Somatic mutations in the chromatin remodeling gene
            <i>ARID1A</i>
            occur in several tumor types

Jones, Siân; Li, Meng; Parsons, D. Williams; Zhang, Xiaosong; Wesseling, Jelle; Kristel, Petra; Schmidt, Marjanka K.; Markowitz, Sanford D.; Yan, Hai; Bigner, Darell D.; Hruban, Ralph H.; Eshleman, James R.; Iacobuzio‐Donahue, Christine A.; Goggins, Michael; Maitra, Anirban; Malek, Sami N.; Powell, Steve M.; Vogelstein, Bert; Kinzler, Kenneth W.; Velculescu, Victor E.; Papadopoulos, Nickolas

doi:10.1002/humu.21633

Cited by 257 publications

(242 citation statements)

References 25 publications

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“…In gastric cancer, an association has been described between MSI and mutations in ARID1A. 12,[14][15][16] As the rate of somatic ARID1A mutations in MSI cases was 12-to 61-fold higher than the global background mutation rate, it was suggested that the ARID1A gene is particularly targeted by MSI. 12 A possible association between ARID1A loss and MSI, as has been reported for gastric cancer, has not been studied in endometrial cancer.…”

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confidence: 99%

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

et al. 2013

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The switch/sucrose non-fermentable (SWI/SNF) subunit ARID1A (AT-rich interactive domain 1A gene) has been recently postulated as a novel tumor suppressor of gynecologic cancer and one of the driver genes in endometrial carcinogenesis. However, specific relationships with established molecular alterations in endometrioid endometrial cancer (EEC) are currently unknown. We analyzed the expression of ARID1A in 146 endometrial cancers (130 EECs and 16 non-EECs) in relation to alterations in the PI3K-Akt pathway (PTEN expression/KRAS/PIK3CA mutations), TP53 status (TP53 immunohistochemistry) and microsatellite instability. To discriminate between microsatellite instability due to somatic MLH1 promoter hypermethylation or germline mutations in one of the mismatch repair genes (Lynch syndrome), we included a 'Lynch syndrome set'. This set included 21 cases with confirmed germline mutations and 15 cases that were suspected to have a germline mutation. Loss of ARID1A expression was exclusively found in EECs in 31% (40/130) of the EEC cases. No loss of expression of the other subunits of the SWI/SNF complex, SMARCD3 and SMARCB1, was detected. Alterations in the PI3K-Akt pathway were more frequent when ARID1A expression was lost. Loss of ARID1A and mutant-like TP53 expression was nearly mutually exclusive (P ¼ 0.0004). In contrast to Lynch-associated tumors, a strong association between ARID1A loss and sporadic microsatellite instability was found. Only five cases (14%) of the 'Lynch syndrome set' as compared with 24 cases (75%, Po0.0001) of the sporadic microsatellite-unstable tumors showed loss of ARID1A. These observations suggest that ARID1A is a causative gene, instead of a target gene, of microsatellite instability by having a role in epigenetic silencing of the MLH1 gene in endometrial cancer. Keywords: ARID1A; endometrial cancer; Lynch syndrome; microsatellite instability Recent genome-wide sequencing studies have demonstrated that the AT-rich interactive domain 1A (ARID1A) gene is frequently mutated in a wide variety of cancer types 1 including a subset of gynecological cancers. 2 In ovarian cancer, near half of the clear-cell subtype and 30% of the endometrioid subtype showed ARID1A mutations, 3 particularly those that are related to endometriosis. 4,5 In endometrial cancer, mutations in the ARID1A gene have been reported in approximately 30% of both low-and high-grade endometrioid endometrial cancers (EECs) but not in serous endometrial carcinomas. [6][7][8] ARID1A encodes a large nuclear protein involved in chromatin remodeling and interacts with several other proteins, including the core protein

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Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

et al. 2013

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“…[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.…”

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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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“…Grasso et al 47 also described a frequent copy number loss on chromosome 5q21 at the location of CHD1, a gene encoding a chromatinremodeling enzyme, and documented loss or mutation in multiple chromatin-remodeling genes, as has been found for multiple tumor types. 47,[52][53][54] They documented that multiple of these chromatinmodifying genes directly interact with the androgen receptor and along with additional regulators, such as FOXA1, can partially explain the androgen-resistant nature of the tumors they sequenced.…”

Section: Somatic Alterations In Tumorsmentioning

confidence: 99%

Genetics and genomics of prostate cancer

Dean¹,

Li²

2013

Asian J Androl

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Prostate cancer (PCa) is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year. Nearly all mortalities from PCa are due to metastatic disease, typically through tumors that evolve to be hormone-refractory or castrate-resistant. Despite intensive epidemiological study, there are few known environmental risk factors, and age and family history are the major determinants. However, there is extreme heterogeneity in PCa incidence worldwide, suggesting that major determining factors have not been described. Genome-wide association studies have been performed and a considerable number of significant, but low-risk loci have been identified. In addition, several groups have analyzed PCa by determination of genomic copy number, fusion gene generation and targeted resequencing of candidate genes, as well as exome and whole genome sequencing. These initial studies have examined both primary and metastatic tumors as well as murine xenografts and identified somatic alterations in TP53 and other potential driver genes, and the disturbance of androgen response and cell cycle pathways. It is hoped that continued characterization of risk factors as well as gene mutation and misregulation in tumors will aid in understanding, diagnosing and better treating PCa.

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Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types

Cited by 257 publications

References 25 publications

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

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

Genetics and genomics of prostate cancer

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