Genomic and functional evidence for an <i>ARID1A</i> tumor suppressor role

Huang, Jianmin; Zhao, Yanling; Liu, Yu; Fletcher, Jonathan A.; Xiao, Sheng

doi:10.1002/gcc.20459

Cited by 75 publications

(65 citation statements)

References 18 publications

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“…It has now been shown that ARID1A is a bona fide tumor suppressor gene in gynecological cancers, among others in an interesting study by Guan et al, 13,14 as was already suggested in many reports. 3,4,6 We have investigated the expression of ARID1A in endometrial cancer, in the complete spectrum from precursor lesions (hyperplasias), via primary tumors to metastases, to gain a better understanding in the timing of the loss of ARID1A in endometrial cancer carcinogenesis and progression.…”

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confidence: 67%

ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas

et al. 2013

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ARID1A (AT-rich interactive domain 1A) has recently been identified as a tumor suppressor gene in various, predominantly gynecological cancers. We wanted to investigate the distribution of ARID1A in endometrial hyperplasia, carcinomas and metastatic lesions to elucidate the timing of expression loss of its protein ARID1A in the course of endometrial cancer carcinogenesis. In addition, we wanted to assess the relationship between the loss of ARID1A and clinicopathological variables in endometrial cancer in general and the endometrioid subtype in particular. We analyzed a prospectively collected series of 535 primary endometrial cancers, 77 metastatic lesions, as well as 38 retrospectively collected endometrial hyperplasias with evaluable immunohistochemical staining for ARID1A. Fresh frozen tissue was available for mRNA microarray analysis in 122 primary tumors in parallel. Loss of ARID1A protein expression was noted in none of the hyperplasias without atypia, 16% of hyperplasias with atypia, 19% of primary endometrioid tumors and 28% of metastatic lesions. Loss of ARID1A in primary tumor was significantly associated with endometrioid grade 1 or 2 and clearcell histology, diploid tumor cells, younger patient age and deeper myometrial infiltration, but not survival. ARID1A RNA expression was significantly correlated with ARID1A protein loss. Thus, loss of ARID1A appears to be an early event in the carcinogenesis of endometrioid uterine carcinomas and the association with deep myometrial infiltration may suggest an importance for invasiveness.

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confidence: 67%

ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas

et al. 2013

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“…As Huang et al (2007) reported that the ARID1A gene was genomically rearranged in a primary breast carcinoma, we also focused on the ARID1A gene in our list. We identified a nonsense mutation, c.944C>T, in exon-9 in the ARID1A gene, which introduces a premature stop codon at amino-acid position 944 ( Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…Several genes encoding hSWI/SNF components have been associated with tumorigenesis (Medina and Sanchez-Cespedes, 2008;Roberts and Biegel, 2009;Rodriguez-Nieto and Sanchez-Cespedes, 2009). Moreover, Huang et al (2007) reported that an antisense cDNA resulting from a genomic rearrangement involving the ARID1A gene in a primary breast carcinoma could transform NIH3T3 cells. During the course of our investigation, mutations in the ARID1A were reported to occur in up to 50% of ovarian clear cell carcinomas (Jones et al, 2010;Wiegand et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer

et al. 2011

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Tumor-suppressor genes (TSGs) have been classically defined as genes whose loss of function in tumor cells contributes to the formation and/or maintenance of the tumor phenotype. TSGs containing nonsense mutations may not be expressed because of nonsense-mediated RNA decay (NMD). We combined inhibition of the NMD process, which clears transcripts that contain nonsense mutations, with the application of high-density single-nucleotide polymorphism arrays analysis to discriminate allelic content in order to identify candidate TSGs in five breast cancer cell lines. We identified ARID1A as a target of NMD in the T47D breast cancer cell line, likely as a consequence of a mutation in exon-9, which introduces a premature stop codon at position Q944. ARID1A encodes a human homolog of yeast SWI1, which is an integral member of the hSWI/SNF complex, an ATPdependent, chromatin-remodeling, multiple-subunit enzyme. Although we did not find any somatic mutations in 11 breast tumors, which show DNA copy-number loss at the 1p36 locus adjacent to ARID1A, we show that low ARID1A RNA or nuclear protein expression is associated with more aggressive breast cancer phenotypes, such as high tumor grade, in two independent cohorts of over 200 human breast cancer cases each. We also found that low ARID1A nuclear expression becomes more prevalent during the later stages of breast tumor progression. Finally, we found that ARID1A reexpression in the T47D cell line results in significant inhibition of colony formation in soft agar. These results suggest that ARID1A may be a candidate TSG in breast cancer.

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“…BAF250A has been linked to the functions of steroid receptors (Inoue et al, 2002). ARID1A is located in 1p36.11 (Kozmik et al, 2001), a region frequently deleted in human cancers (Huang et al, 2007), and may be involved in cancer development. BAF250A is lost in two cell lines, C33a and T47D , and may be deficient in as many as 30% of renal carcinomas and 10% of breast carcinomas (Wang et al, 2004a).…”

Section: Swi/snf Subunits and Their Role In Gene Regulation And Cancermentioning

confidence: 99%

The SWI/SNF complex and cancer

2009

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The mammalian SWI/SNF complexes mediate ATPdependent chromatin remodeling processes that are critical for differentiation and proliferation. Not surprisingly, loss of SWI/SNF function has been associated with malignant transformation, and a substantial body of evidence indicates that several components of the SWI/SNF complexes function as tumor suppressors. This review summarizes the evidence that underlies this conclusion, with particular emphasis upon the two catalytic subunits of the SWI/SNF complexes, BRM, the mammalian ortholog of SWI2/SNF2 in yeast and brahma in Drosophila, and Brahma-related gene-1 (BRG1).

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Genomic and functional evidence for an ARID1A tumor suppressor role

Cited by 75 publications

References 18 publications

ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas

ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas

An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer

The SWI/SNF complex and cancer

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