ARID1A

Gene Summary

Gene:ARID1A; AT rich interactive domain 1A (SWI-like)
Aliases: ELD, B120, OSA1, P270, hELD, BM029, MRD14, hOSA1, BAF250, C1orf4, BAF250a, SMARCF1
Location:1p35.3
Summary:This gene encodes a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. It possesses at least two conserved domains that could be important for its function. First, it has a DNA-binding domain that can specifically bind an AT-rich DNA sequence known to be recognized by a SNF/SWI complex at the beta-globin locus. Second, the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. It is thought that the protein encoded by this gene confers specificity to the SNF/SWI complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:AT-rich interactive domain-containing protein 1A
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

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

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 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.

  • Breast Cancer
  • Transcription Factors
  • Chromosomal Proteins, Non-Histone
  • Exome
  • Endometrial Cancer
  • Staging
  • Transcriptome
  • Cervical Cancer
  • Phosphatidylinositol 3-Kinases
  • Translocation
  • Mutation
  • Genetic Predisposition
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • DNA Helicases
  • Survival Rate
  • ARID1A
  • Nuclear Proteins
  • High-Throughput Nucleotide Sequencing
  • Epigenetics
  • Gene Expression Profiling
  • Genome, Human
  • p53 Protein
  • Endometriosis
  • Transforming Growth Factor beta
  • Endometrioid Carcinoma
  • Immunohistochemistry
  • DNA Sequence Analysis
  • Cancer Gene Expression Regulation
  • Ovarian Cancer
  • Tumor Suppressor Gene
  • DNA-Binding Proteins
  • Clear Cell Adenocarcinoma
  • Chromosome 1
  • Tumor Stem Cell Assay
  • Adenocarcinoma
  • Chromatin Assembly and Disassembly
  • Molecular Sequence Data
  • Base Sequence
  • Tumor Markers
  • Uterine Cancer
  • Microsatellite Instability
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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

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

Latest Publications: ARID1A (cancer-related)

Faraj SF, Chaux A, Gonzalez-Roibon N, et al.
Immunohistochemical expression of ARID1A in penile squamous cell carcinomas: a tissue microarray study of 112 cases.
Hum Pathol. 2015; 46(5):761-6 [PubMed] Related Publications
ARID1A, a member of the chromatin remodeling genes family, has been suggested as a novel tumor suppressor gene in gynecologic malignancies. However, its role in penile cancer has yet to be determined. This study assesses the immunohistochemical expression of ARID1A in penile squamous cell carcinoma (SCC) and its association with pathologic features, human papillomavirus (HPV) status, and previously reported mammalian target of rapamycin pathway markers in the same cohort. Four tissue microarrays were constructed from 112 cases of formalin-fixed, paraffin-embedded penile SCC from Paraguay. Each tumor was sampled 3 to 12 times. ARID1A expression was evaluated by immunohistochemistry using a polyclonal rabbit anti-ARID1A (BAF250A) antibody. An H score was calculated in each spot as the sum of expression intensity (0-3+) by extent (0%-100%). Median H score per case was used for statistical analysis. ARID1A expression was observed in all cases, ranging from 3% to 100% of tumor cells (median, 95%). In 96 cases (86%), ARID1A expression was observed in 90% or more tumor cells. HPV DNA was detected in 20 (38%) of 52 analyzed samples. There was a significant trend of association between ARID1A and histologic grade. ARID1A expression was not associated with histologic subtype (P = .61) or HPV status (P = .18). ARID1A expression decreased with decreasing levels of PTEN expression (P = .01). ARID1A was expressed in penile SCC, in most cases at high levels. A significant trend of association was found between histologic grade and ARID1A expression, with lower ARID1A expression, lower histologic grades, and decreased PTEN expression.

Ozawa Y, Nakamura Y, Fujishima F, et al.
Decreased expression of ARID1A contributes to infiltrative growth of esophageal squamous cell carcinoma.
Tohoku J Exp Med. 2015; 235(3):185-91 [PubMed] Related Publications
The clinical outcome for esophageal squamous cell carcinoma (ESCC) patients is often poor because of the invasive nature of this tumor type. AT-rich interactive domain 1A (ARID1A) functions as a tumor suppressor, and its gene mutation has been reported in various human malignancies. ARID1A is a non-catalytic subunit of the SWItch/Sucrose Non Fermentable (SWI/SNF) chromatin-remodeling complex that regulates gene transcription. Decreased expression of ARID1A protein has been reported to decrease the expression of E-cadherin, an adhesion protein. However, the correlation between ARID1A and E-cadherin expression status in ESCC remains largely unknown. To address this issue, we examined the expression of ARID1A and E-cadherin in tumor specimens excised from 83 ESCC patients using immunohistochemical analysis. The intensity of the ARID1A immunoreactivity was significantly lower in tumors with a growth pattern characterized by ill-defined borders than that in tumors with an expansive growth pattern having a well-demarcated border or tumors with an intermediate growth pattern. Thus, decreased ARID1A immunoreactivity correlated with infiltrative growth of ESCC. In contrast, E-cadherin status did not correlate with the infiltrative growth pattern of ESCC. Moreover, ARID1A expression status did not significantly correlate with any of other clinicopathological factors, E-cadherin expression levels, or the clinical outcome of the patients. On the other hand, the patients with tumors expressing low levels of E-cadherin exhibited significantly lower survival rates than those with high expression. In conclusion, reduced ARID1A expression in tumor tissues contributes to infiltrative growth of ESCC, irrespective of E-cadherin expression levels.

Waddell N, Pajic M, Patch AM, et al.
Whole genomes redefine the mutational landscape of pancreatic cancer.
Nature. 2015; 518(7540):495-501 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Bitler BG, Aird KM, Garipov A, et al.
Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers.
Nat Med. 2015; 21(3):231-8 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.

Kubuschok B, Held G, Pfreundschuh M
Management of diffuse large B-cell lymphoma (DLBCL).
Cancer Treat Res. 2015; 165:271-88 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. While CHOP was the standard combination chemotherapy for 25 years, the incorporation of the CD20 antibody rituximab at the beginning of this century has considerably improved the outcome of all patients with DLBCL: Depending on the prognostic subgroup, only half to one-third of the patients die of their DLBCL compared to pre-rituximab era. Treatment is usually tailored according to the individual risk profile of a DLBCL patient according to the International Prognostic Index (IPI). Assignment of DLBCL according to the gene expression profile into DLBLC originating from a germinal center B cell (GC type) or from an activated B cell (ABC type) has provided novel insights into the pathogenesis of the respective DLBCL, identified molecules which are indispensable for the survival of the lymphoma cells and provided targets for novel "targeted therapies" drugs. Incorporating these new drugs into combination immunochemotherapy or substituting single drugs in the R-CHOP combination will result in even higher cure rates of and/or less toxicity for patients with DLBCL in the decade to come.

Park JH, Lee C, Suh JH, et al.
Decreased ARID1A expression correlates with poor prognosis of clear cell renal cell carcinoma.
Hum Pathol. 2015; 46(3):454-60 [PubMed] Related Publications
Clear cell renal cell carcinoma (CCRCC) is the most common renal cell carcinoma. It has a relatively unfavorable prognosis compared to other common renal cell carcinomas. Recently, comprehensive molecular studies in CCRCC revealed important genetic alterations, including changes in the VHL, PBRM1, and ARID1A genes. The expression of ARID1A protein is associated with tumor progression and prognosis in many cancers. This study aimed to evaluate the nuclear expression of ARID1A in CCRCC and to assess its expression with the clinical prognosis. The nuclear expression of ARID1A was evaluated in 290 cases of CCRCC by immunohistochemistry. To determine the clinicopathological association with ARID1A, each of the cases was divided into 2 groups, low- and high-expression groups, according to the average proportion of nuclear staining. Decreased ARID1A expression was associated with the higher nuclear grade and higher pTNM stage (P < .001 and P = .013, respectively). The ARID1A low-expression group revealed significantly shorter cancer-specific and progression-free survival times (P = .001 and P < .001, respectively). Furthermore, Cox regression analysis showed that ARID1A expression was an independent prognostic factor for progression-free survival (P = .009). These results suggest that nuclear expression of ARID1A may serve as a new prognostic marker in CCRCC patients.

Chen K, Yang D, Li X, et al.
Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.
Proc Natl Acad Sci U S A. 2015; 112(4):1107-12 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

Yamashita Y
Ovarian cancer: new developments in clear cell carcinoma and hopes for targeted therapy.
Jpn J Clin Oncol. 2015; 45(5):405-7 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Until recently, ovarian clear cell carcinoma was recognized by its unique morphology and unfavorable patient outcome primarily due to tumor chemoresistance. Recently, specific molecular characteristics of ovarian clear cell carcinoma, such as PI3CA mutation, ARID1a mutation and MET amplification, have been elucidated. In addition, an association between endometriosis and the tumor has also been a focus of research in recent years. The aim of this review is to discuss the specificity and importance of molecular changes and various intriguing points that are not solved until today. Finally, future aspects, including hopes for the development of novel therapies, are discussed.

Nagymanyoki Z, Mutter GL, Hornick JL, Cibas ES
ARID1A is a useful marker of malignancy in peritoneal washings for endometrial carcinoma.
Cancer Cytopathol. 2015; 123(4):253-7 [PubMed] Related Publications
BACKGROUND: ARID1A (AT-rich interactive domain 1A gene) has recently been identified as a novel tumor suppressor gene and one of the driver genes in endometrial carcinogenesis. Approximately 30% to 40% of endometrial carcinomas harbor mutations in the ARID1A gene, which results in complete loss of ARID1A protein expression. Although ARID1A aberrations are not restricted to endometrial cancer, the authors hypothesized that it might be a useful marker of malignancy in peritoneal washings for patients with endometrial cancer.
METHODS: The cytology archive of Brigham and Women's Hospital was searched to identify cell blocks from peritoneal washings that contained malignant or benign endometrial epithelium. From 2006 through 2013, 17 cases of endometrial carcinoma (EMCA) and 16 cases of endometriosis were identified. Surgical pathology reports and follow-up data were used to confirm the diagnoses. Immunohistochemistry for ARID1A was performed, and slides were scored as 0 (complete loss of staining) or 1 (retained staining) by 2 independent pathologists. The discordant cases were resolved by consensus. The two-tailed Fisher exact probability test was used to calculate statistical significance.
RESULTS: Complete loss of ARID1A expression was found in 8 of 17 EMCA cases (47%) and none of the 16 endometriosis cases (0%) (P = .024). The concordance among the pathologists on first review was high (96.7%).
CONCLUSIONS: The results of the current study demonstrated that ARID1A can be used in peritoneal washings to confirm malignancy in patients with EMCA. Complete loss of ARID1A expression by immunohistochemistry is highly specific for carcinoma, but retained expression is not informative.

Maschietto M, Charlton J, Perotti D, et al.
The IGF signalling pathway in Wilms tumours--a report from the ENCCA Renal Tumours Biology-driven drug development workshop.
Oncotarget. 2014; 5(18):8014-26 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
It is hypothesised that Wilms tumour (WT) results from aberrant renal development due to its embryonic morphology, associated undifferentiated precursor lesions (termed nephrogenic rests) and embryonic kidney-like chromatin and gene expression profiles. From the study of overgrowth syndrome-associated WT, germline dysregulation was identified in the imprinted region at 11p15 affecting imprinted genes IGF2 and H19. This is also detected in ~70% sporadic cases, making this the most common somatic molecular aberration in WT. This review summarises the critical discussion at an international workshop held under the auspices of The European Network for Cancer Research in Children and Adolescents (ENCCA) consortium, where the potential for drug development to target IGF2 and the WT epigenome was debated. Here, we consider current cancer treatments which include targeting the IGF pathway and the use of methylation agents alone or in combination with other drugs in clinical trials of paediatric cancers. Finally, we discuss the possibility of the use of these drugs to treat patients with WT.

Takeshima H, Niwa T, Takahashi T, et al.
Frequent involvement of chromatin remodeler alterations in gastric field cancerization.
Cancer Lett. 2015; 357(1):328-38 [PubMed] Related Publications
A field for cancerization, or a field defect, is formed by the accumulation of genetic and epigenetic alterations in normal-appearing tissues, and is involved in various cancers, especially multiple cancers. Epigenetic alterations are frequently present in chronic inflammation-exposed tissues, but information on individual genes involved in the formation of a field defect is still fragmental. Here, using non-cancerous gastric tissues of cancer patients, we isolated 16 aberrantly methylated genes, and identified chromatin remodelers ACTL6B and SMARCA1 as novel genes frequently methylated in non-cancerous tissues. SMARCA1 was expressed at high levels in normal gastric tissues, but was frequently silenced by aberrant methylation in gastric cancer cells. Moreover, somatic mutations of additional chromatin remodelers, such as ARID1A, SMARCA2, and SMARCA4, were found in 30% of gastric cancers. Mutant allele frequency suggested that the majority of cancer cells harbored a mutation when present. Depletion of a chromatin remodeler, SMARCA1 or SMARCA2, in cancer cell lines promoted their growth. These results showed that epigenetic and genetic alterations of chromatin remodelers are induced at an early stage of carcinogenesis and are frequently involved in the formation of a field defect.

Hao C, Wang L, Peng S, et al.
Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer.
Cancer Lett. 2015; 357(1):179-85 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.

Skulte KA, Phan L, Clark SJ, Taberlay PC
Chromatin remodeler mutations in human cancers: epigenetic implications.
Epigenomics. 2014; 6(4):397-414 [PubMed] Related Publications
Chromatin remodeler complexes exhibit the ability to alter nucleosome composition and positions, with seemingly divergent roles in the regulation of chromatin architecture and gene expression. The outcome is directed by subunit variation and interactions with accessory factors. Recent studies have revealed that subunits of chromatin remodelers display an unexpectedly high mutation rate and/or are inactivated in a number of cancers. Consequently, a repertoire of epigenetic processes are likely to be affected, including interactions with histone modifying factors, as well as the ability to precisely modulate nucleosome positions, DNA methylation patterns and potentially, higher-order genome structure. However, the true significance of chromatin remodeler genetic aberrations in promoting a cascade of epigenetic changes, particularly during initiation and progression of cancer, remains largely unknown.

Ye J, Zhou Y, Weiser MR, et al.
Immunohistochemical detection of ARID1A in colorectal carcinoma: loss of staining is associated with sporadic microsatellite unstable tumors with medullary histology and high TNM stage.
Hum Pathol. 2014; 45(12):2430-6 [PubMed] Related Publications
AT-rich interactive domain-containing protein 1A (ARID1A), a chromatin remodeling gene recently discovered to be a tumor suppressor in ovarian cancers, has been found to be mutated at low frequencies in many other tumors including colorectal carcinoma (CRC). An association between ARID1A alteration and DNA mismatch repair (MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257 CRCs that fulfilled a set of relaxed criteria for Lynch syndrome screening; 59 (23%) were MMR deficient by immunohistochemistry (44 MLH1/PMS2 deficient, 9 MSH2/MSH6 deficient, 4 MSH6 deficient, and 2 PMS2 deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR-deficient tumors (14/59, 13 of the 14 being MLH1/PMS2 deficient) and 4% of MMR-normal tumors (8/198) (P < .05). MLH1 (mutL homolog 1) promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (P = .04), poor tumor differentiation (P < .01), medullary histology (P < .01), and an increased rate of nodal and distant metastasis (P = .03); these patients also trended toward a worse 5-year overall survival. Among MMR-normal tumors, no differences in clinicopathological features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable CRCs that may be medullary but is more likely to present with metastatic disease, warranting further investigation.

Schlenk RF, Kayser S, Bullinger L, et al.
Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation.
Blood. 2014; 124(23):3441-9 [PubMed] Related Publications
The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITDs), as well as concurrent gene mutations, with regard to postremission therapy in 323 patients with FLT3-ITD-positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (P = .004) and IS in the tyrosine kinase domain 1 (TKD1, P = .06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (n = 121) or autologous hematopoietic stem cell transplantation (HSCT, n = 17), an allelic ratio ≥ 0.51 was associated with an unfavorable relapse-free (RFS, P = .0008) and overall survival (OS, P = .004); after allogeneic HSCT (n = 93), outcome was significantly improved in patients with a high allelic ratio (RFS, P = .02; OS, P = .03), whereas no benefit was seen in patients with a low allelic ratio (RFS, P = .38; OS, P = .64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AMLHD93 and AMLHD98A, previously published; AML SG 07-04, ClinicalTrials.gov identifier #NCT00151242.

Burandt E, Bari Noubar T, Lebeau A, et al.
Loss of ALCAM expression is linked to adverse phenotype and poor prognosis in breast cancer: a TMA-based immunohistochemical study on 2,197 breast cancer patients.
Oncol Rep. 2014; 32(6):2628-34 [PubMed] Related Publications
Activated leukocyte cell adhesion molecule (ALCAM) is a membranous cell adhesion protein that is often expressed in breast cancer. Data on the prognostic impact of ALCAM expression is highly controversial in this cancer. To evaluate the clinical impact of ALCAM expression in a sufficiently large patient cohort, we utilized a tissue microarray (TMA) containing more than 2,100 primary breast cancers with clinical follow-up data by immunohistochemistry. TMA spots containing normal breast epithelium showed moderate to strong membranous ALCAM staining. ALCAM staining was strong in 66.2%, moderate in 10.9%, weak in 11.1% and absent in 11.8% of 1,778 (80.9%) interpretable breast cancer tissue spots. Decreased ALCAM expression was significantly associated with advanced tumor size (p=0.0017), unfavorable tumor grade (p<0.0001), negative ER and PR status (p<0.0001 each) as well as high Ki67 labeling index (p<0.0001). Cancers with ACLAM expression loss had a significantly poorer overall (p<0.0001) and disease-specific survival (p=0.0088). This association also held true in the subset of nodal positive cancers (p<0.0001). In conclusion, these data demonstrate that ALCAM is generally expressed in normal and cancerous breast epithelium and that a marked reduction of ALCAM expression characterizes a subset of breast cancer patients with adverse tumor characteristics and unfavorable clinical outcome.

Faraj SF, Chaux A, Gonzalez-Roibon N, et al.
ARID1A immunohistochemistry improves outcome prediction in invasive urothelial carcinoma of urinary bladder.
Hum Pathol. 2014; 45(11):2233-9 [PubMed] Related Publications
AT-rich interactive domain 1A (ARID1A) is tumor suppressor gene that interacts with BRG1 adenosine triphosphatase to form a SWI/SNF chromatin remodeling protein complex. Inactivation of ARID1A has been described in several neoplasms, including epithelial ovarian and endometrial carcinomas, and has been correlated with prognosis. In the current study, ARID1A expression in urothelial carcinoma (UC) of the bladder and its association with clinicopathological parameters and outcome are addressed. Five tissue microarrays were constructed from 136 cystectomy specimens performed for UC at our institution. Nuclear ARID1A staining was evaluated using immunohistochemistry. An H-score was calculated as the sum of the products of intensity (0-3) multiplied by extent of expression (0%-100%). Average H-score per case was used for statistical analysis. ARID1A expression was categorized in low and high using Youden index to define the cut point. ARID1A expression significantly increased from normal to noninvasive UC to invasive UC. For both tumor progression and cancer death, Youden index yielded an H-score of 288 as the optimal cut point for ARID1A expression. Low ARID1A expression showed a tendency for lower risk of tumor progression and cancer mortality. Adding ARID1A expression to pathologic features offers a better model for predicting outcome than pathologic features alone. Low ARID1A expression was more frequently seen in earlier stage disease. There was a tendency for low ARID1A expression to predict better outcome. More importantly, the findings indicate that adding ARID1A expression to pathologic features increases the goodness of fit of the predictive model.

Kosho T, Miyake N, Carey JC
Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing.
Am J Med Genet C Semin Med Genet. 2014; 166C(3):241-51 [PubMed] Related Publications
This issue of Seminars in Medical Genetics, American Journal of Medical Genetics Part C investigates the human diseases caused by mutations in the BAF complex (also known as the mammalian SWI/SNF complex) genes, particularly focusing on Coffin-Siris syndrome (CSS). CSS is a rare congenital malformation syndrome characterized by developmental delay or intellectual disability (ID), coarse facial appearance, feeding difficulties, frequent infections, and hypoplasia/aplasia of the fifth fingernails and fifth distal phalanges. In 2012, 42 years after the first description of CSS in 1970, five causative genes (SMARCB1, SMARCE1, SMARCA4, ARID1A, ARID1B), all encoding components of the BAF complex, were identified as being responsible for CSS through whole exome sequencing and pathway-based genetic screening. The identification of two additional causative genes (PHF6, SOX11) followed. Mutations in another BAF complex gene (SMARCA2) and (TBC1D24) were found to cause clinically similar conditions with ID, Nicolaides-Baraitser syndrome and DOORS syndrome, respectively. Also, ADNP was found to be mutated in an autism/ID syndrome. Furthermore, there is growing evidences for germline or somatic mutations in the BAF complex genes to be causal for cancer/cancer predisposition syndromes. These discoveries have highlighted the role of the BAF complex in the human development and cancer formation. The biology of BAF is very complicated and much remains unknown. Ongoing research is required to reveal the whole picture of the BAF complex in human development, and will lead to the development of new targeted therapies for related disorders in the future.

Jhunjhunwala S, Jiang Z, Stawiski EW, et al.
Diverse modes of genomic alteration in hepatocellular carcinoma.
Genome Biol. 2014; 15(8):436 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous disease with high mortality rate. Recent genomic studies have identified TP53, AXIN1, and CTNNB1 as the most frequently mutated genes. Lower frequency mutations have been reported in ARID1A, ARID2 and JAK1. In addition, hepatitis B virus (HBV) integrations into the human genome have been associated with HCC.
RESULTS: Here, we deep-sequence 42 HCC patients with a combination of whole genome, exome and transcriptome sequencing to identify the mutational landscape of HCC using a reasonably large discovery cohort. We find frequent mutations in TP53, CTNNB1 and AXIN1, and rare but likely functional mutations in BAP1 and IDH1. Besides frequent hepatitis B virus integrations at TERT, we identify translocations at the boundaries of TERT. A novel deletion is identified in CTNNB1 in a region that is heavily mutated in multiple cancers. We also find multiple high-allelic frequency mutations in the extracellular matrix protein LAMA2. Lower expression levels of LAMA2 correlate with a proliferative signature, and predict poor survival and higher chance of cancer recurrence in HCC patients, suggesting an important role of the extracellular matrix and cell adhesion in tumor progression of a subgroup of HCC patients.
CONCLUSIONS: The heterogeneous disease of HCC features diverse modes of genomic alteration. In addition to common point mutations, structural variations and methylation changes, there are several virus-associated changes, including gene disruption or activation, formation of chimeric viral-human transcripts, and DNA copy number changes. Such a multitude of genomic events likely contributes to the heterogeneous nature of HCC.

Penon D, Cito L, Giordano A
Novel findings about management of gastric cancer: a summary from 10th IGCC.
World J Gastroenterol. 2014; 20(27):8986-92 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The Tenth International Gastric Cancer Congress (IGCC) was held in Verona, Italy, from June 19 to 22, 2013. The meeting enclosed various aspects of stomach tumor management, including both tightly clinical approaches, and topics more related to basic research. Moreover, an overview on gastrointestinal stromal tumors was provided too, although here not discussed. Here we will discuss some topics related to molecular biology of gastric cancer (GC), inherent to prognostic, diagnostic and therapeutic tools shown at the conference. Results about well known subjects, such as E-cadherin loss of expression/function, were presented. They revealed that other mutations of the gene were identified, showing a continuous research to improve diagnosis and prognosis of stomach tumor. Simultaneously, new possible molecular markers with an established role for other neoplasms, were discussed, such as mesothelin, stomatin-like protein 2 and Notch-1. Hence, a wide overview including both old and new diagnostic/prognostic tools was offered. Great attention was also dedicated to possible drugs to be used against GC. They included monoclonal antibodies, such as MS57-2.1, drugs used in other pathologies, such as maraviroc, and natural extracts from plants such as biflorin. We would like to contribute to summarize the most impressive studies presented at the IGCC, concerning novel findings about molecular biology of gastric cancer. Although further investigations will be necessary, it can be inferred that more and more tools were developed, so as to better face stomach neoplasms.

Kim TM, Jung SH, Kim MS, et al.
The mutational burdens and evolutionary ages of early gastric cancers are comparable to those of advanced gastric cancers.
J Pathol. 2014; 234(3):365-74 [PubMed] Related Publications
Early gastric cancers (EGCs) precede advanced gastric cancers (AGCs), with a favourable prognosis compared to AGC. To understand the progression mechanism of EGC to AGC, it is required to disclose EGC and AGC genomes in mutational and evolutionary perspectives. We performed whole-exome sequencing and copy number profiling of nine microsatellite (MS)-unstable (MSI-H) (five EGCs and four AGCs) and eight MS-stable (MSS) gastric cancers (four EGCs and four AGCs). In the cancers, we observed well-known driver mutations (TP53, APC, PIK3CA, ARID1A, and KRAS) that were enriched in cancer-related pathways, including chromatin remodelling and tyrosine kinase activity. The MSI-H genomes harboured ten times more mutations, but were largely depleted of copy number alterations (CNAs) compared to the MSS cancers. Interestingly, EGC genomes showed a comparable level of mutations to AGC in terms of the number, sequence composition, and functional consequences (potential driver mutations and affected pathways) of mutations. Furthermore, the CNAs between EGC and AGC genomes were not significantly different in either MSI-H and MSS. Evolutionary analyses using somatic mutations and MSI as molecular clocks further identified that EGC genomes were as old as AGC genomes in both MSS and MSI-H cancers. Our results suggest that the genetic makeup for gastric cancer may already be achieved in EGC genomes and that the time required for transition to AGC may be relatively short. Also, the data suggest a possibility that the mutational profiles obtained from early biopsies may be useful in the clinical settings for the molecular diagnosis and therapeutics of gastric cancer patients.

Buza N, Xu F, Wu W, et al.
Recurrent chromosomal aberrations in intravenous leiomyomatosis of the uterus: high-resolution array comparative genomic hybridization study.
Hum Pathol. 2014; 45(9):1885-92 [PubMed] Related Publications
Uterine intravenous leiomyomatosis (IVL) is a distinct smooth muscle neoplasm with a potential of clinical aggressiveness due to its ability to extend into intrauterine and extrauterine vasculature. In this study, chromosomal alterations analyzed by oligonucleotide array comparative genomic hybridization were performed in 9 cases of IVL. The analysis was informative in all cases with multiple copy number losses and/or gains observed in each tumor. The most frequent recurrent loss of 22q12.3-q13.1 was observed in 6 tumors (66.7%), followed by losses of 22q11.23-q13.31, 1p36.13-p33, 2p25.3-p23.3, and 2q24.2-q32.2 and gains of 6p22.2, 2q37.3 and 10q22.2-q22.3, in decreasing order of frequency. Copy number variants were identified at 14q11.2, 15q11.1-q11.2, and 15q26.2. Genes mapping to the regions of loss include CHEK2, EWS, NF2, PDGFB, and MAP3K7IP1 on chromosome 22q, HEI10 on chromosome 14q, and succinate dehydrogenase subunit B, E2F2, ARID1A KPNA6, EIF3S2 , PTCH2, and PIK3R3 on chromosome 1p. Regional losses on chromosomes 22q and 1p and gains on chromosomes 12q showed overlaps with those previously observed in uterine leiomyosarcomas. In addition, presence of multiple chromosomal aberrations implies a higher level of genetic instability. Follow-up polymerase chain reaction (PCR) sequencing analysis of MED12 gene revealed absence of G> A transition at nucleotides c.130 or c.131 in all 9 cases, a frequent mutation found in uterine leiomyoma and its variants. In conclusion, this is the first report of high-resolution, genome-wide investigation of IVL by oligonucleotide array comparative genomic hybridization. The presence of high frequencies of recurrent regional loss involving several chromosomes is an important finding and likely related to the pathogenesis of the disease.

Abdelzaher E, Abdallah DM
Expression of mesothelioma-related markers in meningiomas: an immunohistochemical study.
Biomed Res Int. 2014; 2014:968794 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Meningiomas are common intracranial tumors. Recently, histogenetic and phenotypic similarities between meningiomas and mesotheliomas have been proposed. We were interested in whether these similarities are reflected on the immunohistochemical level, which would add new potentially diagnostic markers for meningiomas.
METHODS: The expression of mesothelioma-related markers (D2-40, Calretinin, Keratin 5/6, WT1, and Methotheioma-Ab1) was investigated in 87 cases of meningiomas and compared to EMA expression.
RESULTS: 73.6% of meningioma cases were grade I, 20.7% were grade II, and 5.7% were grade III. 83.9% of meningioma cases were classical and 16.1% had special nonmeningothelial features. D2-40 was expressed in 37.9% of cases and was significantly restricted to classical meningiomas. Calretinin and WT1 were negative while Keratin 5/6 and Mesothelioma-Ab1 were weakly expressed in classical variants (5.7% and 3.4%, resp.). EMA was consistently expressed in all cases. Its expression was significantly higher than that of mesothelioma-related markers; this held true also when D2-40 expression was considered separately.
CONCLUSIONS: Mesothelioma-related markers are not extensively expressed in meningiomas, a finding that argues against their proposed histogenetic and phenotypic similarities. Compared to EMA, the significantly lower expression of mesothelioma-related markers and their restricted expression to classical meningioma variants hamper their potential future use as diagnostic markers for meningioma.

Geurts van Kessel A
The cancer genome: from structure to function.
Cell Oncol (Dordr). 2014; 37(3):155-65 [PubMed] Related Publications
The 2014 joint meeting of the International Society for Cellular Oncology (ISCO) and the European Workshop on Cytogenetics and Molecular Genetics of Solid Tumors (EWCMST), organized by Nick Gilbert, Juan Cigudosa and Bauke Ylstra, was held from 11 to 14 May in Malaga, Spain. Since the previous meeting in 2012, the ever increasing availability of new sequencing technologies has enabled the analysis of cancer genomes at an increasingly greater detail. In addition to structural changes in the genome (i.e., translocations, deletions, amplifications), frequent mutations in important regulatory genes have been found to occur, as also frequent alterations in a large number of epigenetic factors. The challenge now is to relate structural changes in cancer genomes to the underlying disease mechanisms and to reveal opportunities for the design of novel (targeted) therapies. During the meeting, various topics related to these challenges and opportunities were addressed, including those dealing with functional genomics, genome instability, biomarkers and diagnostics, cancer genetics and epigenomics. Special attention was paid to therapy-driven cancer evolution (keynote lecture) and relationships between DNA repair, cancer and ageing (Prof. Ploem lecture). Based on the information presented at the meeting, several aspects of the cancer genome and its functional implications are provided in this report.

Samartzis EP, Gutsche K, Dedes KJ, et al.
Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition.
Oncotarget. 2014; 5(14):5295-303 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
ARID1A mutations are observed in various tumors, including ovarian clear cell (OCCC) and endometrioid carcinomas, endometrial, and breast carcinomas. They commonly result in loss of ARID1A-protein expression and frequently co-occur with PI3K/AKT-pathway activating mechanisms. The aim of this study was to test the hypothesis as to whether PI3K/AKT-pathway activation is a critical mechanism in ARID1A-mutated tumors and if consequently ARID1A-deficient tumors show increased sensitivity to treatment with PI3K- and AKT-inhibitors. Upon ARID1A knockdown, MCF7 breast cancer cells and primary MRC5 cells exhibited a significantly increased sensitivity towards the AKT-inhibitors MK-2206 and perifosine, as well as the PI3K-inhibitor buparlisib. Knockdown of ARID1A in MCF7 led to an increase of pAKT-Ser473. AKT-inhibition with MK-2206 led to increased apoptosis and to a decrease of pS6K in ARID1A-depleted MCF7 cells but not in the controls. In five OCCC cell lines ARID1A-deficiency correlated with increased pAKT-Ser473 levels and with sensitivity towards treatment with the AKT-inhibitor MK-2206. In conclusion, ARID1A-deficient cancer cells demonstrate an increased sensitivity to treatment with small molecule inhibitors of the PI3K/AKT-pathway. These findings suggest a specific requirement of the PI3K/AKT pathway in ARID1A-deficient tumors and reveal a synthetic lethal interaction between loss of ARID1A expression and inhibition of the PI3K/AKT pathway.

Wilson-Edell KA, Kehasse A, Scott GK, et al.
RPL24: a potential therapeutic target whose depletion or acetylation inhibits polysome assembly and cancer cell growth.
Oncotarget. 2014; 5(13):5165-76 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Partial loss of large ribosomal subunit protein 24 (RPL24) function is known to protect mice against Akt or Myc-driven cancers, in part via translational inhibition of a subset of cap(eIF4E)-dependently translated mRNAs. The role of RPL24 in human malignancies is unknown. By analyzing a public dataset of matched human breast cancers and normal mammary tissue, we found that breast cancers express significantly more RPL24 than matched normal breast samples. Depletion of RPL24 in breast cancer cells by >70% reduced cell viability by 80% and decreased protein expression of the eIF4E-dependently translated proteins cyclin D1 (75%), survivin (46%) and NBS1 (30%) without altering GAPDH or beta-tubulin levels. RPL24 knockdown also reduced 80S subunit levels relative to 40S and 60S levels. These effects on expression of eIF4E-dependent proteins and ribosome assembly were mimicked by 2-24 h treatment with the pan-HDACi, trichostatin A (TSA), which induced acetylation of 15 different polysome-associated proteins including RPL24. Furthermore, HDAC6-selective inhibition or HDAC6 knockdown induced ribosomal protein acetylation. Via mass spectrometry, we found that 60S-associated, but not, polysome-associated, RPL24 undergoes HDACi-induced acetylation on K27. Thus, RPL24 K27 acetylation may play a role in ribosome assembly. These findings point toward a novel acetylation-dependent polysome assembly mechanism regulating tumorigenesis.

Sun D, Qin L, Xu Y, et al.
Influence of adriamycin on changes in Nanog, Oct-4, Sox2, ARID1 and Wnt5b expression in liver cancer stem cells.
World J Gastroenterol. 2014; 20(22):6974-80 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
AIM: To determine the influence of Adriamycin (ADM) on the changes in Nanog, Oct4, Sox2, as well as, in ARID1 and Wnt5b expression in liver cancer stem cells.
METHODS: The MHCC97-L and HCCLM3 liver cancer cell lines were selected as the cell models in this study, and were routinely cultured. The 50% lethal dose (LD50) in the cell lines was detected by the MTT assay. Expression changes in liver cancer stem cell related genes (Nanog, Oct-4, Sox2, ARID1, and Wnt5b) were detected by western blot following treatment with ADM (LD50).
RESULTS: The LD50 of ADM in MHCC97-L cells was lower than that in HCCLM3 cells (0.4123 ± 0.0236 μmol/L vs 0.5259 ± 0.0125 μmol/L, P < 0.05). Wnt5b and Nanog were expressed in both MHCC97-L and HCCLM3 cells, while only Sox2 was expressed in HCCLM3 cells. However, neither ARID1A nor Oct4 was detected in these two cell lines. Genes, related to the stem cells, showed different expression in liver cancer cells with different metastatic potential following treatment with ADM (LD50). Wnt5b protein increased gradually within 4 h of ADM (LD50) treatment, while Nanog decreased (P < 0.05). After 12 h, Wnt5b decreased gradually, while Nanog increased steadily (P < 0.05). In addition, only Sox2 was expressed in HCCLM3 cells with high metastatic potential following ADM (LD50) treatment. The expression of Sox2 increased gradually with ADM (LD50) in HCCLM3 cells (P < 0.05).
CONCLUSION: ADM increased the death rate of MHCC97-L and HCCLM3 cells, while the growth suppressive effect of ADM was higher in MHCC97-L cells than in HCCLM3 cells.

Weinreb I, Zhang L, Tirunagari LM, et al.
Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin.
Genes Chromosomes Cancer. 2014; 53(10):845-56 [PubMed] Related Publications
Polymorphous low-grade adenocarcinoma (PLGA) and cribriform adenocarcinoma of minor salivary gland (CAMSG) are low-grade carcinomas arising most often in oral cavity and oropharynx, respectively. Controversy exists as to whether these tumors represent separate entities or variants of one spectrum, as they appear to have significant overlap, but also clinicopathologic differences. As many salivary carcinomas harbor recurrent translocations, paired-end RNA sequencing and FusionSeq data analysis was applied for novel fusion discovery on two CAMSGs and two PLGAs. Validated rearrangements were then screened by fluorescence in situ hybridization (FISH) in 60 cases. Histologic classification was performed without knowledge of fusion status and included: 21 CAMSG, 18 classic PLGA, and 21 with "mixed/indeterminate" features. The RNAseq of 2 CAMSGs showed ARID1A-PRKD1 and DDX3X-PRKD1 fusions, respectively, while no fusion candidates were identified in two PLGAs. FISH for PRKD1 rearrangements identified 11 additional cases (22%), two more showing ARID1A-PRKD1 fusions. As PRKD2 and PRKD3 share similar functions with PRKD1 in the diacylglycerol and protein kinase C signal transduction pathway, we expanded the investigation for these genes by FISH. Six additional cases each showed PRKD2 and PRKD3 rearrangements. Of the 26 (43%) fusion-positive tumors, there were 16 (80%) CAMSGs and 9 (45%) indeterminate cases. A PRKD2 rearrangement was detected in one PLGA (6%). We describe novel and recurrent gene rearrangements in PRKD1-3 primarily in CAMSG, suggesting a possible pathogenetic dichotomy from "classic" PLGA. However, the presence of similar genetic findings in half of the indeterminate cases and a single PLGA suggests a possible shared pathogenesis for these tumor types.

Chou A, Toon CW, Clarkson A, et al.
Loss of ARID1A expression in colorectal carcinoma is strongly associated with mismatch repair deficiency.
Hum Pathol. 2014; 45(8):1697-703 [PubMed] Related Publications
ARID1A is a tumor suppressor gene involved in chromatin remodelling. ARID1A mutations and loss of protein expression occur commonly in endometrioid and gynecological clear cell carcinoma where they are associated with mismatch repair (MMR) deficiency. We assessed ARID1A expression in a large cohort of colorectal carcinomas (CRCs). Immunohistochemistry for ARID1A was performed on whole sections from 100 CRCs and on 1876 CRCs in tissue microarray format. There was complete concordance between the staining on whole slides and tissue microarray sections. Loss of staining was found in 110 (5.9%) of 1876 CRCs and was strongly associated with older age, right sided location, large size, BRAF V600E mutation, MMR deficiency, high histological grade and medullary morphology, (all P < .01). There was a trend towards loss of expression being more common in females (P = .06). When subclassified by combined BRAF V600E mutation and MMR status, loss of ARID1A expression was found most commonly in CRCs with the BRAF V600E mutated, MMR- deficient phenotype (58 of 232 cases, 25%, P < .01). In univariate and multivariate analysis, loss of ARID1A expression was not associated with overall survival-hazard ratio 1.05 (0.68-1.64) and 0.60 (0.24-1.44), respectively. All carcinomas arising in patients with known Lynch syndrome (n = 12) were ARID1A positive. We conclude that loss of ARID1A expression occurs in a small but significant proportion of CRCs where it is strongly correlated with mismatch repair deficiency and other clinical and pathological features associated with somatic hypermethylation.

Mortus JR, Zhang Y, Hughes DP
Developmental pathways hijacked by osteosarcoma.
Adv Exp Med Biol. 2014; 804:93-118 [PubMed] Related Publications
Cancer of any type often can be described by an arrest, alteration or disruption in the normal development of a tissue or organ, and understanding of the normal counterpart's development can aid in understanding the malignant state. This is certainly true for osteosarcoma and the normal developmental pathways that guide osteoblast development that are changed in the genesis of osteogenic sarcoma. A carefully regulated crescendo-decrescendo expression of RUNX2 accompanies the transition from mesenchymal stem cell to immature osteoblast to mature osteoblast. This pivotal role is controlled by several pathways, including bone morphogenic protein (BMP), Wnt/β-catenin, fibroblast growth factor (FGF), and protein kinase C (PKC). The HIPPO pathway and its downstream target YAP help to regulate proliferation of immature osteoblasts and their maturation into non-proliferating mature osteoblasts. This pathway also helps regulate expression of the mature osteoblast protein osteocalcin. YAP also regulates expression of MT1-MMP, a membrane-bound matrix metalloprotease responsible for remodeling the extracellular matrix surrounding the osteoblasts. YAP, in turn, can be regulated by the ERBB family protein Her-4. Osteosarcoma may be thought of as a cell held at the immature osteoblast stage, retaining some of the characteristics of that developmental stage. Disruptions of several of these pathways have been described in osteosarcoma, including BMP, Wnt/b-catenin, RUNX2, HIPPO/YAP, and Her-4. Further, PKC can be activated by several receptor tyrosine kinases implicated in osteosarcoma, including the ERBB family (EGFR, Her-2 and Her-4 in osteosarcoma), IGF1R, FGF, and others. Understanding these functions may aid in the understanding the mechanisms underpinning clinical observations in osteosarcoma, including both the lytic and blastic phenotypes of tumors, the invasiveness of the disease, and the tendency for treated tumors to ossify rather than shrink. Through a better understanding of the relationship between normal osteoblast development and osteosarcoma, we may gain insights into novel therapeutic avenues and improved outcomes.

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