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

Abstract

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.

Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

“…ARID1A (AT-rich interactive domain 1A; also known as BAF250) is a key member of the SWI/SNF chromatin-modeling complex, and the gene has recently been reported to be frequently mutated in a wide variety of cancer types (Jones et al 2010;Wiegand et al 2010Wiegand et al , 2011Guan et al 2011b;Gui et al 2011;Wang et al 2011;Mamo et al 2012). While previous studies and our present results suggest its potential role as a tumor suppressor, the molecular mechanism underlying its functional role in cancer is largely unknown.…”

“…Among these genes, ARID1A has attracted wide interest recently. Frequent mutations throughout the gene sequence including multiple truncation mutations have been reported in ovarian (Jones et al 2010;Wiegand et al 2010), gynecological (Guan et al 2011b), bladder (Gui et al 2011), gastric (Wang et al 2011), breast (Mamo et al 2012), and endometrial cancers (Guan et al 2011a;Wiegand et al 2011), suggesting a role as a tumor suppressor. ARID1A encodes BAF250a, a nuclear protein and a key component of the SWI/SNF chromatin-remodeling complex that functions as a regulator of gene expression and chromatin dynamics (Wu et al 2009).…”

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

“…[5][6][7] Mutations in various subunits of the SWI/SNF can influence the epigenetic regulation of genes and have been identified in different cancers in recent years. 5,6 Since the two reports on ARID1A in 2010, high frequencies of mutations in the ARID1A gene and loss of ARID1A protein have been reported in endometrial cancer (26-37%), 8,9 adenocarcinoma of the cervix (32%), 10 gastric cancer (10-14%), 9,11 anaplastic thyroid cancer (14%), 9 colorectal cancer (10%), 11 breast cancer (64%) 12 and several cancer cell lines. ARID1A mutations seem, although also present in other tumor types, predominantly linked to gynecological and in particular endometriumrelated tumors.…”

The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice

“…ARID1A (also called BAF250a), encoding an important component of the mammalian SWI/SNF complex, has emerged as one of the most commonly mutated or downregulated genes in diverse tumors, including gastrointestinal Cajuso et al 2014), endometrial (Liang et al 2012;The Cancer Genome Atlas Research Network et al 2013), ovarian clear cell (Jones et al 2010;Wiegand et al 2010), pancreatic (Waddell et al 2015), lung (Imielinski et al 2012), and breast (Cornen et al 2012;Mamo et al 2012). ARID1A impacts epigenetic gene regulation by altering chromatin structure around promoters of specific loci in conjunction with its associated SWI/SNF complex components (Inoue et al 2011;Chandler et al 2013).…”

“…Sporadic breast cancer (i.e., not associated with inherited neoplasia-driving mutations) accounts for the vast majority of breast cancer cases in the U.S. (80-85%) (American Cancer Society 2014). Although ARID1A has not yet been widely recognized as a key suppressor of breast carcinogenesis, it is heterozygously deleted in a substantial fraction of tumors (Cornen et al 2012;Mamo et al 2012), and low ARID1A expression in tumors of patients with breast cancer correlates significantly with poorer prognosis and overall survival (Mamo et al 2011;Zhao et al 2014;Cho et al 2015;Zhang et al 2015). Here, we report functional evidence that Arid1a loss is critical for mammary tumorigenesis in a mouse model of spontaneous breast cancer and present data on how this leads to deregulated cancer cell growth.…”