ARID1A (AT rich interactive domain 1A (SWI-like))

2013-11-01 Yohan Suryo Rahmanto , Tian-Li Wang Affiliation

Departments of Gynecology\\\/Obstetrics, Oncology Johns Hopkins Medical Institutions CRBII, Rm: 306, 1550 Orleans Street Baltimore, MD 21231, USA

Identity

HGNC

ARID1A

LOCATION

1p36.11

LOCUSID

8289

ALIAS

B120,BAF250,BAF250a,BM029,C1orf4,CSS2,ELD,MRD14,OSA1,P270,SMARCF1,hELD,hOSA1

FUSION GENES

Show Gene Fusions

DNA/RNA

DNA organization of ARID1A.

Description

ARID1A gene is encoded by 20 exons spanning 86,08 Mb.

Transcription

Human ARID1A has 2 transcript variants. The long variant (isoform 1) transcribed into 8585 bp mRNA, the coding sequence is from 374 bp - 7231 bp. The short variant (isoform 2) transcribed into 7934 bp mRNA, the coding sequence is from 374 bp - 6580 bp. Isoform 2 has a shorter exon 18 compared to isoform 1.

Proteins

Note

The longer isoform of ARID1A consists of 2285 amino acids (pI: 6.24), with predicted molecular mass of 242,04 kDa. The shorter isoform of ARID1A consists of 2068 amino acids (pI: 6.08), with predicted molecular mass of 218,33 kDa. Both isoforms contain a single "ARID" DNA binding domain and four "LXXLL" nuclear receptor coactivator motifs.

ARID1A protein.

Description

ARID1A is a member of the SWI/SNF family that can regulate genes transcription by chromatin structure alteration through its helicase and ATPase activities. The encoded ARID1A nuclear protein is part of the BRG/BRM chromatin remodeling complex that has been shown to play an integral role in controlling gene expression.

Expression

Ubiquitously expressed in various normal tissues, with the highest expression seen in brain, blood and female tissues.

Localisation

Mainly located at cell nucleus but not at nucleolus.

Function

ARID1A contains a conserved DNA-binding domain (ARID) that could be important for its function and can specifically bind an AT-rich DNA sequence. ARID1A is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes. Changes in this SNF/SWI complex has been implicated in many cellular processes, including development, differentiation, proliferation, DNA repair, and tumor suppression.
ARID1A has been reported to act as tumor suppressor in gynecological cancers (Guan et al., 2011b). Molecular studies using over-expression and RNAi silencing models have demonstrated that ARID1A negatively regulates cellular proliferation and tumorigenicity. This negative regulation is achieved through molecular collaboration between ARID1A/BRG1 and p53, to regulate tumor-inhibiting p53-downstream target genes such as CDKN1A and SMAD3. Using mutational studies, Guan et al. (2012) have further confirmed ARID1A role as tumor suppressor, with all of the in-frame indel mutants have lost their ability to inhibit cellular proliferation.

Mutations

Germinal

ARID1A mutations have been implicated in Coffin-Siris syndrome, a rare genetic disorder that causes developmental delay and abnormities in 5^th fingers or toes (Tsurusaki et al., 2012; Santen et al., 2013; Wieczorek et al., 2013).

Somatic

ARID1A is located at chromosome 1p that is frequently deleted in tumours. ARID1A sequence mutations, deletions, and rearrangements were identified in ovarian, kidney, breast, lung, pancreatic and stomach cancer.

Implicated in

Entity name

Ovarian clear cell carcinoma

Oncogenesis

ARID1A somatic mutations were identified in 57% of the 42 ovarian clear cell carcinomas (Jones et al., 2010). Maeda et al. (2010) has demonstrated that ARID1a genetic mutations resulted in loss of ARID1A protein expression in 59% of the 149 ovarian clear cell carcinomas.
Study with a larger cohort of 210 patient samples has also demonstrated that ARID1A somatic mutation were found in 46% of patients with ovarian clear-cell carcinoma and 30% of patients ovarian endometrioid carcinoma (Wiegand et al., 2010).
ARID1A inactivation by ARID1A mutations has been suggested as an early molecular event that can lead to tumor progression from benign ovarian endometroid cysts into an aggressive ovarian clear cell and endometrioid carcinoma (Ayhan et al., 2012).

Entity name

Uterine endometroid carcinoma

Oncogenesis

ARID1A mutations were observed in 40% of uterine endometrioid carcinoma with none presented in uterine serous carcinomas (Guan et al., 2011a). All of the mutations in endometrioid carcinomas were the nonsense or insertion/deletion types (Guan et al., 2011a) and expected to result in complete loss or clonal loss of ARID1A expression. Immunostaining confirmed the relatively significant frequency of loss of ARID1A protein expression with 25-26% and 44% in uterine low-grade and high-grade endometrioid carcinomas, respectively (Guan et al., 2011a; Werner et al., 2013; Mao et al., 2013). Hence, mutation-related loss of ARID1A expression has also been hypothesized as an early event and played an important role in tumor progression of uterine endometrioid carcinoma (Ayhan et al., 2012; Werner et al., 2013; Mao et al., 2013).

Entity name

Cervical cancer

Oncogenesis

Loss of ARID1A protein expression was observed in 31% (14/45) of cervical adenocarcinomas/adenosquamous carcinomas with no correlation to any clinicopathological features (Katagiri et al., 2012). Later studies using a large series of cervical cancer tissue specimens, ARID1A expression was found to be significantly decreased in cervical cancer tissues than in non-adjacent normal cervical epithelial tissues (Cho et al., 2013). The decrease of ARID1A expression was also found to be associated with transition from normal cells to cervical carcinoma and a more aggressive tumor phenotype (Cho et al., 2013). Overall survival was also found to be reduced in cervical cancer patients with loss of ARID1A (Cho et al., 2013).

Entity name

Breast cancer

Oncogenesis

Low ARID1A expression was observed in 56% (63/112) of the breast cancers samples and was significantly associated with advanced tumor stage, higher P53 expression, increase Ki-67 and triple negative (ER^-/PR^-/Her-2^-) molecular subtype (Zhang et al., 2012; Mamo et al., 2012). Low ARID1A expression was a predictor of poor overall survival of breast cancer patients (Zhang et al., 2012; Mamo et al., 2012). Breast cancer also exhibited a low rate (3-4%) of ARID1A mutations (Jones et al., 2010; Cornen et al., 2012).

Entity name

Gastric cancer

Oncogenesis

Inactivating mutation of ARID1A has also been identified gastric cancer (Wang et al., 2011; Abe et al., 2012; Zhang et al., 2012). Loss of ARID1A expression has been correlated with increasing depth of tumor infiltration, higher tumor grade, and poor overall patient survival (Abe et al., 2012; Wang et al., 2012). Moreover, ARID1A expression has been shown as an independent prognostic factor of overall survival in multiple studies (Abe et al., 2012; Wang et al., 2012).

Entity name

Coffin-Siris syndrome

Prognosis

Hepatoblastoma and multiple congenital anomalies.

Oncogenesis

ARID1A mutations in individual with Coffin-Siris syndrome lead to a truncation and nonfunctional ARID1A protein (Tsurusaki et al., 2012; Santen et al., 2013; Wieczorek et al., 2013). As a result, affected individuals developed abnormalities, such as missing the fifth fingers or toes and coarse characteristic of facial features. Moreover, cancer was not detected in any of the individual with ARID1A mutation, reported in this study.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
22915242	2012	ARID1A expression loss in gastric cancer: pathway-dependent roles with and without Epstein-Barr virus infection and microsatellite instability.	Abe H et al
22976498	2012	Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma.	Ayhan A et al
23427874	2013	Loss of ARID1A/BAF250a expression is linked to tumor progression and adverse prognosis in cervical cancer.	Cho H et al
22249247	2012	Mutations and deletions of ARID1A in breast tumors.	Cornen S et al
23097632	2012	Functional analysis of in-frame indel ARID1A mutations reveals new regulatory mechanisms of its tumor suppressor functions.	Guan B et al
21412130	2011	Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma.	Guan B et al
21900401	2011	ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers.	Guan B et al
20826764	2010	Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.	Jones S et al
22274316	2012	Frequent loss of tumor suppressor ARID1A protein expression in adenocarcinomas/adenosquamous carcinomas of the uterine cervix.	Katagiri A et al
21614196	2010	Clinicopathological significance of loss of ARID1A immunoreactivity in ovarian clear cell carcinoma.	Maeda D et al
21892209	2012	An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer.	Mamo A et al
24076775	2013	Loss of ARID1A expression correlates with stages of tumor progression in uterine endometrioid carcinoma.	Mao TL et al
23929686	2013	Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients.	Santen GW et al
22426308	2012	Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.	Tsurusaki Y et al
22808142	2012	Decreased expression of the ARID1A gene is associated with poor prognosis in primary gastric cancer.	Wang DD et al
22037554	2011	Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer.	Wang K et al
23080032	2013	ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas.	Werner HM et al
23906836	2013	A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling.	Wieczorek D et al
20942669	2010	ARID1A mutations in endometriosis-associated ovarian carcinomas.	Wiegand KC et al
22484628	2012	Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes.	Zang ZJ et al
21889920	2012	Frequent low expression of chromatin remodeling gene ARID1A in breast cancer and its clinical significance.	Zhang X et al

Other Information

Locus ID:

NCBI: 8289
MIM: 603024
HGNC: 11110
Ensembl: ENSG00000117713

Variants:

dbSNP: 8289
ClinVar: 8289
TCGA: ENSG00000117713
COSMIC: ARID1A

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000117713	ENST00000324856	O14497
ENSG00000117713	ENST00000374152	O14497
ENSG00000117713	ENST00000430799	H0Y488
ENSG00000117713	ENST00000457599	O14497
ENSG00000117713	ENST00000466382	H0YCU6
ENSG00000117713	ENST00000524572	E9PQW6
ENSG00000117713	ENST00000532781	H0YEW5
ENSG00000117713	ENST00000615191	A0A087WUV6
ENSG00000117713	ENST00000636219	A0A1B0GTU5
ENSG00000117713	ENST00000637465	A0A1B0GVT5

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Chromatin organization	REACTOME	R-HSA-4839726
Chromatin modifying enzymes	REACTOME	R-HSA-3247509
RMTs methylate histone arginines	REACTOME	R-HSA-3214858

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38100120	2024	ARID1A loss induces P4HB to activate fibroblasts to support lung cancer cell growth, invasion, and chemoresistance.	2
38166741	2024	ARID1A deficiency promotes progression and potentiates therapeutic antitumour immunity in hepatitis B virus-related hepatocellular carcinoma.	0
38358891	2024	The ARID1A-METTL3-m6A axis ensures effective RNase H1-mediated resolution of R-loops and genome stability.	3
38358974	2024	ARID1A loss is associated with increased NRF2 signaling in human head and neck squamous cell carcinomas.	0
38457226	2024	Treatments, prognostic factors, and genetic heterogeneity in advanced cholangiocarcinoma: A multicenter real-world study.	1
38458187	2024	ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis.	4
38489371	2024	Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations.	2
38508586	2024	Prognostic role of transcription factor ARID1A in patients with endometrial cancer of no specific molecular profile (NSMP) subtype.	0
38587186	2024	ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response.	1
38600891	2024	Deep-targeted gene sequencing reveals ARID1A mutation as an important driver of glioblastoma.	1
38754421	2024	ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity.	0
38858765	2024	Genome-wide DNA methylation in relation to ARID1A deficiency in ovarian clear cell carcinoma.	0
38100120	2024	ARID1A loss induces P4HB to activate fibroblasts to support lung cancer cell growth, invasion, and chemoresistance.	2
38166741	2024	ARID1A deficiency promotes progression and potentiates therapeutic antitumour immunity in hepatitis B virus-related hepatocellular carcinoma.	0
38358891	2024	The ARID1A-METTL3-m6A axis ensures effective RNase H1-mediated resolution of R-loops and genome stability.	3

Citation

Yohan Suryo Rahmanto ; Tian-Li Wang

ARID1A (AT rich interactive domain 1A (SWI-like))

Atlas Genet Cytogenet Oncol Haematol. 2013-11-01

Online version: http://atlasgeneticsoncology.org/gene/44231/arid1a-(at-rich-interactive-domain-1a-(swi-like))