Loss of ARID1A expression in colorectal carcinoma is strongly associated with mismatch repair deficiency

Chou, Angela; Toon, Christopher W.; Clarkson, Adele; Sioson, Loretta; Houang, Michelle; Watson, Nicole; DeSilva, Keshani; Gill, Anthony J.

doi:10.1016/j.humpath.2014.04.009

Cited by 62 publications

(74 citation statements)

References 20 publications

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“…ARID1A is reported to be mutated or lost in 8-29% of GCs [7,12,13,16] and 5.9-10% of CRCs [7,17]. In this study population, we observed loss of ARID1A expression in 8.0% of GCs and 6.1% of CRCs, which is consistent with previous reports, but relatively low.…”

Section: Discussionsupporting

confidence: 91%

“…For instance, Rahman et al [28] reported that loss of ARID1A expression and MSI are not associated in endometrial cancer, while other authors showed that loss of ARID1A expression is closely linked with MSI or mismatch repair deficiency in various cancers [12,17,29]. Two opposing hypotheses have been formulated: (1) ARID1A mutation is the result of MSI [12] and (2) loss of ARID1A leads to epigenetic alterations, which result in MLH1 promoter hypermethylation and sporadic MSI [29].…”

Section: Discussionmentioning

confidence: 99%

“…Only one previous study explored the prognostic impact of ARID1A loss in CRC. The authors demonstrated that loss of ARID1A expression is associated with old age, large tumor size and high histological grade, but not OS [17]. Wang et al [12] reported that ARID1A mutation is independently associated with better oncologic outcome in GC.…”

Section: Discussionmentioning

confidence: 99%

“…Although some authors have identified several somatic mutations in the ARID1A gene in CRC and GC [7,12], loss of ARID1A expression is reported to be relatively uncommon [15]. Moreover, conflicting results have been published on the clinical correlation and prognostic impact of ARID1A mutation or expression loss in CRC and GC [12,13,14,15,16,17]. Thus, the current study was designed to explore the clinicopathologic characteristics and prognostic significance of ARID1A expression loss in CRC and GC patients.…”

Section: Introductionmentioning

confidence: 99%

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Loss of AT-Rich Interactive Domain 1A Expression in Gastrointestinal Malignancies

et al. 2014

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Objective: AT-rich interactive domain 1A (ARID1A) has recently been identified as a novel tumor suppressor in various tumor types. This study was designed to explore the clinical relevance and prognostic impact of ARID1A expression loss in colorectal cancer (CRC) and gastric cancer (GC). Methods: Immunohistochemistry for ARID1A was performed using tissue microarray blocks containing 196 CRCs and 275 GCs, along with paired normal mucosa. Data on clinicopathologic variables and oncologic outcomes of patients were collected and analyzed. Results: We identified 6.1% (12/196) CRC and 8.0% (22/275) GC cases showing loss of ARID1A expression. Expression of ARID1A in paired mucosal epithelial cells was normal in all patients. Loss of ARID1A expression was significantly correlated with negative lymphatic invasion (p = 0.003) in CRC, with large tumor size (p = 0.037) in GC, and with expanding tumor border in both tumor types (CRC, p = 0.010; GC, p = 0.031). However, no association was evident between ARID1A expression and 5-year overall survival in both tumor types. Conclusions: Loss of ARID1A expression is uncommon and not associated with oncologic outcome but may be related to less invasive clinicopathologic features in CRC and GC. Further studies with a larger number of subjects are needed to establish the possible prognostic impact of ARID1A expression loss. © 2014 S. Karger AG, Basel

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of AT-Rich Interactive Domain 1A Expression in Gastrointestinal Malignancies

et al. 2014

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“…Our finding was further supported by other studies that showed frequent BRAF V600E mutation in these ARID1A-loss MMR-deficient tumors. In contrast, MMR deficiency due to germline mutation (ie, Lynch syndrome) seemed to occur primarily in cases with retained ARID1A [17,18]. In the current study, we showed that the association between ARID1A loss and MMR deficiency was already present in early stage CRCs.…”

Section: Discussionmentioning

confidence: 48%

ARID1A expression in early stage colorectal adenocarcinoma: an exploration of its prognostic significance

et al. 2016

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Summary ARID1A is a chromatin remodeling gene that is mutated in a number of cancers including colorectal carcinoma (CRC). Loss of ARID1A has been associated with an adverse outcome in some types of cancer. However, literature data have not been consistent. Major limitations of some outcome studies include small sample size and heterogeneous patient population. In this study, we evaluated the prognostic value of ARID1A in a homogeneous group of early stage CRC patients, a population where prognostic markers are particularly relevant. We collected a retrospective series of 578 stage I or II CRCs. All patients underwent surgery with curative intent and without neoadjuvant or adjuvant therapy. ARID1A expression was analyzed by immunohistochemistry using tissue microarray. We found ARID1A loss in 49 of 552 analyzable tumors (8.9%). Compared with the ARID1A-retained group, cases with ARID1A loss were associated with female sex (P < .001), mismatch-repair protein deficiency (P < .001), poor differentiation (P < .001), lymphovascular invasion (P = .001), and higher pT stage (P = .047). However, at a median follow-up of 49 months, ARID1A loss did not correlate with overall, disease-specific, or recurrence-free survival. This is the first systematic analysis to evaluate the prognostic significance of ARID1A in stage I/II CRCs, and our data indicate that ARID1A loss lacks prognostic significance in this population despite its association with other adverse features. Such data are clinically relevant, as efforts are ongoing in identifying markers that can detect the small but significant subset of early stage CRCs that will have a poor outcome.

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SWI / SNF Chromatin Remodelling and Human Cancer

Reisman

Thompson

Marquez-Vilendrer

et al. 2016

Encyclopedia of Life Sciences

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Brahma (BRM) and Brahma‐related gene 1 (BRG1) are two mutually exclusively catalytic subunits of the switch in mating type/sucrose nonfermenting complex. These two key anticancer proteins are frequently targeted and silenced during cancer development. The anticancer function of BRM can be abrogated when it becomes acetylated or when it is epigenetically silenced. Central to BRM silencing is the presence of two inherited insertional polymorphisms within the BRM promoter that are statistically linked to cancer risk. Both BRM acetylation and silencing can be reversed by a number of compound families and might be important to how flavonoids and NSAIDS inhibit cancer. While BRG1 is very frequently mutated in most human cancers, it is more commonly inactivated by aberrant splicing and by an AKT‐pathway‐mediated‐translation block. While BRG1 and BRM are tied to deoxyribonucleic acid repair, growth control, differentiation, development, as well as epithelial–mesenchymal transition and are estimated to regulate 4–8% of the human genome, the inactivation of either protein is only modestly tumourigenic. This occurs in part because BRG1 and BRM are functionally redundant, which blunts the tumourigenic effect when only one gene is aberrantly silenced. Further insights into the mechanisms that regulate these genes may lead to novel therapeutic strategies that may reverse the silencing of these two important anticancer genes. Key Concepts Reversal of the epigenetic silencing of a gene may serve as a basis for drug therapy. Anticancer genes are epigenetically regulated by insertional polymorphisms. The functional redundancy of BRG1 and BRM thwarts cancer development. Post‐translational modification of BRM and BRG1 alters the cellular roles of these proteins from growth inhibitors to growth promoters. The loss of cofactors (i.e. BRG1 and/or BRM) for RB‐mediated‐growth inhibition could preclude the function of CDK inhibitors used clinically. Specific SWI/SNF subunits are commonly mutated and inactivated in specific cancer types. Diminished SWI/SNF activity, but not the complete abrogation of function, is tumourigenic.

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Loss of ARID1A expression in colorectal carcinoma is strongly associated with mismatch repair deficiency

Cited by 62 publications

References 20 publications

Loss of AT-Rich Interactive Domain 1A Expression in Gastrointestinal Malignancies

Loss of AT-Rich Interactive Domain 1A Expression in Gastrointestinal Malignancies

ARID1A expression in early stage colorectal adenocarcinoma: an exploration of its prognostic significance

SWI / SNF Chromatin Remodelling and Human Cancer

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