: We found FBXW7 to be mutated in eight (8.1%) melanoma patients in our cohort (n = 103). Protein expression analysis in human tissue samples (n = 96) and melanoma cell lines (n = 20) showed FBXW7 inactivation as a common event in melanoma (40.0% of cell lines). As a result of FBXW7 loss, we observed an accumulation of its substrates, such as NOTCH1. Ectopic expression of mutant forms of FBXW7 (by 2.4-fold), as well as silencing of FBXW7 in immortalized melanocytes, accelerated tumor formation in vivo (by 3.9-fold). Its inactivation led to NOTCH1 activation, upregulation of NOTCH1 target genes (by 2.6-fold), and promotion of tumor angiogenesis and resulted in tumor shrinkage upon NOTCH1 inhibition (by fivefold).
CONCLUSIONS: Our data provides evidence on FBXW7 as a critical tumor suppressor mutated and inactivated in melanoma that results in sustained NOTCH1 activation and renders NOTCH signaling inhibition as a promising therapeutic strategy in this setting.

Cialfi S, Palermo R, Manca S, et al.
Loss of Notch1-dependent p21(Waf1/Cip1) expression influences the Notch1 outcome in tumorigenesis.
Cell Cycle. 2014; 13(13):2046-55 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Notch signaling plays a complex role in carcinogenesis, and its signaling pathway has both tumor-suppressor and oncogenic components. In this study we investigated the effects of reactive oxygen species (ROS) on Notch1 signaling outcome in keratinocyte biology. We demonstrate that Notch1 function contributes to the arsenic-induced keratinocyte transformation. We found that acute exposure to arsenite increases oxidative stress and inhibits proliferation of keratinocyte cells by upregulation of p21(waf1/Cip1). The necessity of p21(waf1/Cip1) for arsenite-induced cell death was demonstrated by targeted downregulation of p21(waf1/Cip1) by using RNA interference. We further demonstrated that on acute exposure to arsenite, p21(waf1/Cip1) is upregulated and Notch1 downmodulated, whereas on chronic exposure to arsenite, malignant progression of arsenite-treated keratinocytes cells was accompanied by regained expression and activity of Notch1. Notch1 activity in arsenite-transformed keratinocytes inhibits arsenite-induced upregulation of p21(waf1/Cip1) by sustaining c-myc expression. We further demonstrated that c-myc collaborates with Nrf2, a key regulator for the maintenance of redox homeostasis, to promote metabolic activities that support cell proliferation and cytoprotection. Therefore, Notch1-mediated repression of p21(waf1/Cip1) expression results in the inhibition of cell death and keratinocytes transformation. Our results not only demonstrate that sustained Notch1 expression is at least one key event implicated in the arsenite human skin carcinogenic effect, but also may provide mechanistic insights into the molecular aspects that determine whether Notch signaling will be either oncogenic or tumor suppressive.

Laforest A, Aparicio T, Zaanan A, et al.
ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma.
Eur J Cancer. 2014; 50(10):1740-6 [PubMed] Related Publications
AIM OF THE STUDY: Small bowel adenocarcinoma (SBA) is a rare and aggressive tumour with poor outcomes. Because of its low incidence, the number prospective studies remains insufficient leading to poor knowledge and absence of standard of care. Aiming to better understand small bowel carcinogenesis we investigated the frequency of somatic mutations in a large data set of patients in more than 740 mutational hotspots among 46 genes.
METHODS: In total, 83 SBA cases were selected from two European databases. The sequencing was performed using the Ion 316 Chip. Additionally we looked into ERBB2 expression and microsatellite instability (MSI) status.
RESULTS: The tumours most frequently were duodenal (47%) and stage ⩾3 (63%). Eight genes were mutated with a frequency >5%: KRAS, TP53, APC, SMAD4, PIK3CA, ERBB2, BRAF and FBXW7. ERBB2 alterations are present in 10 patients (12%) through mutations (7 cases) or amplifications (3 cases). ERBB2 mutations were significantly associated with duodenal tumour location (P=0.04). In this group, there was a positive association with dMMR status (P=0.006) and APC mutation (P=0.02) but negative association with p53 mutations (P=0.038).
CONCLUSIONS: This study describes the first large screening of somatic mutations in SBA using next generation sequencing. The ERBB2 mutation was revealed to be one of the most frequent alterations in SBA with a distribution dependent on tumour location. In most cases ERBB2 mutation was identical (p.L755S). In clinical practice, this may suggest that more than 10% of the patients with SBA could be treated using an anti-ERBB2-targeted agent.

Sun Y, Li X
The canonical wnt signal restricts the glycogen synthase kinase 3/fbw7-dependent ubiquitination and degradation of eya1 phosphatase.
Mol Cell Biol. 2014; 34(13):2409-17 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome, and abnormally high levels of Eya1 are linked to breast cancer progression and poor prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific functions and oncogenic activities. Here, we show that Eya1 is posttranslationally modified by ubiquitin and that its ubiquitination level is self-limited to prevent premature degradation. Eya1 has an evolutionarily conserved CDC4 phosphodegron (CPD) signal, a target site of glycogen synthase kinase 3 (GSK3) kinase and Fbw7 ubiquitin ligase, which is required for Eya1 ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 significantly decrease Eya1 ubiquitination. Conversely, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the canonical Wnt signal suppresses Eya1 ubiquitination. Compound Eya1(+/-); Wnt9b(+/-) mutants exhibit an increased penetrance of renal defect, indicating that they function in the same genetic pathway in vivo. Together, these findings reveal that the canonical Wnt and PI3K/Akt signal pathways restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, and they further suggest that dysregulation of this novel axis contributes to tumorigenesis.

Beldjord K, Chevret S, Asnafi V, et al.
Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.
Blood. 2014; 123(24):3739-49 [PubMed] Related Publications
With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.

Huhn S, Bevier M, Pardini B, et al.
Colorectal cancer risk and patients' survival: influence of polymorphisms in genes somatically mutated in colorectal tumors.
Cancer Causes Control. 2014; 25(6):759-69 [PubMed] Related Publications
PURPOSE: The first two studies aiming for the high-throughput identification of the somatic mutation spectrum of colorectal cancer (CRC) tumors were published in 2006 and 2007. Using exome sequencing, they described 69 and 140 candidate cancer genes (CAN genes), respectively. We hypothesized that germline variants in these genes may influence CRC risk, similar to APC, which is causing CRC through germline and somatic mutations.
METHODS: After excluding the well-established CRC genes APC, KRAS, TP53, and ABCA1, we analyzed 35 potentially functional single-nucleotide polymorphisms (SNPs) in 10 CAN genes (OBSCN, MLL3, PKHD1, SYNE1, ERCC6, FBXW7, EPHB6/TRPV6, ELAC1/SMAD4, EPHA3, and ADAMTSL3) using KBiosciences Competitive Allele-Specific PCR™ genotyping assays. In addition to CRC risk (1,399 CRC cases, 838 controls), we also considered the influence of the SNPs on patients' survival (406 cases).
RESULTS: In spite of the fact that our in silico analyses suggested functional relevance for the studied genes and SNPs, our data did not support a strong influence of the studied germline variants on CRC risk and survival. The strongest association with CRC risk and survival was found for MLL3 (rs6464211, OR 1.50, p = 0.002, dominant model; HR 2.12, p = 0.020, recessive model). Two SNPs in EPHB6/TRPV6 (dominant model) showed marginal associations with survival (rs4987622 HR 0.58 p = 0.028 and rs6947538 HR 0.64, p = 0.036, respectively).
CONCLUSION: Although somatic mutations in the CAN genes have been related to the development and progression of various types of cancers in several next-generation sequencing or expression analyses, our study suggests that the studied potentially functional germline variants are not likely to affect CRC risk or survival.

Yu J, Zhang W, Gao F, et al.
FBW7 increases chemosensitivity in hepatocellular carcinoma cells through suppression of epithelial-mesenchymal transition.
Hepatobiliary Pancreat Dis Int. 2014; 13(2):184-91 [PubMed] Related Publications
BACKGROUND: FBW7 is a tumor suppressor which regulates a network of proteins with central roles in cell division, cell growth and differentiation. This study aimed to evaluate the role of FBW7 in chemosensitivity and epithelial-mesenchymal transition (EMT) in different hepatocellular carcinoma (HCC) cell lines and to investigate the relevant underlying mechanisms.
METHODS: Different human HCC cell lines (Hep3B, Huh-7, and SNU-449) were cultured. The cell viability was evaluated by cell counting kit-8, and FBW7 mRNA transcription and protein expression were quantitated by real-time PCR and Western blotting. Expressions of vimentin (mesenchymal biomarker) and E-cadherin (epithelial biomarker) were evaluated by Western blotting and immunocytochemistry. Cell invasion was assayed by Transwell migration, and FBW7 plasmid or siRNA was used to evaluate the effect of FBW7 overexpression or silencing on cell chemosensitivity.
RESULTS: FBW7 expression affected tumor cell chemosensitivity to doxorubicin and tumor cell invasive capacity in different HCC cell lines. FBW7hi (high FBW7 expression) Hep3B and FBW7mi (median FBW7 expression) Huh-7 cells were more sensitive to doxorubicin and lower in invasive capacity than FBW7lo (low FBW7 expression) SNU-449 cells. Silencing of FBW7 in Huh-7 and Hep3B cells induced the resistance to doxorubicin and enhanced cell invasion, whereas overexpression of FBW7 in SNU-449 cells restored the sensitivity to doxorubicin and significantly reduced invasive capacity. Furthermore, doxorubicin induced EMT toward mesenchyme in HCC cells. Downregulation of FBW7 in Huh-7 and Hep3B cells or upregulation of FBW7 in SNU-449 cells altered the direction of EMT.
CONCLUSIONS: The level of FBW7 expression impacted the tumor resistance to doxorubicin and the invasion capability of HCC cells. FBW7 therefore may be a potential target for the chemotherapy of HCC through the regulation of EMT.

Mühlbacher V, Zenger M, Schnittger S, et al.
Acute lymphoblastic leukemia with low hypodiploid/near triploid karyotype is a specific clinical entity and exhibits a very high TP53 mutation frequency of 93%.
Genes Chromosomes Cancer. 2014; 53(6):524-36 [PubMed] Related Publications
B lymphoblastic leukemia/lymphoma (ALL) are subdivided by the WHO classification into five subgroups defined by specific translocations and two further subgroups defined by the number of chromosomes. The hypodiploid subgroup is heterogeneous and comprises ALL with a chromosome number of <46. To characterize a specific subset with low hypodiploid karyotype, we performed chromosome banding analysis, FISH, array comparative genomic hybridization, and mutational analyses of FBXW7, NOTCH1, KRAS, NRAS, TP53, and IKZF1 in 29 cases. We observed a nonrandom pattern of chromosome losses, including chromosomes 3, 7, 13, 15, 16, and 17. A deletion encompassing the CDKN2A/B locus was the only recurrent structural abnormality. A duplication of the low hypodiploid karyotype occurred frequently, resulting in a near triploid karyotype based on the definition by merely counting chromosomes but in fact was a very low tetraploid chromosome set. Mutational analyses revealed no mutations in IKZF1, FBXW7, NOTCH1, and KRAS and only one mutation in NRAS. However, we discovered a high frequency of TP53 mutations in 93% (27/29) of cases. In 26/27 cases with TP53 mutation, the second TP53 allele was lost due to monosomy 17. Median overall survival was short (18.5 months), which might be related to the high frequency of TP53 alterations. Therefore, ALL with low hypodiploidy is characterized by a typical pattern of chromosome losses and a remarkably high TP53 mutation frequency. Our data suggest the introduction of a novel WHO entity within the B lymphoblastic leukemia/lymphoma group showing low hypodiploid/very low tetraploid karyotype and concomitant TP53 mutation.

Meric-Bernstam F, Frampton GM, Ferrer-Lozano J, et al.
Concordance of genomic alterations between primary and recurrent breast cancer.
Mol Cancer Ther. 2014; 13(5):1382-9 [PubMed] Related Publications
There is growing interest in delivering genomically informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next-generation sequencing was performed on formalin-fixed paraffin-embedded (FFPE) samples, profiling 3,320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy-number alterations (CNA), and select rearrangements were assessed in 74 tumors from 43 patients (36 primary and 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered "actionable." Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7, and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, and AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified CNAs, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. Forty of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most patients with breast cancer. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors before treatment may provide additional insights, as both gains and losses of targets are observed.

Jardim DL, Wheler JJ, Hess K, et al.
FBXW7 mutations in patients with advanced cancers: clinical and molecular characteristics and outcomes with mTOR inhibitors.
PLoS One. 2014; 9(2):e89388 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
PURPOSE: FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. Preclinical data suggest that FBXW7 mutations sensitize cells to mTOR inhibitors. Clinicopathologic characteristics of cancer patients with FBXW7 mutations and their responses to mTOR inhibitors remain unknown.
METHODS: Using multiplex gene panels we evaluated how the FBXW7 mutation affected the cancer phenotype of patients referred to a phase I clinic starting January 2012. Whenever possible patients positive for FBXW7 mutation were treated with regimens containing an mTOR inhibitors and their outcomes were reviewed.
RESULTS: FBXW7 mutations were detected in 17 of 418 patients (4.0%). Among tumor types with more than 10 patients tested, FBXW7 mutations occurred in colorectal cancer (7/49; 14.3%), squamous cell cancer of head and neck (2/18; 11.1%), liver (1/13; 7.7%), and ovarian cancers (1/40; 2.5%). No one clinical, pathological or demographic feature was characteristic of the FBXW7-mutated patient population. The mutation occurred in isolation in only 2/17 (12%) patients, and KRAS was frequently found as a concomitant mutation, especially in patients with colorectal cancer (6/7; 86%). Ten patients were treated on a protocol containing an mTOR inhibitor, with a median time to treatment failure of 2.8 months (range, 1.3-6.8). One patient with liver cancer (fibrolamellar subtype) continues to have a prolonged stable disease for 6.8+ months.
CONCLUSION: In patients with advanced cancers, somatic mutations in FBXW7 usually occur with other simultaneous molecular aberrations, which can contribute to limited therapeutic efficacy of mTOR inhibitors.

Despierre E, Yesilyurt BT, Lambrechts S, et al.
Epithelial ovarian cancer: rationale for changing the one-fits-all standard treatment regimen to subtype-specific treatment.
Int J Gynecol Cancer. 2014; 24(3):468-77 [PubMed] Related Publications
OBJECTIVE: Epithelial ovarian cancers (EOCs) are, although still treated as a single disease entity, often classified into type I tumors (low-grade serous, mucinous, endometrioid, clear cell) and type II tumors (high-grade serous, undifferentiated cancers, carcinosarcomas). The aim of our study was to determine the incidence, clinical relevance, and prognostic and predictive impact of somatic mutations in both types I and II EOCs.
METHODS: Two hundred sixty-two evaluable, primary, high-risk stage I (grade 3, or aneuploid grade 1 or 2, or clear cell) and stage II-IV EOCs, collected at the University Hospitals Leuven and within the European Organisation for Research and Treatment of Cancer 55971 trial, were genotyped for hotspot mutations in KRAS (COSMIC [Catalogue of Somatic Mutations in Cancer] coverage >97%), BRAF (>94%), NRAS (>97%), PIK3CA (>79%), PTEN, FBXW7 (>57%), AKT2, AKT3, and FOXL2, using Sequenom MassARRAY.
RESULTS: Of the 13% histopathologically classified type I tumors, 49% were KRAS or PIK3CA mutant versus only 2.9% in the type II tumors (87%). Mucinous subtypes harbored significantly more KRAS mutations than all nonmucinous tumors (50% vs 4%, P < 0.001). PIK3CA mutations were predominantly found in clear cell carcinomas (46.2%) and endometrioid carcinoma (20%) and were frequently associated with endometriosis. Moreover, low-grade serous tumors were more frequently KRAS or BRAF mutated (44%) than high-grade serous tumors (0.6%). KRAS or PIK3CA mutation did not correlate with progression-free survival or overall survival. Mutations in NRAS, PTEN, FBXW7, AKT2, AKT3, and FOXL2 were rare (<1%).
CONCLUSIONS: Somatic mutations are rare in type II EOCs, whereas type I EOCs contain distinct diseases with different driver mutations. In general, these tumors respond worse to standard paclitaxel carboplatin therapy. Clinical trials with molecular targeted therapy in the different subtypes of type I tumors are urgently needed using this theragnostic information.

Tan Y, Sun D, Jiang W, et al.
PP2A-B55β antagonizes cyclin E1 proteolysis and promotes its dysregulation in cancer.
Cancer Res. 2014; 74(7):2006-14 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Cyclin E1 regulates the initiation of S-phase in cellular division. However, in many cancers, cyclin E1 is aberrantly overexpressed and this molecular phenotype correlates with increased tumor aggressiveness and poor patient survival. The molecular cause(s) of cyclin E1 abnormalities in cancers is poorly understood. Here, we show that cyclin E1 overexpression in cancer is promoted by dysregulation of the protein phosphatase PP2A-B55β. PP2A-B55β targets the N- and C-terminal phosphodegrons of cyclin E1 for dephosphorylation, thus protecting it from degradation mediated by the SCF(Fbxw7) ubiquitin ligase. Augmented B55β expression stabilizes cyclin E1 and promotes its overexpression in cancer-derived cell lines and breast tumors. Conversely, B55β ablation enforces the degradation of cyclin E1 and inhibits cancer cell proliferation in vitro and tumor formation in vivo. Therefore, PP2A-B55β promotes cyclin E1 overexpression by antagonizing its degradation and its inhibition could represent a therapeutic mechanism for abrogating cyclin E1 function in cancers.

Brim H, Abu-Asab MS, Nouraie M, et al.
An integrative CGH, MSI and candidate genes methylation analysis of colorectal tumors.
PLoS One. 2014; 9(1):e82185 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Different DNA aberrations processes can cause colorectal cancer (CRC). Herein, we conducted a comprehensive molecular characterization of 27 CRCs from Iranian patients.
MATERIALS AND METHODS: Array CGH was performed. The MSI phenotype and the methylation status of 15 genes was established using MSP. The CGH data was compared to two established lists of 41 and 68 cancer genes, respectively, and to CGH data from African Americans. A maximum parsimony cladogram based on global aberrations was established.
RESULTS: The number of aberrations seem to depend on the MSI status. MSI-H tumors displayed the lowest number of aberrations. MSP revealed that most markers were methylated, except RNF182 gene. P16 and MLH1 genes were primarily methylated in MSI-H tumors. Seven markers with moderate to high frequency of methylation (SYNE1, MMP2, CD109, EVL, RET, LGR and PTPRD) had very low levels of chromosomal aberrations. All chromosomes were targeted by aberrations with deletions more frequent than amplifications. The most amplified markers were CD248, ERCC6, ERGIC3, GNAS, MMP2, NF1, P2RX7, SFRS6, SLC29A1 and TBX22. Most deletions were noted for ADAM29, CHL1, CSMD3, FBXW7, GALNS, MMP2, NF1, PRKD1, SMAD4 and TP53. Aberrations targeting chromosome X were primarily amplifications in male patients and deletions in female patients. A finding similar to what we reported for African American CRC patients.
CONCLUSION: This first comprehensive analysis of CRC Iranian tumors reveals a high MSI rate. The MSI tumors displayed the lowest level of chromosomal aberrations but high frequency of methylation. The MSI-L were predominantly targeted with chromosomal instability in a way similar to the MSS tumors. The global chromosomal aberration profiles showed many similarities with other populations but also differences that might allow a better understanding of CRC's clinico-pathological specifics in this population.

Kuhn E, Ayhan A, Bahadirli-Talbott A, et al.
Molecular characterization of undifferentiated carcinoma associated with endometrioid carcinoma.
Am J Surg Pathol. 2014; 38(5):660-5 [PubMed] Related Publications
Uterine and ovarian undifferentiated carcinomas (UCs) are often associated with low-grade endometrioid carcinomas (EMCs) and are characterized by a solid growth pattern and a lack of appreciable features of differentiation. As compared with pure EMC, UC is highly malignant, and the molecular pathogenesis that leads to disease aggressiveness remains largely unknown. This study interrogates the molecular pathogenesis of UCs by comparing the molecular alterations between the UC and the EMC components. A total of 20 UCs were studied, 12 of which contained both UC and EMC components. Mutation analysis was performed for the genes commonly mutated in EMC, and immunohistochemistry was used to determine the expression pattern of β-catenin and PTEN. Sequencing analysis revealed that UCs harbored somatic mutations in PIK3CA (50%), CTNNB1 (30%), TP53 (30%), FBXW7 (20%), and PPP2R1A (20%). All somatic mutations detected in EMCs were also present in concurrent UCs. Moreover, additional somatic mutations were detected in the UC component in 5 (42%) cases with concurrent EMC and UC. Concordance of immunostaining pattern for β-catenin and PTEN was recorded in all 12 matched EMCs and UCs, except 4 cases in which nuclear accumulation of β-catenin staining was detected in one of the components but not in the other. Our findings support a clonal relationship between EMCs and their associated UCs. Additional molecular genetics alteration, including mutations of CTNNB1, PPP2R1A, and TP53, may contribute to tumor progression from EMC to UC.

Shern JF, Chen L, Chmielecki J, et al.
Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.
Cancer Discov. 2014; 4(2):216-31 [PubMed] Related Publications
UNLABELLED: Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma.
SIGNIFICANCE: This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention.

Fogelstrand L, Staffas A, Wasslavik C, et al.
Prognostic implications of mutations in NOTCH1 and FBXW7 in childhood T-ALL treated according to the NOPHO ALL-1992 and ALL-2000 protocols.
Pediatr Blood Cancer. 2014; 61(3):424-30 [PubMed] Related Publications
BACKGROUND: In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.
PROCEDURE: We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.
RESULTS: Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P = 0.14) or event-free survival (EFS) (P = 0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.2 ± 1.9 (mean ± SEM), MYB 8.7 ± 0.8 (mean ± SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 ± 0.7, MYB 5.1 ± 1.2, P = 0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P = 0.02) and EFS (P = 0.028) was seen.
CONCLUSIONS: Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated.

Ross JS, Wang K, Rand JV, et al.
Comprehensive genomic profiling of relapsed and metastatic adenoid cystic carcinomas by next-generation sequencing reveals potential new routes to targeted therapies.
Am J Surg Pathol. 2014; 38(2):235-8 [PubMed] Related Publications
We hypothesized that next-generation sequencing could reveal actionable genomic alterations (GAs) and potentially expand treatment options for patients with advanced adenoid cystic carcinoma (ACC). Genomic profiling using next-generation sequencing was performed on hybridization-captured, adapter ligation libraries derived from 28 relapsed and metastatic formalin-fixed paraffin-embedded ACC. The 3230 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer were fully sequenced using the Illumina HiSeq 2000. All classes of GAs were evaluated. Actionable GAs were defined as those impacting targeted anticancer therapies on the market or in registered clinical trials. A total of 44 GAs were identified in the 28 ACC tumors, with 12 of 28 (42.9%) of tumors harboring at least 1 potentially actionable GA. The most common nonactionable GAs were identified in KD6MA (5 cases; 18%), ARID1A (4 cases; 14%), RUNX1 (2 cases; 7%), and MYC (2 cases; 7%). Actionable GAs included NOTCH1 (3 cases; 11%), MDM2 (2 cases; 7%), PDGFRA (2 cases; 7%), and CDKN2A/B (p16) (2 cases; 7%). Other potentially actionable GAs identified in a single case included: mutations in AKT1, BAP1, EGFR, and PIK3CA, homozygous deletion of FBXW7, and amplifications of CDK4, FGFR1, IGF1R, KDR, KIT, and MCL1. The frequency of GA in ACC is lower than that seen in the more common solid tumors. Comprehensive genomic profiling of ACC can identify actionable GAs in a subset of patients that could influence therapy for these difficult-to-treat progressive neoplasms.

Bialkowska AB, Liu Y, Nandan MO, Yang VW
A colon cancer-derived mutant of Krüppel-like factor 5 (KLF5) is resistant to degradation by glycogen synthase kinase 3β (GSK3β) and the E3 ubiquitin ligase F-box and WD repeat domain-containing 7α (FBW7α).
J Biol Chem. 2014; 289(9):5997-6005 [PubMed] Free Access to Full Article Related Publications
Krüppel-like factor 5 (KLF5) is a zinc finger transcription factor that is highly expressed in the crypt epithelial cells of the intestine and plays a critical role in regulating proliferation of both normal intestinal epithelial cells and colorectal cancer cells. Stability of the KLF5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3β (GSK3β) and recognition by F-box and WD repeat domain-containing 7 (FBW7) of a phosphodegron sequence surrounding serine 303 in KLF5. A genomic analysis of colorectal cancer tissues identified a somatic mutation (P301S) in KLF5 within the phosphodegron sequence. We hypothesized that due to its close proximity to the phosphodegron sequence, the P301S mutation may affect signaling that is involved in proper KLF5 degradation. We demonstrated that the P301S KLF5 mutant has a longer half-life than wild type (WT) KLF5. Furthermore, P301S KLF5 has a higher transcriptional activity than WT KLF5 as demonstrated by luciferase assays using cyclin D1 and CDC2 promoter constructs. In contrast to WT KLF5, P301S KLF5 does not physically interact with FBW7α. Concomitantly, the P301S KLF5 mutant displays reduced levels of phosphorylation at serine 303 in comparison with WT KLF5. These results of our study indicate that amino acid residue 301 of KLF5 is critical for proper recognition of the phosphodegron sequence by FBW7α and that the P301S mutation inhibits this recognition, leading to a degradation-resistant protein with elevated levels and enhanced transcriptional activity. These findings raise a potentially oncogenic role for the P301S KLF5 mutant in colorectal cancer.

Ojesina AI, Lichtenstein L, Freeman SS, et al.
Landscape of genomic alterations in cervical carcinomas.
Nature. 2014; 506(7488):371-5 [PubMed] Free Access to Full Article Related Publications
Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.

Yu HG, Wei W, Xia LH, et al.
FBW7 upregulation enhances cisplatin cytotoxicity in non- small cell lung cancer cells.
Asian Pac J Cancer Prev. 2013; 14(11):6321-6 [PubMed] Related Publications
INTRODUCTION: Lung cancer is extremely harmful to human health and has one of the highest worldwide incidences of all malignant tumors. Approximately 80% of lung cancers are classified as non-small cell lung cancers (NSCLCs). Cisplatin-based multidrug chemotherapy regimen is standard for such lesions, but drug resistance is an increasing problem. F-box/WD repeat-containing protein 7 (FBW7) is a member of the F-box protein family that regulates cell cycle progression, and cell growth and differentiation. FBW7 also functions as a tumor suppressor.
METHODS: We used cell viability assays, Western blotting, and immunofluorescence combined with siRNA interference or plasmid transfection to investigate the underlying mechanism of cisplatin resistance in NSCLC cells.
RESULTS: We found that FBW7 upregulation significantly increased cisplatin chemosensitivity and that cells expressing low levels of FBW7, such as NCI-H1299 cells, have a mesenchymal phenotype. Furthermore, siRNA-mediated silencing or plasmid-mediated upregulation of FBW7 resulted in altered epithelial-mesenchymal transition (EMT) patterns in NSCLC cells. These data support a role for FBW7 in regulating the EMT in NSCLC cells.
CONCLUSION: FBW7 is a potential drug target for combating drug resistance and regulating the EMT in NSCLC cells.

Villaruz LC, Socinski MA
Temsirolimus therapy in a patient with lung adenocarcinoma harboring an FBXW7 mutation.
Lung Cancer. 2014; 83(2):300-1 [PubMed] Related Publications
We report the identification of an FBXW7 mutation in a patient with adenocarcinoma of the lung, whose tumor had previously been shown to be EGFR and ALK wild type and who had previously progressed on multiple lines of systemic therapy. She experienced both clinical and radiographic benefit from treatment with the mTOR inhibitor temsirolimus.

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