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Somatic Mutations in the Chromatin Remodeling Gene ARID1A Occur in Several Tumor Types

Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA.
Human Mutation (Impact Factor: 5.05). 01/2012; 33(1):100-3. DOI: 10.1002/humu.21633
Source: PubMed

ABSTRACT Mutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas (OCCCs). To determine the prevalence of mutations in other tumor types, we evaluated 759 malignant neoplasms including those of the pancreas, breast, colon, stomach, lung, prostate, brain, and blood (leukemias). We identified truncating mutations in 6% of the neoplasms studied; nontruncating somatic mutations were identified in an additional 0.4% of neoplasms. Mutations were most commonly found in gastrointestinal samples with 12 of 119 (10%) colorectal and 10 of 100 (10%) gastric neoplasms, respectively, harboring changes. More than half of the mutated colorectal and gastric cancers displayed microsatellite instability (MSI) and the mutations in these tumors were out-of-frame insertions or deletions at mononucleotide repeats. Mutations were also identified in 2-8% of tumors of the pancreas, breast, brain (medulloblastomas), prostate, and lung, and none of these tumors displayed MSI. These findings suggest that the aberrant chromatin remodeling consequent to ARID1A inactivation contributes to a variety of different types of neoplasms.

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Available from: Jelle Wesseling, Jul 30, 2015
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    • "Recently, inactivating mutations in AT-rich interactive domain 1A (ARID1A) have been recognized in several tumors [11] [12], suggesting that it is a tumor suppressor gene in many different cell types, including ovarian and endometrial epithelium [13] [14]. However, its role in penile cancer has yet to be determined. "
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    ABSTRACT: 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. Copyright © 2015 Elsevier Inc. All rights reserved.
    Human pathology 02/2015; 46(5). DOI:10.1016/j.humpath.2015.01.018 · 2.81 Impact Factor
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    • "These studies were followed by several reports that identified mutation or loss of ARID1A in gastric cancer [5] [6] [7] [8]. In addition, studies have now reported that AR- ID1A loss is associated with microsatellite instability (MSI) [4] [5] [8] and Epstein-Barr virus (EBV) infection [5] [7]. Mutations in ARID1A in gastric cancer have also been shown to be negatively associated with mutations in TP53 [5]. "
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    ABSTRACT: ARID1A/BAF250a has been recently implicated as a tumor suppressor in gastric cancer. We sought to clarify the clinical significance of BAF250a/ARID1A in relation to other clinical parameters and relevant biomarkers in gastric carcinoma. Cases from two separate cohorts of gastric carcinoma patients from Vancouver (N = 173) and Toronto (N = 80) were selected for the construction of tissue microarrays, which were used to assess the immunohistochemical status of BAF250a (Anti-ARID1A), mismatch repair (MMR) proteins and p53, as well as in situ hybridization for HER2 amplification and EBV infection. The Toronto cohort contained a higher proportion of early-stage cases (p = 0.019), and a smaller proportion of cases from the proximal stomach (p < 0.001). Overall, immunohistochemical loss of BAF250a was observed in 22.5% of gastric adenocarcinomas from the Vancouver group and 20% from Toronto. In both cohorts, loss of BAF250a was positively associated with loss of mismatch repair protein expression (p < 0.0001 and p = 0.035, respectively). Loss of BAF250a expression was independently associated with poor overall survival in the Toronto cohort (p = 0.0015), whereas no significant association with survival was observed in the Vancouver cohort. BAF250a loss was not significantly associated with any additional clinical parameters in either cohort. HER2 amplification was confirmed as a negative prognostic factor in both cohorts. These findings suggest that ARID1A/BAF250a may be of prognostic significance in a subset of patients with early-stage gastric cancer, and that pathological assessment should increasingly employ a multimarker approach.
    Human pathology 06/2014; 45(6). DOI:10.1016/j.humpath.2014.02.006 · 2.81 Impact Factor
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    • "ARID1A encodes a protein which is a member of the SWI/SNF chromatin remodeling complex and is believed to function as a tumor suppressor [28] [29]. ARID1A mutations have been previously reported in 29% of ovarian tumors, with the highest prevalence in clear cell carcinomas (up to 57%) [29] [30]. In the current study only 1 (33%) of the clear cell carcinomas featured an ARID1A mutation. "
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    ABSTRACT: Targeted next generation sequencing (NGS) was evaluated for its ability to identify unanticipated targetable genomic alterations (GA) for patients with relapsed ovarian epithelial carcinoma (OC). DNA sequencing was performed for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor ligated, hybridization-captured libraries using DNA isolated from FFPE sections from 48 histologically verified relapsed OC specimens. The original primary tumor was sequenced in 26 (54%) of the cases and recurrent/metastatic tumor site biopsies were sequenced in 22 (46%) of the cases. Actionability was defined as: GA that predict sensitivity or resistance to approved or standard therapies or are inclusion or exclusion criteria for specific experimental therapies in NCI registered clinical trials. There were 38 (80%) serous, 5 (10%) endometrioid, 3 (6%) clear cell, 1 mucinous (2%) and 1 (2%) undifferentiated carcinomas. 141 GA were identified with an average of 2.9 GA (range 0-8) per tumor, of which 67 were actionable for an average of 1.4 actionable GA per patient (range 0-5). 33/48 (69%) of OC patient samples harbored at least one actionable GA. Most common GA were TP53 (79%); MYC (25%); BRCA1/2 (23%); KRAS (16.6%) and NF1 (14.5%). One tumor featured an ERBB2 point mutation. One of 3 (33%) of clear cell tumors featured cMET amplification validated by both FISH and IHC. NGS assessment of therapy resistant OC identifies an unexpectedly high frequency of GA that could influence targeted therapy selection for the disease.
    Gynecologic Oncology 06/2013; 130(3). DOI:10.1016/j.ygyno.2013.06.019 · 3.69 Impact Factor
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