Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a high risk of developing cancerous (malignant) growths called rhabdoid tumors. These highly aggressive tumors are called rhabdoid because their cells resemble rhabdomyoblasts, which are cells that are normally found in embryos before birth and develop into muscles used for movement (skeletal muscles).

Rhabdoid tumors are rare in the general population. They usually occur in the first year of life, and are much less likely to appear after age 4. In people with RTPS, the tumors occur at an average age of 4 to 7 months, and can even occur before birth. Affected individuals may have multifocal synchronous tumors, which means that multiple tumors that develop independently (primary tumors) occur at the same time. The rhabdoid tumors that occur in RTPS usually grow and spread more quickly than those in children without this predisposition, and affected individuals often do not survive past childhood.

More than half of all malignant rhabdoid tumors (MRTs) develop in the cerebellum, which is the part of the brain that coordinates movement. Rhabdoid tumors in the brain and spinal cord (central nervous system) are called atypical teratoid/rhabdoid tumors (AT/RTs).

Rhabdoid tumors also occur outside the central nervous system. These tumors include rhabdoid tumors of the kidneys (RTKs) and tumors that develop in other organs and tissues of the body (called extrarenal malignant rhabdoid tumors or eMRTs). The type of rhabdoid tumor can vary among individuals with RTPS, even within the same family.

Tumors other than rhabdoid tumors can also occur in people with RTPS. Some affected children develop noncancerous (benign) tumors called schwannomas, which grow on nerve cells. Women with RTPS are at increased risk of developing a rare type of ovarian cancer called small cell cancer of the ovary hypercalcemic type (SCCOHT).

In 85 to 95 percent of affected individuals, RTPS is caused by mutations in the SMARCB1 gene. These cases are sometimes known as RTPS1. A small number of cases (called RTPS2) are caused by mutations in the SMARCA4 gene. These genes provide instructions for making proteins that form pieces (subunits) of several different protein groups called SWI/SNF protein complexes. SWI/SNF complexes regulate gene activity (expression) by a process known as chromatin remodeling. Chromatin is the network of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed.

Through their ability to regulate gene activity, SWI/SNF complexes are involved in many processes, including repairing damaged DNA; copying (replicating) DNA; and controlling the growth, division, and maturation (differentiation) of cells. Through these processes, the proteins produced from the SMARCB1 and SMARCA4 genes, as well as other SWI/SNF subunits, are thought to act as tumor suppressors, which keep cells from growing and dividing too rapidly or in an uncontrolled way.

RTPS is caused by a mutation in the SMARCB1 or SMARCA4 gene that is present in cells throughout the body (called a germline mutation). An additional genetic change that deletes the normal copy of the gene is needed for a tumor to develop. This additional change is acquired during a person's lifetime and is present only in the cancerous cells. Such changes are known as somatic mutations. In combination, the germline and somatic mutations lead to the absence or dysfunction of the protein produced from the SMARCB1 or SMARCA4 gene. This deficiency likely impairs the tumor suppressor function of the proteins, but the specific mechanism that leads to rhabdoid tumors is unknown.

Normal Function

The SMARCA4 gene provides instructions for making a protein called BRG1, which forms one piece (subunit) of several different protein groupings called SWI/SNF protein complexes. SWI/SNF complexes regulate gene activity (expression) by a process known as chromatin remodeling. Chromatin is the network of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed. The BRG1 protein uses a molecule called ATP to provide energy for chromatin remodeling, although the protein's specific role in remodeling is unclear.

Through their ability to regulate gene activity, SWI/SNF complexes are involved in many processes, including repairing damaged DNA; copying (replicating) DNA; and controlling the growth, division, and maturation (differentiation) of cells. Through these processes, the BRG1 protein and other SWI/SNF subunits are thought to act as tumor suppressors, which keep cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Coffin-Siris syndrome

Approximately 40 variants (also known as mutations) in the SMARCA4 gene have been found to cause Coffin-Siris syndrome. This condition is characterized by delayed development, abnormalities of the fifth (pinky) fingers or toes, and characteristic facial features that are described as coarse. The SMARCA4 gene variants involved in Coffin-Siris syndrome are germline variants, which means that they are present in cells throughout the body. The variants change single protein building blocks (amino acids) in or remove an amino acid from the BRG1 protein. Although it is unclear how these changes affect SWI/SNF complexes, researchers suggest that SMARCA4 gene variants result in abnormal chromatin remodeling. Disturbance of this process alters the activity of many genes and disrupts several cellular processes, which could explain the diverse signs and symptoms of Coffin-Siris syndrome. People with Coffin-Siris syndrome do not appear to have an increased risk of cancer (see below).

Rhabdoid tumor predisposition syndrome

At least six germline variants in the SMARCA4 gene have been identified in people with rhabdoid tumor predisposition syndrome (RTPS). RTPS is characterized by a high risk of developing cancerous (malignant) growths called rhabdoid tumors. These tumors most often occur in the brain and spinal cord (central nervous system) or in the kidney, but they can occur in other organs and tissues of the body. Some affected children also develop noncancerous (benign) tumors called schwannomas, which grow on nerves. Women with RTPS are at increased risk of developing a rare type of ovarian cancer called small cell cancer of the ovary, hypercalcemic type (SCCOHT).

In addition to the germline variant affecting one copy of the SMARCA4 gene in each cell, an additional genetic change that deletes the normal copy of the gene is needed for a tumor to develop. This additional change is present only in the cancerous cells. Such changes are known as somatic variants. In combination, the germline and somatic variants lead to the absence of BRG1 protein. This absence likely impairs the tumor suppressor functions of the protein, but the specific mechanism that leads to rhabdoid tumors is unknown.

Lung cancer

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Other cancers

Somatic variants in both copies of the SMARCA4 gene, which result in the absence of SMARCA4 protein, cause noninherited (sporadic) rhabdoid tumors in children. Somatic variants in the SMARCA4 gene have also been found in certain other types of cancer, particularly lung cancer and other cancers in the chest called SMARCA4-deficiency thoracic sarcomas. The mechanism by which variants in the SMARCA4 gene contribute to these tumors is unknown, although it is thought that changes in SWI/SNF complexes are involved. These changes may impair normal cell differentiation, which leads to the overgrowth of certain cell types, causing cancer. Alternatively, abnormal SWI/SNF complexes may disrupt the regulation of genes that help control the growth and division of cells, which leads to cancer. It is likely that other genetic changes in addition to SMARCA4 gene variants are necessary for cancer development.

Other Names for This Gene

• ATP-dependent helicase SMARCA4
• BAF190
• BAF190A
• brahma protein-like 1
• BRG1
• BRG1-associated factor 190A
• BRM/SWI2-related gene 1
• FLJ39786
• hSNF2b
• MRD16
• nuclear protein GRB1
• protein brahma homolog 1
• protein BRG-1
• RTPS2
• SMCA4_HUMAN
• SNF2
• SNF2-beta
• SNF2-like 4
• SNF2L4
• SNF2LB
• sucrose nonfermenting-like 4
• SWI2
• transcription activator BRG1

Genomic Location

Normal Function

The SMARCB1 gene provides instructions for making a protein that forms one piece (subunit) of several different protein groupings called SWI/SNF protein complexes. SWI/SNF complexes regulate gene activity (expression) by a process known as chromatin remodeling. Chromatin is the network of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed.

Through their ability to regulate gene activity, SWI/SNF complexes are involved in many processes, including repairing damaged DNA; copying (replicating) DNA; and controlling the growth, division, and maturation (differentiation) of cells. Through these processes, the SMARCB1 protein and other SWI/SNF subunits are thought to act as tumor suppressors, which keep cells from growing and dividing too rapidly or in an uncontrolled way.

The role of the SMARCB1 protein within the SWI/SNF complex is not fully understood.

Health Conditions Related to Genetic Changes

Coffin-Siris syndrome

At least 11 variants (also known as mutations) in the SMARCB1 gene have been found to cause Coffin-Siris syndrome. This condition is characterized by delayed development, abnormalities of the fifth (pinky) fingers or toes, and characteristic facial features that are described as coarse. The SMARCB1 gene variants involved in Coffin-Siris syndrome are germline variants, which means that they are present in cells throughout the body. The variants change or remove single protein building blocks (amino acids) in the SMARCB1 protein. Although it is unclear how these changes affect SWI/SNF complexes, researchers suggest that SMARCB1 gene variants result in abnormal chromatin remodeling. Disturbance of this process alters the activity of many genes and disrupts several cell activities, which could explain the diverse signs and symptoms of Coffin-Siris syndrome. People with Coffin-Siris syndrome do not appear to have an increased risk of cancer (see below).

Rhabdoid tumor predisposition syndrome

More than 50 germline variants in the SMARCB1 gene have been identified in people with rhabdoid tumor predisposition syndrome (RTPS). RTPS is characterized by a high risk of developing cancerous (malignant) growths called rhabdoid tumors. These tumors most often occur in the brain and spinal cord (central nervous system) or in the kidney, but they can occur in other organs and tissues of the body. Some affected children also develop noncancerous (benign) tumors called schwannomas, which grow on nerves. Women with RTPS are at increased risk of developing a rare type of ovarian cancer called small cell cancer of the ovary, hypercalcemic type (SCCOHT).

In addition to the germline variant affecting one copy of the SMARCB1 gene in each cell, an additional genetic change that deletes the normal copy of the gene is needed for a tumor to develop. This additional change is present only in the cancerous cells. Such changes are known as somatic variants. In combination, the germline and somatic variants lead to the absence or dysfunction of SMARCB1 protein. This deficiency likely impairs the tumor suppressor functions of the proteins, but the specific mechanism that leads to rhabdoid tumors is unknown.

Schwannomatosis

More than two dozen variants in the SMARCB1 gene have been found in people with schwannomatosis, a disorder characterized by multiple noncancerous (benign) tumors called schwannomas that grow on nerves. This type of tumor arises from Schwann cells, which are specialized cells that normally form an insulating layer around the nerve.

SMARCB1 gene variants associated with schwannomatosis lead to production of an altered SMARCB1 protein whose function is reduced but not eliminated. The altered protein is less able to control how cells grow and divide, which can allow tumors to develop. However, it is unknown why these variants are predominantly associated with schwannomas, instead of other tumor types, in people with schwannomatosis.

It appears that germline variants in SMARCB1 alone are not enough to trigger the development of schwannomas. Additional somatic variants that are acquired during a person's lifetime and are present only in certain cells may also be required for schwannomas to form.

Some people who have a variant in the SMARCB1 gene never develop tumors, which is a situation known as reduced penetrance.

Other cancers

Somatic variants in both copies of the SMARCB1 gene, which result in the absence of SMARCB1 protein, cause noninherited (sporadic) rhabdoid tumors in children. As in RTPS (described above), the absence of SMARCB1 protein likely impairs the tumor suppressor functions of the proteins, but the specific mechanism that leads to rhabdoid tumors is unknown.

Other Names for This Gene

• BAF47
• BRG1-associated factor 47
• hSNF5
• hSNFS
• INI1
• integrase interactor 1 protein
• MRD15
• PPP1R144
• RDT
• RTPS1
• Sfh1p
• SNF5
• SNF5 homolog
• SNF5_HUMAN
• SNF5L1
• Snr1
• sucrose nonfermenting, yeast, homolog-like 1
• SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to predispose the affected individual to rhabdoid tumors.

The majority of cases of RTPS are caused by SMARCB1 gene mutations. These cases usually occur in people with no history of the disorder in their family. They result from a new mutation in the gene that occurs in a parent's egg or sperm cell and is found in all the child's cells.

In most known cases of RTPS caused by SMARCA4 gene mutations, an affected person inherits the mutation from one parent who has the altered gene but has not developed any rhabdoid tumors.

In the United States, rhabdoid tumors occur in about 1 per million children under age 15. RTPS is thought to account for between a quarter and a third of these tumors.