Introduction

Leiomyosarcoma (LMS) is a rare and aggressive malignant tumour that occurs in smooth muscle tissue.¹ LMS most commonly occurs in the uterus, retroperitoneum, and blood vessels, accounting for approximately 10–20% of all soft tissue sarcomas.²

It is a difficult tumour to treat and tends to recur despite successful surgery and chemotherapy.² As such, researchers have turned to epigenetics to understand the causes and symptoms of this type of tumour.

In this article, we explore the types of epigenetic alterations that underpin LMS progression and how these alterations can be utilised to find potential treatments for this type of cancer.

What is epigenetics?

Epigenetics refers to the study of reversible and heritable changes in gene expression that do not affect the underlying DNA sequence.³ Unlike genetic mutations that alter the DNA sequence, epigenetic modifications often act as a regulatory mechanism that influences whether a gene is switched ‘on’ or ‘off’ in a given cell at a given time.

Epigenetic mechanisms are vital for maintaining normal cellular processes such as cell differentiation, cell and tissue development and the ability of a cell to adapt to changes in its environment.⁴ As such, dysregulation of epigenetic mechanisms leads to disease initiation and progression.⁵

The major epigenetic mechanisms include:

• DNA methylation: The addition of specific chemical tags called methyl groups to specific parts of the DNA sequence (cytosine bases), often leading to the gene being turned off and therefore silenced⁶
• Histone modifications: DNA is wrapped around specific proteins called histones.⁷ These proteins determine how tightly DNA is packed, and therefore, adding or removing tags from histones affects gene activity.⁸ If coiled tighter, it leads to gene silencing. If coiled loosely, it usually results in the gene being reactivated⁹
• Non-coding RNAs: Specific RNA molecules, usually called MicroRNAs or long-non-coding RNA (lncRNA).^10,11 These RNA molecules are key to controlling gene expression after it has been replicated in transcription

In the context of tumorigenesis and cancer progression, epigenetic dysregulation plays a key role by silencing tumour-suppressor genes, activating oncogenes, altering DNA repair mechanisms and promoting immune evasion, all of which collectively enable the cancer to grow and become deadly.^2,3

What is Leiomyosarcoma?

As mentioned earlier, Leiomyosarcoma is a rare form of cancer that grows from soft muscle tissues.¹ It can occur anywhere in the body, but most commonly occurs where tissues predominantly consist of smooth muscles, such as the uterus, blood vessels, stomach linings, and the intestines.²

LMS is known for its aggressive, diverse and hard-to-treat symptoms. It can grow very aggressively, spread to other parts of the body and metastasise, making it extremely difficult to treat.² Furthermore, treatment options are limited as LMS has a high recurrence rate and is often resistant to standard chemotherapy.

While some specific gene mutations drive cancers, LMS does not always have a predictable genetic profile, making it more challenging to pinpoint the root mutation that led to cancer formation and progression. Dysregulation of genes, such as TP53, RB1, and ATRX have all been identified as key genes in causing LMS progression; however, mutations in these genes are not the primary reason for LMS initiation or its aggressive behaviour during tumour progression.

As such, it has become essential for researchers to study how different epigenetic alterations affect LMS. 

Effects of epigenetic changes on LMS

DNA methylation

It silences genes that are crucial for controlling cell growth and DNA repair. In particular, a group of genes called tumour-suppressor genes is responsible for mediating mutations that can lead to cancerous growth.¹³ Silencing of these genes leads to cell division when it should not be, and defies legit cell death of damaged or mutated cells. This can often lead to tumour formation and eventually cancer. Moreover, silencing of tumour-suppressor genes leads to the loss of normal methylation throughout the genome and therefore, destabilises the genome, which can activate DNA elements that were otherwise turned off and lead to further mutations, causing the cancerous growth to expand unchecked.^10,13

Histone modification

Gene expression depends on how tightly DNA is wrapped around histone proteins.⁷ If tightly packed, the gene is silenced. If loosely packed, the gene is expressed.⁸ Specific chemical tags on the histone proteins are responsible for determining whether DNA should be tightly or loosely coiled, and therefore determine whether the gene is expressed or not.⁸ As such, modifications in histones can cause unnecessary gene expression that can lead to uncontrolled cell proliferation.⁹ Moreover, if certain genes are expressed, the cells become more resilient, allowing them to survive under stressful conditions.⁹ This leads to tumours becoming more aggressive and invasive. Furthermore, adaptability in cancerous cells leads to poor responses to treatments because the tumour can adapt to the hostile environment created by cancer treatments like chemotherapy, making them extremely hard to treat. This, in turn, leads to reduced patient survival.

Alterations in non-coding RNA

Non-coding RNAs (ncRNA) have regulatory jobs within the genome, primarily in fine-tuning gene expression. There are two major types of ncRNAs:

MicroRNAs (miRNA)

Tiny pieces of RNA that block certain genes from being translated into proteins.¹⁵ In healthy cells, miRNAs are responsible for keeping the cell cycle in check and preventing abnormal cell growth.^16,17 However, in LMS, these miRNAs are usually underexpressed, which means there are fewer miRNAs to control cell replication and therefore, create a higher likelihood of abnormal cell growth.¹⁷ This, in turn, makes it easier for certain cancer-promoting pathways to be activated.

Long non-coding RNAs (lncRNA)

Longer RNAs that interact with DNA, proteins and other RNAs to affect gene activity. In LMS, lncRNAs can reprogram chromatin and change the way genes are expressed.¹⁸ This can lead to tumours becoming more invasive and prone to metastasis.^11,18 In certain cases, specific lncRNAs have been linked with enhanced spread of tumours throughout the body as well as faster metastatic rate.¹¹

Due to overlapping functions, epigenetic changes do not occur in isolation.¹⁶ Usually, one epigenetic change can act as a catalyst to enable the other, and this cascade can create a combined effect that not only enables the tumour to grow and spread faster but also makes it more adaptable and resistant to cancer treatments, making it extremely difficult to successfully treat.^15,11

Can epigenetics help treat LMS?

Considering epigenetic changes play a critical role in the manifestation and progression of LMS, research has shifted to consider epigenetics as a potential therapeutic pathway to treat the disease.

Epigenetic therapies are designed to repair the systems that control gene activity.¹⁹ In general, epigenetic therapies aim to restore normal cell function, such as proper cell division, adequate response to cell damage and timely cell death.¹⁹

In LMS, epigenetic therapy can be utilised to:

• Reactivate tumour-suppressor genes that were switched off due to mutations like DNA methylation¹⁹
• Silence oncogenes that drive cancer to minimise cancer growth¹⁹

These changes can essentially ‘reset’ the gene expressions that lead to LMS. This can lead researchers to be able to slow tumour growth, improve immune detection of the cancer and decrease the chances of a recurrence. Being able to manipulate the cancer via epigenetic changes can lead to making tumours more responsive to alternative treatments such as chemotherapy or immunotherapy, increasing the chances of a successful remission.^17,19

Summary

Leiomyosarcoma (LMS) is a rare and aggressive cancer that develops in smooth muscle tissue and is very difficult to treat due to its high recurrence rate and resistance to usual treatments. While genetic mutations have been linked to LMS progression, they don’t fully explain the disease’s unpredictable behaviour. Instead, research has linked LMS manifestation and progression to changes in epigenetics. 

Epigenetics refers to reversible changes in gene expression without a change in the DNA sequence. DNA methylation, histone modification and non-coding RNA alterations are all examples of epigenetic changes that may lead to LMS. These epigenetic changes don’t act in isolation but instead build on each other, contributing to LMS’s aggressiveness, adaptability, and treatment resistance.

Researchers are increasingly focusing on epigenetic alteration as a potential therapeutic target due to their reversible nature. With epigenetic therapies, they aim to restore normal gene expression and reactivate tumour-suppressor genes and silence oncogenes. This approach could help slow tumour growth, increase treatment sensitivity, and reduce recurrence, creating a new pathway to treat and manage this challenging disease.