Introduction

Liposarcoma is a rare group of cancer which usually begins in fat cells. These are typically in the arms and legs, but can develop anywhere in the body. This condition is most common in adults over 40. Liposarcoma in the arms or legs may cause: a growing lump, pain and swelling, and weakness of the limb that is affected.¹ Liposarcoma found in the abdomen can cause symptoms such as abdominal pain and swelling, feeling full sooner, and constipation.² Diagnosis of liposarcoma often relies on imaging as well as tissue examination. The main treatment for this condition is surgical removal of the tumour, often combined with radiotherapy or chemotherapy. There are four main subtypes of liposarcoma: well-differentiated, dedifferentiated, myxoid, and pleomorphic.³ The most common is the well-differentiated subtype. This article will explore the different types of genetic and molecular risk factors for liposarcoma development.

Genetic risk factors associated with liposarcoma

Genetic markers are variations or changes to the DNA sequence itself. They represent structural or sequence level alterations in the genome that can be inherited or acquired in tumour cells. 

Chromosomal aberrations and gene amplifications

A characteristic feature of well-differentiated and dedifferentiated liposarcoma is the presence of giant rod chromosomes.⁴ These contain amplified genes on chromosome 12, particularly segments from the 12q13-15 region. Research has shown that this area contains many oncogenes such as MDM2, CDK4, HMGA2, OS1 and others.⁵ These genes are critical. The MDM2 gene has a primary function of inhibiting the activity of the p53 tumour suppressor protein.⁶ This is significant as p53 inhibits cell proliferation in response to DNA damage. The CDK4 gene has an important role in cell cycle control and normal development.⁷ When this gene is overproduced, it drives uncontrolled growth. HMGA2 also influences how DNA is packaged and controls which genes are turned off, which further contributes to tumour development. Extra copies of these certain genes act like a ‘stuck accelerator pedal’, which constantly drives cell growth when it should be under control. Together, these amplifications create an ideal environment for the cancer to develop. 

When a well-differentiated tumour acquires additional abnormalities, such as mutations or amplifications, it may transform into the de-differentiated form of liposarcoma. This is the more aggressive form of the condition. ‘De-differentiation’ usually involves loss of other tumor suppressor genes, such as TP53, RB1, and PTEN. The loss of these genes further removes safeguards against DNA instability or uncontrolled division. This then leads to more cells becoming abnormal and resistant to treatment.

Fusion genes and oncogenic translocations

Myxoid liposarcomas account for around 40% of all adult liposarcomas.⁸ Both myxoid and round cell liposarcomas can be defined by a specific chromosomal translocation. The most common translocation is t(12;16)(q12;p11), which is found in 90% of myxoid liposarcomas.⁹ This change causes the fusion of two genes called FUS and DDIT3. Another fusion that may occur, although less frequently, is known as EWSR1- DDIT3. The FUS and DDIT3 fusion gene, which is an oncogene, acts as an abnormal transcription factor that promotes cancer development. It does this by inhibiting cell differentiation and therefore leading to tumour growth and metastasis.

Complex changes in pleomorphic liposarcoma

The most unstable form of liposarcoma is the pleomorphic subtype. This subtype shows widespread chromosomal rearrangements and numerous mutations. The most common changes occur in TP53, RB1 as well as genes involved in DNA repair and control of the cell cycle. Due to its aggressive nature, this subtype of liposarcomas has a poorer survival rate compared to the other 3 subtypes. 

Molecular pathways implicated in liposarcoma development

Genetic changes and abnormalities disturb numerous molecular signalling pathways which control how cells divide and grow. Each pathway plays a vital role in keeping cell behaviour balanced. When these pathways are disturbed, fat cells lose their normal regulation and begin to grow uncontrollably, which then leads to tumour formation. As mentioned above, the p53 pathway is affected. This pathway is one of the most critical pathways. When MMD2 is amplified, it suppresses p53, which allows cells with damaged DNA to not only survive but also multiply.

Another major pathway that is disrupted is cell cycle regulation. This pathway ensures that cells only divide when it is appropriate. The critical genes in this pathway are CDK4 and MDM2. Too much of the CDK4 causes the stop signals to be lost, disrupting the regulation of the cell cycle. The cells continue to divide unchecked. The constant cycling and growth contributes directly to the formation and expansion of liposarcoma tumours. 

The PI3/AKT/mTOR pathway also becomes abnormally activated in some liposarcomas, specifically when the PTEN gene is lost or mutated. This signalling pathway promotes cell survival, cell growth and cell cycle progression.¹⁰  When overactive, this pathway can enhance cells survival and resistance to stress, which allows tumour cells to thrive in challenging environments. 

Furthermore, signaling pathways such as MAPK and JAK/STAT are often found to be overactive in liposarcoma cells. Both pathways transmit messages from the cell’s surface to the nucleus, which tell the cells to grow and also divide. If they are constantly turned on, there is a continuous growth signal which fuels the tumour progression. 

It is also important to note that liposarcoma cells also lose their ability to mature into normal fat cells. This process is known as adipogenic differentiation. This loss of ability is mostly due to disruption of pathways which involve key transcription factors such as PPARy and others, which are responsible for turning immature cells into fully developed fat cells. This is a hallmark of liposarcomas, especially the well-differentiated and myxoid subtypes. 

Hereditary and Predisposing Genetic Factors

Although most liposarcomas develop by chance, a small number of cases arise in people with hereditary cancer syndromes. Individuals with Li-Fraumeni syndrome, which happens due to a mutation in the TP53 gene,¹¹ have a higher risk of developing cancers, including liposarcoma. A similar case presents itself with hereditary retinoblastoma, which is caused by a mutation in the RB1 gene.¹² Another example would be neurofibromatosis type 1 which has been linked to a higher incidence of certain sarcomas. 

FAQS

What is the gene for liposarcoma?

There are many different genes that indicate a risk factor for liposarcoma development. The most common is MDM2, and it is therefore often used as a biomarker. Other genes that are significant include CDK4 as well as HMGA2.

Can liposarcoma be hereditary?

In a small set of cases, liposarcoma has been linked to hereditary conditions such as Li-Fraumeni syndrome. 

What are the main risk factors for liposarcoma development?

Genetic and molecular risk factors include abnormalities in certain genes and the disruption of molecular signalling pathways. Other risk factors include: radiation, certain family syndromes, damage to the lymphatic system and exposure to toxic chemicals. 

Where is liposarcoma most commonly found?

It is usually found in the arms, legs, and abdomen although it can be found anywhere in the body. Liposarcomas always develop from fat cells.

Summary

Liposarcoma is a rare group of cancer. It is most commonly found in the arms and legs, and can cause symptoms such as pain and swelling. There are four different subtypes which include: well-differentiated, dedifferentiated, myxoid and pleomorphic. A hallmark feature of both well-differentiated, and dedifferentiated liposarcomas is abnormal chromosomes and gene amplifications. The genes that are amplified are typically oncogenes such as MDM2 and CDK4. This then leads to the disruption of molecular pathways. For myxoid liposarcomas the cause is usually fusion genes which also promote cancer development. For pleomorphic liposarcomas the genetic and molecular risk factor usually stems from a wide range of chromosomal abnormalities such as rearrangements and mutations. Individuals with certain conditions such as Li-Fraumeni syndrome have a higher risk factor for development of liposarcomas. This is due to the inherent mutations of certain genes such as TP53.