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: 5.14). 01/2012; 33(1):100-3. DOI: 10.1002/humu.21633
Source: PubMed


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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    • "areofteninactivatedviapromoterhyper-methylation.TheassociationofMSIwithCGIhypermethylation atmultipletumorsuppressorgenesstronglyimplicatesCIMPastheunderlyingcauseofgenomic instabilityinMSI(Weisenbergeretal.2006).MSIalsocorrelateswithlossofgenomicimprinting(Cuiet al.1998),andmutationsattheSWI/SNFchromatin-remodelinggeneARID1A(Jonesetal.2012). "
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    ABSTRACT: The intestinal epithelium is an ideal model system for the study of normal and pathological differentiation processes. The mammalian intestinal epithelium is a single cell layer comprising proliferative crypts and differentiated villi. The crypts contain both proliferating and quiescent stem cell populations that self-renew and produce all the differentiated cell types, which are replaced every 3-5 days. The genetics of intestinal development, homeostasis, and disease are well defined, but less is known about the contribution of epigenetics in modulating these processes. Epigenetics refers to heritable phenotypic traits, including gene expression, which are independent of mutations in the DNA sequence. We have known for several decades that human colorectal cancers contain hypomethylated DNA, but the causes and consequences of this phenomenon are not fully understood. In contrast, tumor suppressor gene promoters are often hypermethylated in colorectal cancer, resulting in decreased expression of the associated gene. In this review, we describe the role that epigenetics plays in intestinal homeostasis and disease, with an emphasis on results from mouse models. We highlight the importance of producing and analyzing next-generation sequencing data detailing the epigenome from intestinal stem cell to differentiated intestinal villus cell.
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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.
    Full-text · Article · Feb 2015 · Human pathology
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    • "Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) are frequently observed in a wide variety of gynecological and non-gynecological cancers [1, 2]. These occur in approximately 50% of endometriosis-associated ovarian clear cell (OCCC) and 30% of endometrioid ovarian carcinomas (EnOC) [3, 4], in endometrial carcinomas, with a loss of expression in 20-30% depending on the histological subtype [5, 6], as well as in breast carcinomas (mutations in 4-35%) [7, 8]. Non-gynecological carcinomas with frequent ARID1A mutations include pancreatic carcinomas (mutations in 8-45%) [9, 10], gastric adenocarcinomas (mutations in 8-29%) [11-13], hepatocellular carcinomas (mutations in 10-17%) [14-16], as well as clear cell renal cell carcinomas [17, 18]. "
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