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LIPOSARCOMA & FIBROSARCOMA - History of Genetics

LIPOSARCOMA

Liposarcoma is one of the rare types of cancer developing in the fatty tissues of the body, most commonly seen in the regions such as abdomen, thighs and behind the knees; can also spread to other parts of the body including the organs. There is no known cause but certain risk factors may increase a person's chances of developing this cancer, including genetics and previous exposure to radiation or toxic chemicals. Here mutations occur sporadically (at random) or are acquired over a person's lifetime, not inherited from parents.

The generalized symptoms seen in case of liposarcoma includes: -

  • A growing lump of tissue under the skin.

  • Pain.

  • Swelling.

  • Weakness of the affected limb.

Liposarcomas may be classified morphologically based on which specific oncogenes were identified and noted. These subtypes include; well-differentiated liposarcoma/de-differentiated Liposarcoma (WD/DDLPS), myxoid/round cell liposarcoma (MLPS) and pleomorphic liposarcoma (PLPS).


1) Well-differentiated liposarcoma/de-differentiated liposarcoma (WD/DDLPS):

A characteristic feature of WD/DDLPS is the presence of supernumerary ring and/or giant rod chromosomes. These chromosomes contain amplified segments from the 12q13–15 region. Intensive research has identified several oncogenes residing in this region including MDM2, CDK4, HMGA2, TSPAN31, OS1, OS9, CHOP and GLI1. The most compelling evidence to date demonstrates an oncogenic role in WD/DDLPS include:


MDM2 gene;

MDM2 is amplified and overexpressed in a number of most other cancers, highlighting its importance in tumorigenesis; located on the long arm 13–14 of chromosome 12 (12q13-14); having a role on encoding a negative regulator of the tumor suppressor, p53. MDM2 binds to the transcription activation domain of p53, blocking its transcription and recruitment of transcription coactivators. MDM2 also acts as a ubiquitin ligase targeting p53 for proteasomal degradation through both cytoplasmic and nuclear proteasomes.


CDK4 gene;

CDK4 (Cyclin-Dependent Kinase 4) is shown to be amplified in over 90% of cases. A relatively compact gene that spans 4.16 kb of genomic DNA on the long arm of chromosome 12, in the telomere-to-centromere orientation. The CDK4 gene encodes a 33-kD protein that forms complexes with the cyclin D family, to enable G1-S transition. These CDK4/Cyclin D complexes phosphorylate pRb (encoded by RB1), with resultant activation of E2F target genes including E-type cyclins.


TSPAN31;

TSPAN31 was as frequently amplified as MDM2 in most of the sarcomas. Recent studies have suggested a role for the c-Jun N-terminal kinase (JNK) pathway. Co-amplification of 1p32 and 6q23, that contain c-Jun, and Apoptosis Signaling Kinase 1 (ASK1), are seen in DDLPS. The proto-oncogene c-Jun encodes part of the activator protein transcription factor (AP-1) complex involved in cell proliferation, transformation and apoptosis. ASK1 activates JNK ultimately leading to c-Jun activation and PPARγ inactivation. PPARγ is involved in the adipocytic differentiation process and its inhibition may result in de-differentiation.


2) Myxoid/round cell liposarcoma (MLPS):

MLPS accounting for more than one third of Liposarcomas and 10% of all adult soft tissue sarcomas, are characterized by the presence of spindle or ovoid cells set in a myxoid stroma with signet ring lipoblasts and a distinctive chicken-wire pattern vasculature. Unusual sites of metastasis are common in MLPS with a propensity to metastasize to soft tissue and bone rather than lung. Thirty-one percent of MLPS patients develop metastasis with bone metastases constituting 56% of these.


FUS-CHOP gene;

Located on chromosome 12, FUS-CHOP gene fusion - characterized by the recurrent translocation t(12;16)(q13;p11), is present in over 95% of cases. Mostly, the amino terminal domain of FUS (also known as TLS) is fused to C/EBP homologous protein (CHOP, also known as DDIT3 or GADD153). In rare cases, an alternative translocation event is found t(12;22)(q13;q12) that results in formation of the novel fusion oncogene where EWS takes the place of FUS.


3) Pleomorphic liposarcoma (PLPS):

60% of PLPS have a deletion of 13q14.2-q14.3, a region that includes the tumor suppressor RB1. Additional deletions include; 17p13 and 17q11.2. 16.7% of PLPS cases had mutations identified in p53.


TP53 gene;

It’s deleted or mutated in 17–60% of cases; located on chromosome 17. (17p13.1). It provides instructions for making a protein called tumor protein - p53.


RB1 gene;

It’s deleted in 60% of cases; located on chromosome 13 - more specifically, 13q14.1-q14.2. Its common function is seen as binding and repressing E2F targets. A tumor suppressor gene identified whose mutational inactivation is the cause of a human cancer.


Treatment option for Liposarcoma is multimodal, with surgical removal and radiotherapy used for local control and chemotherapy for systemic disease. Few therapeutic options are available for aggressive local or metastatic disease. MLPS tumors are also highly radiosensitive. Given the small subgroup that is chemo-sensitive, and the overriding lack of chemo-curative disease there are avenues and a need for novel molecular therapies.


FIBROSARCOMA

A rare, highly malignant cancer, affecting cells called fibroblasts; have the potential to form tumours at nearly every part of the body. The causes of fibrosarcoma may include; a weakened or damaged lymph system, chemical or radiation exposure or even through inherited genetic abnormalities.

They are predominantly located either adjacent to bones or in deep soft tissue. In addition, fibrosarcoma have possibilities to arise inside the bones, could be either as a primary or secondary tumor. Their symptoms usually take a relatively longer time to appear but when they do, symptoms include:

  • Cough or breathlessness.

  • Vomiting blood.

  • Pain in the abdomen and in the area of the tumor, which might feel like a sprain.

  • Swelling around the bone, which often does not show up until the tumor is quite large.

  • Difficulty moving a joint or limb.

  • Numbness in areas of the body, due to the tumor pressing on nerves.

  • Fragile, easily broken bones.


TP53 gene:

TP53 gene is located on the short arm of chromosome 17 (17p13.1). The gene spans about 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. It encodes specific proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.

Likewise, new targeting strategies for TP53 have been disclosed; rejuvenation of the wtp53 role from mutp53, restoration of wild-type p53 (wtp53) activity through inhibition of TP53 negative regulators, depletion of mutp53, and targeting of vulnerabilities in cells with TP53 deletions or mutations. It’s a leading cause of most other cancers too.


CDKN2A gene:

CDKN2A gene is located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21. It regulates monocyte/macrophage proliferation. Patients reveal homozygous deletion with minimal overlapping region at the CDKN2A [cyclin-dependent kinase inhibitor 2A. Deletion seems to be the main mechanism of the inactivation of these genes in fibrosarcoma of the bone.


CDKN2B gene;

This gene lies adjoining the tumor suppressor gene - CDKN2A in a part that’s frequently mutated and deleted in a broad number of tumors. It encodes a cyclin - dependent kinase inhibitor, which constructs a complex with CDK4 / CDK6, and blocks the activation of the CDK kinases, thus, the encoded protein powers as a cell growth regulator, managing cell cycle G1 sequence.


EWSR1 gene:

EWSR1 (EWS RNA Binding Protein 1) is located on human chromosome 22, specifically 22q12.2.it’s a Protein Coding gene, codes for EWS – RNA binding protein. In this case specifically it highly comes in associations with transcription factors giving rise to genes with powerful chromatin regulatory action, proficient of initiating complex gene expression activities in permissive precursor cells. These include; EWSR1-ATF1 fusion gene and EWSR1-CREB3L1 fusion genes. This gene is a major cause of other cancer types as well.


The best current therapy of fibrosarcoma is generous surgical removal from site. The response rates of fibrosarcoma towards radio- and chemotherapy being very low are now paving way towards a high need for novel molecular therapies.



Commentaires


LIPOSARCOMA & FIBROSARCOMA - History of Genetics

LIPOSARCOMA

Liposarcoma is one of the rare types of cancer developing in the fatty tissues of the body, most commonly seen in the regions such as abdomen, thighs and behind the knees; can also spread to other parts of the body including the organs. There is no known cause but certain risk factors may increase a person's chances of developing this cancer, including genetics and previous exposure to radiation or toxic chemicals. Here mutations occur sporadically (at random) or are acquired over a person's lifetime, not inherited from parents.

The generalized symptoms seen in case of liposarcoma includes: -

  • A growing lump of tissue under the skin.

  • Pain.

  • Swelling.

  • Weakness of the affected limb.

Liposarcomas may be classified morphologically based on which specific oncogenes were identified and noted. These subtypes include; well-differentiated liposarcoma/de-differentiated Liposarcoma (WD/DDLPS), myxoid/round cell liposarcoma (MLPS) and pleomorphic liposarcoma (PLPS).


1) Well-differentiated liposarcoma/de-differentiated liposarcoma (WD/DDLPS):

A characteristic feature of WD/DDLPS is the presence of supernumerary ring and/or giant rod chromosomes. These chromosomes contain amplified segments from the 12q13–15 region. Intensive research has identified several oncogenes residing in this region including MDM2, CDK4, HMGA2, TSPAN31, OS1, OS9, CHOP and GLI1. The most compelling evidence to date demonstrates an oncogenic role in WD/DDLPS include:


MDM2 gene;

MDM2 is amplified and overexpressed in a number of most other cancers, highlighting its importance in tumorigenesis; located on the long arm 13–14 of chromosome 12 (12q13-14); having a role on encoding a negative regulator of the tumor suppressor, p53. MDM2 binds to the transcription activation domain of p53, blocking its transcription and recruitment of transcription coactivators. MDM2 also acts as a ubiquitin ligase targeting p53 for proteasomal degradation through both cytoplasmic and nuclear proteasomes.


CDK4 gene;

CDK4 (Cyclin-Dependent Kinase 4) is shown to be amplified in over 90% of cases. A relatively compact gene that spans 4.16 kb of genomic DNA on the long arm of chromosome 12, in the telomere-to-centromere orientation. The CDK4 gene encodes a 33-kD protein that forms complexes with the cyclin D family, to enable G1-S transition. These CDK4/Cyclin D complexes phosphorylate pRb (encoded by RB1), with resultant activation of E2F target genes including E-type cyclins.


TSPAN31;

TSPAN31 was as frequently amplified as MDM2 in most of the sarcomas. Recent studies have suggested a role for the c-Jun N-terminal kinase (JNK) pathway. Co-amplification of 1p32 and 6q23, that contain c-Jun, and Apoptosis Signaling Kinase 1 (ASK1), are seen in DDLPS. The proto-oncogene c-Jun encodes part of the activator protein transcription factor (AP-1) complex involved in cell proliferation, transformation and apoptosis. ASK1 activates JNK ultimately leading to c-Jun activation and PPARγ inactivation. PPARγ is involved in the adipocytic differentiation process and its inhibition may result in de-differentiation.


2) Myxoid/round cell liposarcoma (MLPS):

MLPS accounting for more than one third of Liposarcomas and 10% of all adult soft tissue sarcomas, are characterized by the presence of spindle or ovoid cells set in a myxoid stroma with signet ring lipoblasts and a distinctive chicken-wire pattern vasculature. Unusual sites of metastasis are common in MLPS with a propensity to metastasize to soft tissue and bone rather than lung. Thirty-one percent of MLPS patients develop metastasis with bone metastases constituting 56% of these.


FUS-CHOP gene;

Located on chromosome 12, FUS-CHOP gene fusion - characterized by the recurrent translocation t(12;16)(q13;p11), is present in over 95% of cases. Mostly, the amino terminal domain of FUS (also known as TLS) is fused to C/EBP homologous protein (CHOP, also known as DDIT3 or GADD153). In rare cases, an alternative translocation event is found t(12;22)(q13;q12) that results in formation of the novel fusion oncogene where EWS takes the place of FUS.


3) Pleomorphic liposarcoma (PLPS):

60% of PLPS have a deletion of 13q14.2-q14.3, a region that includes the tumor suppressor RB1. Additional deletions include; 17p13 and 17q11.2. 16.7% of PLPS cases had mutations identified in p53.


TP53 gene;

It’s deleted or mutated in 17–60% of cases; located on chromosome 17. (17p13.1). It provides instructions for making a protein called tumor protein - p53.


RB1 gene;

It’s deleted in 60% of cases; located on chromosome 13 - more specifically, 13q14.1-q14.2. Its common function is seen as binding and repressing E2F targets. A tumor suppressor gene identified whose mutational inactivation is the cause of a human cancer.


Treatment option for Liposarcoma is multimodal, with surgical removal and radiotherapy used for local control and chemotherapy for systemic disease. Few therapeutic options are available for aggressive local or metastatic disease. MLPS tumors are also highly radiosensitive. Given the small subgroup that is chemo-sensitive, and the overriding lack of chemo-curative disease there are avenues and a need for novel molecular therapies.


FIBROSARCOMA

A rare, highly malignant cancer, affecting cells called fibroblasts; have the potential to form tumours at nearly every part of the body. The causes of fibrosarcoma may include; a weakened or damaged lymph system, chemical or radiation exposure or even through inherited genetic abnormalities.

They are predominantly located either adjacent to bones or in deep soft tissue. In addition, fibrosarcoma have possibilities to arise inside the bones, could be either as a primary or secondary tumor. Their symptoms usually take a relatively longer time to appear but when they do, symptoms include:

  • Cough or breathlessness.

  • Vomiting blood.

  • Pain in the abdomen and in the area of the tumor, which might feel like a sprain.

  • Swelling around the bone, which often does not show up until the tumor is quite large.

  • Difficulty moving a joint or limb.

  • Numbness in areas of the body, due to the tumor pressing on nerves.

  • Fragile, easily broken bones.


TP53 gene:

TP53 gene is located on the short arm of chromosome 17 (17p13.1). The gene spans about 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. It encodes specific proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.

Likewise, new targeting strategies for TP53 have been disclosed; rejuvenation of the wtp53 role from mutp53, restoration of wild-type p53 (wtp53) activity through inhibition of TP53 negative regulators, depletion of mutp53, and targeting of vulnerabilities in cells with TP53 deletions or mutations. It’s a leading cause of most other cancers too.


CDKN2A gene:

CDKN2A gene is located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21. It regulates monocyte/macrophage proliferation. Patients reveal homozygous deletion with minimal overlapping region at the CDKN2A [cyclin-dependent kinase inhibitor 2A. Deletion seems to be the main mechanism of the inactivation of these genes in fibrosarcoma of the bone.


CDKN2B gene;

This gene lies adjoining the tumor suppressor gene - CDKN2A in a part that’s frequently mutated and deleted in a broad number of tumors. It encodes a cyclin - dependent kinase inhibitor, which constructs a complex with CDK4 / CDK6, and blocks the activation of the CDK kinases, thus, the encoded protein powers as a cell growth regulator, managing cell cycle G1 sequence.


EWSR1 gene:

EWSR1 (EWS RNA Binding Protein 1) is located on human chromosome 22, specifically 22q12.2.it’s a Protein Coding gene, codes for EWS – RNA binding protein. In this case specifically it highly comes in associations with transcription factors giving rise to genes with powerful chromatin regulatory action, proficient of initiating complex gene expression activities in permissive precursor cells. These include; EWSR1-ATF1 fusion gene and EWSR1-CREB3L1 fusion genes. This gene is a major cause of other cancer types as well.


The best current therapy of fibrosarcoma is generous surgical removal from site. The response rates of fibrosarcoma towards radio- and chemotherapy being very low are now paving way towards a high need for novel molecular therapies.



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