Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dedifferentiated carcinoma of the endometrium or the ovary is an aggressive epithelial malignancy that comprises an endometrioid carcinoma together with an undifferentiated carcinoma. We recently reported that inactivation of BRG1 or INI1, core subunits of the switch/sucrose non-fermenting (SWI/SNF) complex, was the likely molecular event underlying dedifferentiation in about half of dedifferentiated carcinomas. In this study, we performed a genomic screen that included other members of the SWI/SNF complex to better delineate the molecular basis in the remainder of these tumours. We identified concurrent inactivating mutations involving ARID1A and ARID1B in 12 of 24 BRG1/INI1-intact, 0 of 3 INI1-deficient and 0 of 16 BRG1-deficient dedifferentiated carcinomas. All ARID1A and ARID1B co-mutated tumours displayed loss of ARID1A expression in the undifferentiated component with 11 of 12 tumours also displaying absent staining in the endometrioid component. ARID1B expression was absent in the undifferentiated component in all 12 tumours, whereas the corresponding endometrioid component showed intact expression. Clinically, ARID1A/ARID1B co-inactivated tumours showed similar aggressive behaviour to BRG1 or INI1-inactivated tumours. Given that ARID1A and ARID1B are the only known DNA-binding subunits of the SWI/SNF-A complex, additional inactivation of ARID1B in an ARID1A-deficient background appears to represent an alternative mechanism of disruption of SWI/SNF-mediated transcriptional regulation, resulting in arrested cellular differentiation in endometrial and ovarian endometrioid cancer.
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PMID:Concurrent ARID1A and ARID1B inactivation in endometrial and ovarian dedifferentiated carcinomas. 2756 91

Undifferentiated endometrial carcinoma is an aggressive type of endometrial carcinoma that typically presents with advanced stage disease and rapid clinical progression. In contrast to dedifferentiated endometrial carcinoma, undifferentiated carcinoma lacks a concurrent differentiated (typically low-grade endometrioid) carcinoma component, though the undifferentiated component of dedifferentiated carcinoma is similar histologically and immunophenotypically to pure undifferentiated carcinoma. We recently identified 3 mutually exclusive mechanisms of switch/sucrose nonfermentable (SWI/SNF) complex inactivation (BRG1 inactivation, INI1 inactivation or ARID1A/ARID1B co-inactivation) that are associated with histologic dedifferentiation in the majority of dedifferentiated endometrial carcinoma. In the current study, we aimed to determine by immunohistochemistry whether these patterns of SWI/SNF inactivation also occur in undifferentiated endometrial carcinomas. Of the 34 undifferentiated carcinomas examined, 17 (50%) exhibited SWI/SNF complex inactivation, with 11 tumors showing complete loss of both ARID1A and ARID1B, 5 showing complete loss of BRG1 and 1 showing complete loss of INI1. Ten of the remaining 17 undifferentiated carcinomas showed the following alterations: 5 tumors (15%) showed loss of ARID1A only with intact ARID1B, BRG1, and INI1 expression, 4 tumors (12%) showed mutated patterns of p53 staining with intact SWI/SNF protein expression, and 1 tumor (3%) harbored a POLE exonuclease domain mutation (P286R). SWI/SNF complex-inactivated tumors presented more frequently with extrauterine disease spread than those with intact expression (88% vs. 41%, respectively). In addition, patients with SWI/SNF complex-inactivated tumors had a significantly worse disease-specific survival (P=0.02). The findings here demonstrate frequent SWI/SNF complex inactivation in undifferentiated endometrial carcinomas, which has future implications regarding therapies that target chromatin remodelling and epigenetic control.
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PMID:Undifferentiated Endometrial Carcinomas Show Frequent Loss of Core Switch/Sucrose Nonfermentable Complex Proteins. 2886 77

Switch/sucrose nonfermenting complex subunits, such as BRG1, INI1, and ARID1B, are inactivated in a subset of endometrial undifferentiated carcinoma and dedifferentiated carcinoma (DC). Limited information is currently available on their prevalence in other subtypes or the nosological status of endometrial carcinoma with their deficiencies. This study immunohistochemically examined the expression status of BRG1, INI1, and ARID1B using 570 archived cases of endometrial carcinoma and carcinosarcoma resected at a single institution. We identified 1 BRG1-deficient undifferentiated carcinoma, 8 BRG1/INI1/ARID1B-deficient DC, and 3 BRG1-deficient clear-cell carcinomas. None of the cases of endometrioid and serous carcinomas or carcinosarcoma showed deficiencies of these subunits. We then compared 8 BRG1/INI1/ARID1B-deficient DC with 6 BRG1/INI1/ARID1B-intact DC and 28 carcinosarcomas, the latter of which was often confused with DC. Histologically, BRG1/INI1/ARID1B-intact and BRG1/INI1/ARID1B-deficient DC shared a monotonous solid appearance with rhabdoid and epithelioid cells and a myxoid stroma; however, abrupt keratinization and cell spindling was absent in BRG1/INI1/ARID1B-deficient tumors. The median overall survival of patients with BRG1/INI1/ARID1B-deficient DC was 3.8 months, which was worse than those with BRG1/INI1/ARID1B-intact DC (P=0.008) and with carcinosarcoma (P=0.004). BRG1/INI1/ARID1B-deficient DC may be a separate entity with an aggressive behavior to be distinguished from BRG1/INI1/ARID1B-intact DC and carcinosarcoma. Regarding clear-cell carcinoma (n=12), BRG1 deficiency appeared to be mutually exclusive with abnormal ARID1A, BRM, and p53 expression. Further studies are needed to clarify whether BRG1 deficiency plays a role in the pathogenesis of clear-cell carcinoma.
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PMID:BRG1, INI1, and ARID1B Deficiency in Endometrial Carcinoma: A Clinicopathologic and Immunohistochemical Analysis of a Large Series From a Single Institution. 3291 19

Dedifferentiated endometrial carcinoma (DDEC) is a rare but highly aggressive type of endometrial cancer, in which an undifferentiated carcinoma arises from a low-grade endometrioid endometrial carcinoma. The low-grade component is often eclipsed, likely due to an outgrowth of the undifferentiated component, and the tumor may appear as a pure undifferentiated endometrial carcinoma (UEC). We and others have recently identified inactivating mutations of SMARCA4, SMARCB1 or ARID1B, subunits of the SWI/SNF chromatin-remodeling complex, that are unique to the undifferentiated component and are present in a large portion of DDEC and UEC. However, the understanding of whether and how these mutations drive cancer progression and histologic dedifferentiation is hindered by lack of cell line models of DDEC or UEC. Here, we established the first UEC cell line, VOA1066, which is highly tumorigenic in vivo. This cell line has a stable genome with very few somatic mutations, which do include inactivating mutations of ARID1A and ARID1B (2 mutations each), and a heterozygous hotspot DICER1 mutation in its RNase IIIb domain. Immunohistochemistry staining confirmed the loss of ARID1B, but ARID1A staining was retained due to the presence of a truncating non-functional ARID1A protein. The heterozygous DICER1 hotspot mutation has little effect on microRNA biogenesis. No additional DICER1 hotspot mutations have been identified in a cohort of 33 primary tumors. Therefore, we have established the first UEC cell line with dual inactivation of both ARID1A and ARID1B as the main genomic feature. This cell line will be useful for studying the roles of ARID1A and ARID1B mutations in the development of UEC.
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PMID:Establishment and characterization of VOA1066 cells: An undifferentiated endometrial carcinoma cell line. 3305 29