Abstract
Since the Cancer Genome Atlas (TCGA) project identified four distinct groups based on molecular alterations, mutation analyses have been integrated into the characterization of endometrial carcinomas (ECs). ARID1A seems to be the subunit more involved in the loss of function of the SWI/SNF complex in ECs. The aim of this study is to define the relevance of ARID1A alterations in a cohort of EC, studying the possible associations between DNA mutation (genomic level), RNA expression (transcriptomic level), and protein expression (proteomic level). A total of 50 endometrial carcinomas were characterized for ARID1A mutations (using targeted DNA next-generation sequencing—NGS), ARID1A gene expression (using RNAseq and qRT-PCR), and ARID1A protein expression (using immunohistochemistry—IHC). Moreover, we have investigated if ARID1A mutations may alter the protein structure, using the Protein Data Bank sequence. We found a good correlation between ARID1A mutations and protein immunostaining, even if we did not find statistically significant differences in the ARID1A expression levels. In conclusion, our data demonstrated that the molecular characterization of ARID1A should be associated with IHC analysis, mainly in those cases harboring “novel” ARID1A mutations or in those alterations with “uncertain” pathogenic significance.
Highlights
The annual incidence rates of endometrial cancer (EC) range between 15 and 25 per 100,000 women in western countries [1,2]
Molecular alterations have been integrated into the characterization of ECs since the Cancer Genome Atlas (TCGA) project identified four distinct groups based on molecular alterations [3,4,5,6,7,8,9,10,11]
The aim of this study is to define the relevance of ARID1A alterations in a cohort of EC studying the possible association between DNA mutation, RNA expression, and protein expression, to better define which ARID1A mutations may be considered for EC classification
Summary
The annual incidence rates of endometrial cancer (EC) range between 15 and 25 per 100,000 women in western countries [1,2]. The same criteria are used to tailor surgery and to select patients for adjuvant therapy. Among the several subunits making up SWI/SNF, ARID1A seems to be the one more involved in the loss of function of the complex in EC. Mutations in the ARID1A gene may result in the loss of ARID1A protein expression, with consequent alterations in the SWI/SNF functions. This loss of function determines defects in the cell cycle checkpoint activation in response to DNA damage [15], deregulation of the signals involved in cell self-renewal, survival and proliferative capacity [16], and an alteration in the expression of genes regulated by nuclear hormonal receptors
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