Gene Summary

Gene:FAT4; FAT atypical cadherin 4
Aliases: FATJ, FAT-J, CDHF14, CDHR11, HKLLS2, VMLDS2, NBLA00548
Summary:The protein encoded by this gene is a member of the protocadherin family. This gene may play a role in regulating planar cell polarity (PCP). Studies in mice suggest that loss of PCP signaling may cause cystic kidney disease, and mutations in this gene have been associated with Van Maldergem Syndrome 2. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Mar 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protocadherin Fat 4
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 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.

  • Signal Transduction
  • Repressor Proteins
  • Vascular Endothelial Growth Factor Receptor-2
  • fms-Like Tyrosine Kinase 3
  • Staging
  • Mutation
  • CpG Islands
  • Ultraviolet Rays
  • Gene Knockdown Techniques
  • Cancer Gene Expression Regulation
  • Chromatin
  • Phosphoproteins
  • DNA Mutational Analysis
  • Tumor Suppressor Gene
  • Epigenetics
  • Single Nucleotide Polymorphism
  • Survival Rate
  • beta Catenin
  • Cadherins
  • DNA Methylation
  • Tumor Suppressor Proteins
  • Apoptosis
  • Biomarkers, Tumor
  • Cell Proliferation
  • DNA Sequence Analysis
  • Case-Control Studies
  • Splenic Neoplasms
  • Neoplastic Cell Transformation
  • Chromosome 4
  • Transcription Factors
  • Risk Factors
  • rho GTP-Binding Proteins
  • High-Throughput Nucleotide Sequencing
  • Alleles
  • MicroRNAs
  • Esophageal Cancer
  • Genetic Predisposition
  • RT-PCR
  • Exome
  • Oligonucleotide Array Sequence Analysis
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: FAT4 (cancer-related)

He P, Sun L, Zhu D, et al.
Knock-Down of Endogenous Bornavirus-Like Nucleoprotein 1 Inhibits Cell Growth and Induces Apoptosis in Human Oligodendroglia Cells.
Int J Mol Sci. 2016; 17(4):435 [PubMed] Free Access to Full Article Related Publications
Endogenous bornavirus-like nucleoprotein elements (EBLNs) have been discovered in the genomes of various animals including humans, whose functions have been seldom studied. To explore the biological functions of human EBLNs, we constructed a lentiviral vector expressing a short-hairpin RNA against human EBLN1, which successfully inhibited EBLN1 expression by above 80% in infected human oligodendroglia cells (OL cells). We found that EBLN1 silencing suppressed cell proliferation, induced G2/M phase arrest, and promoted apoptosis in OL cells. Gene expression profiling demonstrated that 1067 genes were up-regulated, and 2004 were down-regulated after EBLN1 silencing. The top 10 most upregulated genes were PI3, RND3, BLZF1, SOD2, EPGN, SBSN, INSIG1, OSMR, CREB3L2, and MSMO1, and the top 10 most-downregulated genes were KRTAP2-4, FLRT2, DIDO1, FAT4, ESCO2, ZNF804A, SUV420H1, ZC3H4, YAE1D1, and NCOA5. Pathway analysis revealed that these differentially expressed genes were mainly involved in pathways related to the cell cycle, the mitogen-activated protein kinase pathway, p53 signaling, and apoptosis. The gene expression profiles were validated by using quantitative reverse transcription polymerase chain reaction (RT-PCR) for detecting these 20 most-changed genes. Three genes closely related to glioma, RND3, OSMR, and CREB3L2, were significantly upregulated and might be the key factors in EBLN1 regulating the proliferation and apoptosis of OL cells. This study provides evidence that EBLN1 plays a key role in regulating cell life and death, thereby opening several avenues of investigation regarding EBLN1 in the future.

Yoshida S, Yamashita S, Niwa T, et al.
Epigenetic inactivation of FAT4 contributes to gastric field cancerization.
Gastric Cancer. 2017; 20(1):136-145 [PubMed] Related Publications
BACKGROUND: Gastric cancer (GC) is highly influenced by aberrant methylation, and accumulation of aberrant methylation in gastric mucosae produces an epigenetic field for cancerization. Nevertheless, the individual driver genes involved in such field cancerization are still unclear. Here, we aimed to demonstrate that FAT4, a novel tumor suppressor identified by exome sequencing of GC, is methylation-silenced and that such methylation is involved in epigenetic field cancerization for GC.
METHODS: A transcription start site was determined by the 5' rapid amplification of complementary DNA ends method. DNA methylation was analyzed by bisulfite sequencing with use of a next-generation sequencer or quantitative methylation-specific PCR. Gene expression was analyzed by quantitative reverse transcription PCR.
RESULTS: A single transcription start site was identified for FAT4 in gastric epithelial cells, and a CpG island was located in the FAT4 promoter region. FAT4 was highly methylated in two of 13 GC cell lines and was not expressed in them. Removal of FAT4 methylation by a DNA demethylating agent (5-aza-2'-deoxycytidine) restored its expression in the two cell lines. In primary GC samples, FAT4 was methylated in 12 of 82 GCs (14.6 %). FAT4 methylation was associated with the presence of the CpG island methylator phenotype but not with prognosis, tumor invasion, lymph node metastasis, or histological types. In noncancerous gastric mucosae, high FAT4 methylation levels were associated with the presence of GC and Helicobacter pylori infection.
CONCLUSIONS: FAT4 was methylation-silenced in GCs. Its methylation in gastric mucosae was associated with H. pylori infection and likely contributed to epigenetic field cancerization.

Dobashi A, Tsuyama N, Asaka R, et al.
Frequent BCOR aberrations in extranodal NK/T-Cell lymphoma, nasal type.
Genes Chromosomes Cancer. 2016; 55(5):460-71 [PubMed] Related Publications
Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK-STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer-related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples. Several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%), and MIR17HG (8%) were identified. The pattern of BCOR aberrations (1 nonsense and 5 frame-shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. The literature was reviewed and the public data on BCOR aberrations was reanalyzed and it was found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene.

Shi JY, Xing Q, Duan M, et al.
Inferring the progression of multifocal liver cancer from spatial and temporal genomic heterogeneity.
Oncotarget. 2016; 7(3):2867-77 [PubMed] Free Access to Full Article Related Publications
Multifocal tumors developed either as independent tumors or as intrahepatic metastases, are very common in primary liver cancer. However, their molecular pathogenesis remains elusive. Herein, a patient with synchronous two hepatocellular carcinoma (HCC, designated as HCC-A and HCC-B) and one intrahepatic cholangiocarcinoma (ICC), as well as two postoperative recurrent tumors, was enrolled. Multiregional whole-exome sequencing was applied to these tumors to delineate the clonality and heterogeneity. The three primary tumors showed almost no overlaps in mutations and copy number variations. Within each tumor, multiregional sequencing data showed varied intratumoral heterogeneity (21.6% in HCC-A, 20.4% in HCC-B, 53.2% in ICC). The mutational profile of two recurrent tumors showed obvious similarity with HCC-A (86.7% and 86.6% respectively), rather than others, indicating that they originated from HCC-A. The evolutionary history of the two recurrent tumors indicated that intrahepatic micro-metastasis could be an early event during HCC progression. Notably, FAT4 was the only gene mutated in two primary HCCs and the recurrences. Mutation prevalence screen and functional experiments showed that FAT4, harboring somatic coding mutations in 26.7% of HCC, could potently inhibit growth and invasion of HCC cells. In HCC patients, both FAT4 expression and FAT4 mutational status significantly correlated with patient prognosis. Together, our findings suggest that spatial and temporal dissection of genomic alterations during the progression of multifocal liver cancer may help to elucidate the basis for its dismal prognosis. FAT4 acts as a putative tumor suppressor that is frequently inactivated in human HCC.

Mason CC, Khorashad JS, Tantravahi SK, et al.
Age-related mutations and chronic myelomonocytic leukemia.
Leukemia. 2016; 30(4):906-13 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

Cai J, Feng D, Hu L, et al.
FAT4 functions as a tumour suppressor in gastric cancer by modulating Wnt/β-catenin signalling.
Br J Cancer. 2015; 113(12):1720-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: FAT4, a cadherin-related protein, was shown to function as a tumour suppressor; however, its role in human gastric cancer remains largely unknown. Here, we investigated the role of FAT4 in gastric cancer and examined the underlying molecular mechanisms.
METHODS: The expression of FAT4 was evaluated by immunohistochemistry, western blotting, and qRT-PCR in relation to the clinicopathological characteristics of gastric cancer patients. The effects of FAT4 silencing on cell proliferation, migration, and invasion were assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay, and migration and invasion assays in gastric cancer cell lines in vitro and in a mouse xenograft model in vivo.
RESULTS: Downregulation of FAT4 expression in gastric cancer tissues compared with adjacent normal tissues was correlated with lymph-node metastasis and poor survival. Knockdown of FAT4 promoted the growth and invasion of gastric cancer cells via the activation of Wnt/β-catenin signalling, and induced epithelial-to-mesenchymal transition (EMT) in gastric cancer cells, as demonstrated by the upregulation and downregulation of mesenchymal and epithelial markers. Silencing of FAT4 promoted tumour growth and metastasis in a gastric cancer xenograft model in vivo.
CONCLUSIONS: FAT4 has a tumour suppressor role mediated by the modulation of Wnt/β-catenin signalling, providing potential novel targets for the treatment of gastric cancer.

Ma L, Cui J, Xi H, et al.
Fat4 suppression induces Yap translocation accounting for the promoted proliferation and migration of gastric cancer cells.
Cancer Biol Ther. 2016; 17(1):36-47 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Fat4 functions as a Hippo signaling regulator which is involved in mammalian tissue development, differentiation and tumorigenesis. Loss of Fat4 due to frequent gene mutation was detected in a variety of tumors including gastric cancer, where Fat4 was recognized as a tumor suppressor, repressing cancer cell proliferation and adhesion. However, the detailed mechanisms linking Fat4 to its diverse functions and clinicopathological characteristics in gastric cancer remain unclear. Here, we silenced Fat4 using Fat4-shRNA in gastric cancer cells and found that this suppression led to the increase in phosphorylated Yap and nuclear accumulation of Yap, which associated to the promoted proliferation, migration and cell cycle progression. Then we transfected a full-length Fat4 into the Fat4-silenced cells, and found the decrease in phosphorylated Yap and inhibition of the cell cycle progression. Intriguingly, Fat4 reduction also leads to the accumulation of cytoplasmic β-catenin via the loss of restraining to cytoplasmic Yap instead of β-catenin transcription promotion. The Fat4-silenced cells which were treated with 5-FU, Cisplatin, Oxaliplatin and Paclitaxel individually demonstrated less sensitivities to these chemotherapy drugs compared with the control cells. Furthermore, immunohistochemical analysis revealed that Fat4 expression was significantly reduced in gastric cancer tissues compared with adjacent noncancerous tissues, and negatively correlated with tumor infiltration, lymph node metastasis and cumulative survival rate. In conclusion, Fat4 expression is deceased in gastric cancer cells, leading to nuclear translocation of Yap and correlates with poor prognosis.

Garg M, Nagata Y, Kanojia D, et al.
Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse.
Blood. 2015; 126(22):2491-501 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.

Sebio A, Matsusaka S, Zhang W, et al.
Germline polymorphisms in genes involved in the Hippo pathway as recurrence biomarkers in stages II/III colon cancer.
Pharmacogenomics J. 2016; 16(4):312-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The Hippo pathway regulates tissue growth and cell fate. In colon cancer, Hippo pathway deregulation promotes cellular quiescence and resistance to 5-Fluorouracil (5-Fu). In this study, 14 polymorphisms in 8 genes involved in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4 and RASSF1A) were evaluated as recurrence predictors in 194 patients with stages II/III colon cancer treated with 5-Fu-based adjuvant chemotherapy. Patients with a RASSF1A rs2236947 AA genotype had higher 3-year recurrence rate than patients with CA/CC genotypes (56 vs 33%, hazard ratio (HR): 1.87; P=0.017). Patients with TAZ rs3811715 CT or TT genotypes had lower 3-year recurrence rate than patients with a CC genotype (28 vs 40%; HR: 0.66; P=0.07). In left-sided tumors, this association was stronger (HR: 0.29; P=0.011) and a similar trend was found in an independent Japanese cohort. These promising results reveal polymorphisms in the Hippo pathway as biomarkers for stages II and III colon cancer.The Pharmacogenomics Journal advance online publication, 15 September 2015; doi:10.1038/tpj.2015.64.

Lin Y, Wu Z, Guo W, Li J
Gene mutations in gastric cancer: a review of recent next-generation sequencing studies.
Tumour Biol. 2015; 36(10):7385-94 [PubMed] Related Publications
Gastric cancer (GC) is one of the most common malignancies worldwide. Although some driver genes have been identified in GC, the molecular compositions of GC have not been fully understood. The development of next-generation sequencing (NGS) provides a high-throughput and systematic method to identify all genetic alterations in the cancer genome, especially in the field of mutation detection. NGS studies in GC have discovered some novel driver mutations. In this review, we focused on novel gene mutations discovered by NGS studies, along with some well-known driver genes in GC. We organized mutated genes from the perspective of related biological pathways. Mutations in genes relating to genome integrity (TP53, BRCA2), chromatin remodeling (ARID1A), cell adhesion (CDH1, FAT4, CTNNA1), cytoskeleton and cell motility (RHOA), Wnt pathway (CTNNB1, APC, RNF43), and RTK pathway (RTKs, RAS family, MAPK pathway, PIK pathway) are discussed. Efforts to establish a molecular classification based on NGS data which is valuable for future targeted therapy for GC are introduced. Comprehensive dissection of the molecular profile of GC cannot only unveil the molecular basis for GC but also identify genes of clinical utility, especially potential and specific therapeutic targets for GC.

Cheng F, Liu C, Lin CC, et al.
A Gene Gravity Model for the Evolution of Cancer Genomes: A Study of 3,000 Cancer Genomes across 9 Cancer Types.
PLoS Comput Biol. 2015; 11(9):e1004497 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Cancer development and progression result from somatic evolution by an accumulation of genomic alterations. The effects of those alterations on the fitness of somatic cells lead to evolutionary adaptations such as increased cell proliferation, angiogenesis, and altered anticancer drug responses. However, there are few general mathematical models to quantitatively examine how perturbations of a single gene shape subsequent evolution of the cancer genome. In this study, we proposed the gene gravity model to study the evolution of cancer genomes by incorporating the genome-wide transcription and somatic mutation profiles of ~3,000 tumors across 9 cancer types from The Cancer Genome Atlas into a broad gene network. We found that somatic mutations of a cancer driver gene may drive cancer genome evolution by inducing mutations in other genes. This functional consequence is often generated by the combined effect of genetic and epigenetic (e.g., chromatin regulation) alterations. By quantifying cancer genome evolution using the gene gravity model, we identified six putative cancer genes (AHNAK, COL11A1, DDX3X, FAT4, STAG2, and SYNE1). The tumor genomes harboring the nonsynonymous somatic mutations in these genes had a higher mutation density at the genome level compared to the wild-type groups. Furthermore, we provided statistical evidence that hypermutation of cancer driver genes on inactive X chromosomes is a general feature in female cancer genomes. In summary, this study sheds light on the functional consequences and evolutionary characteristics of somatic mutations during tumorigenesis by propelling adaptive cancer genome evolution, which would provide new perspectives for cancer research and therapeutics.

Furukawa T, Sakamoto H, Takeuchi S, et al.
Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas.
Sci Rep. 2015; 5:8829 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Acinar cell carcinoma of the pancreas is a rare tumor with a poor prognosis. Compared to pancreatic ductal adenocarcinoma, its molecular features are poorly known. We studied a total of 11 acinar cell carcinomas, including 3 by exome and 4 by target sequencing. Exome sequencing revealed 65 nonsynonymous mutations and 22 indels with a mutation rate of 3.4 mutations/Mb per tumor, on average. By accounting for not only somatic but also germline mutations with loss of the wild-type allele, we identified recurrent mutations of BRCA2 and FAT genes. BRCA2 showed somatic or germline premature termination mutations, with loss of the wild-type allele in 3 of 7 tumors. FAT1, FAT3, and FAT4 showed somatic or germline missense mutations in 4 of 7 tumors. The germline FAT mutations were with loss of the wild-type allele. Loss of BRCA2 expression was observed in 5 of 11 tumors. One patient with a BRCA2-mutated tumor experienced complete remission of liver metastasis following cisplatinum chemotherapy. In conclusion, acinar cell carcinomas show a distinct mutation pattern and often harbor somatic or germline mutations of BRCA2 and FAT genes. This result may warrant assessment of BRCA2 abrogation in patients with the carcinoma to determine their sensitivity to chemotherapy.

Ito T, Taniguchi H, Fukagai K, et al.
Inhibitory mechanism of FAT4 gene expression in response to actin dynamics during Src-induced carcinogenesis.
PLoS One. 2015; 10(2):e0118336 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Oncogenic transformation is characterized by morphological changes resulting from alterations in actin dynamics and adhesive activities. Emerging evidence suggests that the protocadherin FAT4 acts as a tumor suppressor in humans, and reduced FAT4 gene expression has been reported in breast and lung cancers and melanoma. However, the mechanism controlling FAT4 gene expression is poorly understood. In this study, we show that transient activation of the Src oncoprotein represses FAT4 mRNA expression through actin depolymerization in the immortalized normal human mammary epithelial cell line MCF-10A. Src activation causes actin depolymerization via the MEK/Erk/Cofilin cascade. The MEK inhibitor U0126 blocks the inhibitory effect of Src on FAT4 mRNA expression and Src-induced actin depolymerization. To determine whether actin dynamics act on the regulation of FAT4 mRNA expression, we treated MCF-10A cells with the ROCK inhibitor Y-27632. Y-27632 treatment decreased FAT4 mRNA expression. This suppressive effect was blocked by siRNA-mediated knockdown of Cofilin1. Furthermore, simultaneous administration of Latrunculin A (an actin depolymerizing agent), Y-27632, and Cofilin1 siRNA to the cells resulted in a marked reduction of FAT4 mRNA expression. Intriguingly, we also found that FAT4 mRNA expression was reduced under both low cell density and low stiffness conditions, which suggests that mechanotransduction affects FAT4 mRNA expression. Additionally, we show that siRNA-mediated FAT4 knockdown induced the activity of the Hippo effector YAP/TAZ in MCF-10A cells. Taken together, our results reveal a novel inhibitory mechanism of FAT4 gene expression through actin depolymerization during Src-induced carcinogenesis in human breast cells.

Crobach S, Ruano D, van Eijk R, et al.
Target-enriched next-generation sequencing reveals differences between primary and secondary ovarian tumors in formalin-fixed, paraffin-embedded tissue.
J Mol Diagn. 2015; 17(2):193-200 [PubMed] Related Publications
Differentiating primary endometrioid or mucinous ovarian tumors from secondary ovarian tumors can be challenging. We compared somatic mutation profiles of primary and secondary ovarian cancers to investigate if these profiles can help diagnose ovarian tumors. Cancer-related genes (n = 115) were screened by target-enriched next-generation sequencing in formalin-fixed, paraffin-embedded tumor tissue from 43 primary endometrioid and mucinous ovarian carcinomas and 28 proven colorectal cancer metastases to the ovary. Results were validated by high-resolution melting curve analysis and Sanger sequencing. TP53, NOTCH1, PIK3CA, and FAT4 versus APC, TP53, KRAS, and FAT4 mutations were the most common in the primary ovarian tumors and ovarian colorectal cancer metastases, respectively. An inactivating APC mutation was found in 4.7% of primary ovarian tumors (2 of 43; 95% CI, 1.6%-10.9%). In contrast, inactivating APC mutations were identified in 71% of colorectal cancer metastases (20 of 28; 95% CI, 55%-88%) (P < 0.001; sensitivity: 71.4%, 95% CI, 51.1%-86.0%; specificity: 95.4%, 95% CI, 82.9%-99.1%). Loss of heterozygosity and APC promoter hypermethylation did not differ significantly between the primary and secondary ovarian tumors. NOTCH1 mutations were observed specifically in primary ovarian tumors, although at a low frequency, but not in metastases (6 of 41; 14.6%; 95% CI, 3.8%-25.4%). APC mutation analysis can be used to differentiate primary endometrioid and mucinous ovarian tumors from colorectal cancer metastases to the ovary.

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.

Yu J, Wu WK, Li X, et al.
Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer.
Gut. 2015; 64(4):636-45 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Characterisation of colorectal cancer (CRC) genomes by next-generation sequencing has led to the discovery of novel recurrently mutated genes. Nevertheless, genomic data has not yet been used for CRC prognostication.
OBJECTIVE: To identify recurrent somatic mutations with prognostic significance in patients with CRC.
METHOD: Exome sequencing was performed to identify somatic mutations in tumour tissues of 22 patients with CRC, followed by validation of 187 recurrent and pathway-related genes using targeted capture sequencing in additional 160 cases.
RESULTS: Seven significantly mutated genes, including four reported (APC, TP53, KRAS and SMAD4) and three novel recurrently mutated genes (CDH10, FAT4 and DOCK2), exhibited high mutation prevalence (6-14% for novel cancer genes) and higher-than-expected number of non-silent mutations in our CRC cohort. For prognostication, a five-gene-signature (CDH10, COL6A3, SMAD4, TMEM132D, VCAN) was devised, in which mutation(s) in one or more of these genes was significantly associated with better overall survival independent of tumor-node-metastasis (TNM) staging. The median survival time was 80.4 months in the mutant group versus 42.4 months in the wild type group (p=0.0051). The prognostic significance of this signature was successfully verified using the data set from the Cancer Genome Atlas study.
CONCLUSIONS: The application of next-generation sequencing has led to the identification of three novel significantly mutated genes in CRC and a mutation signature that predicts survival outcomes for stratifying patients with CRC independent of TNM staging.

Yamamoto H, Watanabe Y, Maehata T, et al.
An updated review of gastric cancer in the next-generation sequencing era: insights from bench to bedside and vice versa.
World J Gastroenterol. 2014; 20(14):3927-37 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Gastric cancer (GC) is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. There is an increasing understanding of the roles that genetic and epigenetic alterations play in GCs. Recent studies using next-generation sequencing (NGS) have revealed a number of potential cancer-driving genes in GC. Whole-exome sequencing of GC has identified recurrent somatic mutations in the chromatin remodeling gene ARID1A and alterations in the cell adhesion gene FAT4, a member of the cadherin gene family. Mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) have been found in 47% of GCs. Whole-genome sequencing and whole-transcriptome sequencing analyses have also discovered novel alterations in GC. Recent studies of cancer epigenetics have revealed widespread alterations in genes involved in the epigenetic machinery, such as DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs and microRNAs. Recent advances in molecular research on GC have resulted in the introduction of new diagnostic and therapeutic strategies into clinical settings. The anti-human epidermal growth receptor 2 (HER2) antibody trastuzumab has led to an era of personalized therapy in GC. In addition, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor receptor (VEGFR)-2, is the first biological treatment that showed survival benefits as a single-agent therapy in patients with advanced GC who progressed after first-line chemotherapy. Using NGS to systematically identify gene alterations in GC is a promising approach with remarkable potential for investigating the pathogenesis of GC and identifying novel therapeutic targets, as well as useful biomarkers. In this review, we will summarize the recent advances in the understanding of the molecular pathogenesis of GC, focusing on the potential use of these genetic and epigenetic alterations as diagnostic biomarkers and novel therapeutic targets.

Parry M, Rose-Zerilli MJ, Gibson J, et al.
Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma.
PLoS One. 2013; 8(12):e83244 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The pathogenesis of splenic marginal zone lymphoma (SMZL) remains largely unknown. Recent high-throughput sequencing studies have identified recurrent mutations in key pathways, most notably NOTCH2 mutations in >25% of patients. These studies are based on small, heterogeneous discovery cohorts, and therefore only captured a fraction of the lesions present in the SMZL genome. To identify further novel pathogenic mutations within related biochemical pathways, we applied whole exome sequencing (WES) and copy number (CN) analysis to a biologically and clinically homogeneous cohort of seven SMZL patients with 7q abnormalities and IGHV1-2*04 gene usage. We identified 173 somatic non-silent variants, affecting 160 distinct genes. In additional to providing independent validation of the presence of mutation in several previously reported genes (NOTCH2, TNFAIP3, MAP3K14, MLL2 and SPEN), our study defined eight additional recurrently mutated genes in SMZL; these genes are CREBBP, CBFA2T3, AMOTL1, FAT4, FBXO11, PLA2G4D, TRRAP and USH2A. By integrating our WES and CN data we identified three mutated putative candidate genes targeted by 7q deletions (CUL1, EZH2 and FLNC), with FLNC positioned within the well-characterized 7q minimally deleted region. Taken together, this work expands the reported directory of recurrently mutated cancer genes in this disease, thereby expanding our understanding of SMZL pathogenesis. Ultimately, this work will help to establish a stratified approach to care including the possibility of targeted therapy.

Tenedini E, Bernardis I, Artusi V, et al.
Targeted cancer exome sequencing reveals recurrent mutations in myeloproliferative neoplasms.
Leukemia. 2014; 28(5):1052-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
With the intent of dissecting the molecular complexity of Philadelphia-negative myeloproliferative neoplasms (MPN), we designed a target enrichment panel to explore, using next-generation sequencing (NGS), the mutational status of an extensive list of 2000 cancer-associated genes and microRNAs. The genomic DNA of granulocytes and in vitro-expanded CD3+T-lymphocytes, as a germline control, was target-enriched and sequenced in a learning cohort of 20 MPN patients using Roche 454 technology. We identified 141 genuine somatic mutations, most of which were not previously described. To test the frequency of the identified variants, a larger validation cohort of 189 MPN patients was additionally screened for these mutations using Ion Torrent AmpliSeq NGS. Excluding the genes already described in MPN, for 8 genes (SCRIB, MIR662, BARD1, TCF12, FAT4, DAP3, POLG and NRAS), we demonstrated a mutation frequency between 3 and 8%. We also found that mutations at codon 12 of NRAS (NRASG12V and NRASG12D) were significantly associated, for primary myelofibrosis (PMF), with highest dynamic international prognostic scoring system (DIPSS)-plus score categories. This association was then confirmed in 66 additional PMF patients composing a final dataset of 168 PMF showing a NRAS mutation frequency of 4.7%, which was associated with a worse outcome, as defined by the DIPSS plus score.

Murphy AJ, Pierce J, de Caestecker C, et al.
Aberrant activation, nuclear localization, and phosphorylation of Yes-associated protein-1 in the embryonic kidney and Wilms tumor.
Pediatr Blood Cancer. 2014; 61(2):198-205 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The Yes-associated-protein-1 (YAP1) is a novel, direct regulator of stem cell genes both in development and cancer. FAT4 is an upstream regulator that induces YAP1 cytosolic sequestering by phosphorylation (p-Ser 127) and therefore inhibits YAP1-dependent cellular proliferation. We hypothesized that loss of FAT4 signaling would result in expansion of the nephron progenitor population in kidney development and that YAP1 subcellular localization would be dysregulated in Wilms tumor (WT), an embryonal malignancy that retains gene expression profiles and histologic features reminiscent of the embryonic kidney.
METHODS: Fetal kidneys from Fat4(-/-) mice were harvested at e18.5 and markers of nephron progenitors were investigated using immunohistochemical analysis. To examine YAP1 subcellular localization in WT, a primary WT cell line (VUWT30) was analyzed by immunofluorescence. Forty WT specimens evenly distributed between favorable and unfavorable histology (n = 20 each), and treatment failure or success (n = 20 each) was analyzed for total and phosphorylated YAP1 using immunohistochemistry and Western blot.
RESULTS: Fat4(-/-) mouse fetal kidneys exhibit nuclear YAP1 with increased proliferation and expansion of nephron progenitor cells. In contrast to kidney development, subcellular localization of YAP1 is dysregulated in WT, with a preponderance of nuclear p-YAP1. By Western blot, median p-YAP1 quantity was 5.2-fold greater in unfavorable histology WT (P = 0.05).
CONCLUSIONS: Fetal kidneys in Fat4(-/-) mice exhibit a phenotype reminiscent of nephrogenic rests, a WT precursor lesion. In WT, YAP1 subcellular localization is dysregulated and p-YAP1 accumulation is a novel biomarker of unfavorable histology.

Wadhwa R, Song S, Lee JS, et al.
Gastric cancer-molecular and clinical dimensions.
Nat Rev Clin Oncol. 2013; 10(11):643-55 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.

Du J, Ji J, Gao Y, et al.
Nonsynonymous polymorphisms in FAT4 gene are associated with the risk of esophageal cancer in an Eastern Chinese population.
Int J Cancer. 2013; 133(2):357-61 [PubMed] Related Publications
FAT4 plays a crucial role in carcinogenesis as a key component of the Hippo signaling pathway. We hypothesized that potential functional polymorphisms in the FAT4 gene may modify the risk of esophageal cancer. To test this hypothesis, we evaluated the association between four nonsynonymous polymorphisms (rs1039808, rs12508222, rs1567047 and rs1014867) in FAT4 and esophageal cancer risk in a case-control study of 2,139 esophageal cancer cases and 2,273 controls in a Chinese population. We found that the T allele of rs1014867 (Pro4972Ser) was significantly associated with a decreased risk of esophageal cancer (odds ratio [OR]=0.77, 95% confidence interval [95% CI]=0.66-0.90; p=1.42 × 10(-3)). We also observed a borderline significant association between rs1039808 (Ala807Val) and esophageal cancer risk (OR=0.90, 95% CI=0.82-1.00; p=0.050), which was more prominent in non-drinkers (OR=0.82, 95% CI=0.71-0.94; p=6.53 × 10(-3)). Furthermore, we detected a significant interaction between rs1039808 genotypes and alcohol drinking on esophageal cancer risk (p=0.013). These findings indicate that the nonsynonymous variants rs1014867 (Pro4972Ser) and rs1039808 (Ala807Val) of FAT4 may contribute to esophageal cancer susceptibility.

Katoh M
Function and cancer genomics of FAT family genes (review).
Int J Oncol. 2012; 41(6):1913-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
FAT1, FAT2, FAT3 and FAT4 are human homologs of Drosophila Fat, which is involved in tumor suppression and planar cell polarity (PCP). FAT1 and FAT4 undergo the first proteolytic cleavage by Furin and are predicted to undergo the second cleavage by γ‑secretase to release intracellular domain (ICD). Ena/VAPS‑binding to FAT1 induces actin polymerization at lamellipodia and filopodia to promote cell migration, while Scribble‑binding to FAT1 induces phosphorylation and functional inhibition of YAP1 to suppress cell growth. FAT1 is repressed in oral cancer owing to homozygous deletion or epigenetic silencing and is preferentially downregulated in invasive breast cancer. On the other hand, FAT1 is upregulated in leukemia and prognosis of preB‑ALL patients with FAT1 upregulation is poor. FAT4 directly interacts with MPDZ/MUPP1 to recruit membrane‑associated guanylate kinase MPP5/PALS1. FAT4 is involved in the maintenance of PCP and inhibition of cell proliferation. FAT4 mRNA is repressed in breast cancer and lung cancer due to promoter hypermethylation. FAT4 gene is recurrently mutated in several types of human cancers, such as melanoma, pancreatic cancer, gastric cancer and hepatocellular carcinoma. FAT1 and FAT4 suppress tumor growth via activation of Hippo signaling, whereas FAT1 promotes tumor migration via induction of actin polymerization. FAT1 is tumor suppressive or oncogenic in a context‑dependent manner, while FAT4 is tumor suppressive. Copy number aberration, translocation and point mutation of FAT1, FAT2, FAT3, FAT4, FRMD1, FRMD6, NF2, WWC1, WWC2, SAV1, STK3, STK4, MOB1A, MOB1B, LATS1, LATS2, YAP1 and WWTR1/TAZ genes should be comprehensively investigated in various types of human cancers to elucidate the mutation landscape of the FAT‑Hippo signaling cascades. Because YAP1 and WWTR1 are located at the crossroads of adhesion, GPCR, RTK and stem‑cell signaling network, cancer genomics of the FAT signaling cascades could be applied for diagnostics, prognostics and therapeutics in the era of personalized medicine.

Zang ZJ, Cutcutache I, Poon SL, et al.
Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes.
Nat Genet. 2012; 44(5):570-4 [PubMed] Related Publications
Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.

Nikolaev SI, Rimoldi D, Iseli C, et al.
Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.
Nat Genet. 2011; 44(2):133-9 [PubMed] Related Publications
We performed exome sequencing to detect somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in two metastases derived from the same individual. Two melanomas with non-canonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK1 and MEK2, respectively) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. Furthermore, missense and nonsense somatic mutations were frequently found in three candidate melanoma genes, FAT4, LRP1B and DSC1.

Rauch TA, Wang Z, Wu X, et al.
DNA methylation biomarkers for lung cancer.
Tumour Biol. 2012; 33(2):287-96 [PubMed] Related Publications
Changes in DNA methylation patterns are an important characteristic of human cancer including lung cancer. In particular, hypermethylation of CpG islands is a signature of malignant progression. Methylated CpG islands are promising diagnostic markers for the early detection of cancer. However, the full extent and sequence context of DNA hypermethylation in lung cancer has remained unknown. We have used the methylated CpG island recovery assay and high-resolution microarray analysis to find hypermethylated CpG islands in squamous cell carcinomas (SCC) and adenocarcinomas of the lung. Each tumor contained several hundred hypermethylated CpG islands. In an initial microarray screen, 36 CpG islands were methylated in five of five (=100%) of the SCC tumors tested and 52 CpG islands were methylated in at least 75% of the adenocarcinomas tested (n=8). Using sodium-bisulfite-based approaches, 12 CpG islands (associated with the BARHL2, EVX2, IRX2, MEIS1, MSX1, NR2E1, OC2, OSR1, OTX1, PAX6, TFAP2A, and ZNF577 genes) were confirmed to be methylated in 85% to 100% of the squamous cell carcinomas and 11 CpG islands (associated with the CHAD, DLX4, GRIK2, KCNG3, NR2E1, OSR1, OTX1, OTX2, PROX1, RUNX1, and VAX1 genes) were methylated in >80% of the adenocarcinomas. From the list of genes that were methylated in lung adenocarcinomas, we identified the gene FAT4 and found that this gene was methylated in 39% of the tumors. FAT4 is the closest mammalian homologue of the Drosophila tumor suppressor Fat which is an important component of the Hippo growth control pathway. Many of these newly discovered methylated CpG islands hold promise for becoming biomarkers for the early detection of lung cancer.

Wu YH, Hu TF, Chen YC, et al.
The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility.
Blood. 2011; 118(10):2896-905 [PubMed] Related Publications
miRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is up-regulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNA-mRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting KSHV-regulated miRNAs or genes might allow the development of novel therapeutic strategies that induce angiogenesis or allow the treatment of pathogenic (lymph)angiogenesis.

Sadeqzadeh E, de Bock CE, Zhang XD, et al.
Dual processing of FAT1 cadherin protein by human melanoma cells generates distinct protein products.
J Biol Chem. 2011; 286(32):28181-91 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The giant cadherin FAT1 is one of four vertebrate orthologues of the Drosophila tumor suppressor fat. It engages in several functions, including cell polarity and migration, and in Hippo signaling during development. Homozygous deletions in oral cancer suggest that FAT1 may play a tumor suppressor role, although overexpression of FAT1 has been reported in some other cancers. Here we show using Northern blotting that human melanoma cell lines variably but universally express FAT1 and less commonly FAT2, FAT3, and FAT4. Both normal melanocytes and keratinocytes also express comparable FAT1 mRNA relative to melanoma cells. Analysis of the protein processing of FAT1 in keratinocytes revealed that, like Drosophila FAT, human FAT1 is cleaved into a non-covalent heterodimer before achieving cell surface expression. The use of inhibitors also established that such cleavage requires the proprotein convertase furin. However, in melanoma cells, the non-cleaved proform of FAT1 is also expressed at the cell surface together with the furin-cleaved heterodimer. Moreover, furin-independent processing generates a potentially functional proteolytic product in melanoma cells, a persistent 65-kDa membrane-bound cytoplasmic fragment no longer in association with the extracellular fragment. In vitro localization studies of FAT1 showed that melanoma cells display high levels of cytosolic FAT1 protein, whereas keratinocytes, despite comparable FAT1 expression levels, exhibited mainly cell-cell junctional staining. Such differences in protein distribution appear to reconcile with the different protein products generated by dual FAT1 processing. We suggest that the uncleaved FAT1 could promote altered signaling, and the novel products of alternate processing provide a dominant negative function in melanoma.

Qi C, Zhu YT, Hu L, Zhu YJ
Identification of Fat4 as a candidate tumor suppressor gene in breast cancers.
Int J Cancer. 2009; 124(4):793-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Fat, a candidate tumor suppressor in Drosophila, is a component of Hippo signaling pathway involved in controlling organ size. We found that a approximately 3 Mbp deletion in mouse chromosome 3 caused tumorigenesis of a non-tumorigenic mammary epithelial cell line. The expression of Fat4 gene, one member of the Fat family, in the deleted region was inactivated, which resulted from promoter methylation of another Fat4 allele following the deletion of one Fat4 allele. Re-expression of Fat4 in Fat4-deficient tumor cells suppressed the tumorigenecity whereas suppression of Fat4 expression in the non-tumorigenic mammary epithelial cell line induced tumorigenesis. We also found that Fat4 expression was lost in a large fraction of human breast tumor cell lines and primary tumors. Loss of Fat4 expression in breast tumors was associated with human Fat4 promoter methylation. Together, these findings suggest that Fat4 is a strong candidate for a breast tumor suppressor gene.

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