Epigenetics of Endometrial Cancer: The Role of Chromatin Modifications and Medicolegal Implications

Abstract

Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Risk factors for EC include metabolic alterations (obesity, metabolic syndrome, insulin resistance), hormonal imbalance, age at menopause, reproductive factors, and inherited conditions, such as Lynch syndrome. For the inherited forms, several genes had been implicated in EC occurrence and development, such as POLE, MLH1, TP53, PTEN, PIK3CA, PIK3R1, CTNNB1, ARID1A, PPP2R1A, and FBXW7, all mutated at high frequency in EC patients. However, gene function impairment is not necessarily caused by mutations in the coding sequence of these and other genes. Gene function alteration may also occur through post-transcriptional control of messenger RNA translation, frequently caused by microRNA action, but transcriptional impairment also has a profound impact. Here, we review how chromatin modifications change the expression of genes whose impaired function is directly related to EC etiopathogenesis. Chromatin modification plays a central role in EC. The modification of chromatin structure alters the accessibility of genes to transcription factors and other regulatory proteins, thus altering the intracellular protein amount. Thus, DNA structural alterations may impair gene function as profoundly as mutations in the coding sequences. Hence, its central importance is in the diagnostic and prognostic evaluation of EC patients, with the caveat that chromatin alteration is often difficult to identify and needs investigations that are specific and not broadly used in common clinical practice. The different phases of the healthy endometrium menstrual cycle are characterized by differential gene expression, which, in turn, is also regulated through epigenetic mechanisms involving DNA methylation, histone post-translational modifications, and non-coding RNA action. From a medicolegal and policy-making perspective, the implications of using epigenetics in cancer care are briefly explored as well. Epigenetics in endometrial cancer is not only a topic of biomedical interest but also a crossroads between science, ethics, law, and public health, requiring integrated approaches and careful regulation.

Keywords: chromatin modification; endometrial cancer; epigenetics; medical responsibility.

Figure 1

Graphical representation of the main events leading to DNA structure alteration in EC. Gene expression may either be enhanced or silenced through chromatin compaction regulation (bottom), which may be achieved by DNA methylation (top left), histone modifications (top center), or chromatin remodeling (top right); alteration of the expression of key genes may induce or enhance EC formation or progression. See text for further explanations and protein abbreviations. Additional abbreviations: Me: Methyl group; A: Acetyl group.

Figure 2

A simplified workflow illustrating the main steps necessary for the identification of candidate biomarkers in the EC.

Figure 3

Chromatin assay usage in EC research, according to the NCBI Sequence Read Archive (SRA), and analyzed using artificial intelligence. Numbers over each bar represent the number of studies employing each assay type.