Atypical Teratoid Rhabdoid Tumor (ATRT) is a rare, highly aggressive malignant tumor of the central nervous system that primarily affects infants and young children. ATRT arises due to fundamental changes in the genetic code, meaning its origin is inherently genetic. While ATRT is caused by a gene mutation, the vast majority of cases occur spontaneously and are not inherited from a parent. A small percentage of children diagnosed with ATRT carry a mutation that was either inherited or occurred very early in development, leading to a strong predisposition for cancer.
The Specific Gene Mutation Behind ATRT
The development of ATRT is directly linked to the inactivation of a specific gene known as \(SMARCB1\), sometimes referred to as \(INI1\). This gene functions as a tumor suppressor, regulating cell growth and preventing the uncontrolled division that characterizes cancer. \(SMARCB1\) is a fundamental component of the SWI/SNF chromatin remodeling complex, which organizes DNA and controls gene expression. When \(SMARCB1\) is lost or inactivated, the complex fails to function correctly, disrupting gene expression and allowing cells to proliferate unchecked. For a tumor to form, both copies of the \(SMARCB1\) gene—one inherited from each parent—must be functionally inactivated. This follows the established “two-hit” hypothesis for tumor suppressor genes. The resulting loss of the \(SMARCB1\) protein is a key diagnostic marker for ATRT.
Understanding Sporadic and Inherited Cases
ATRT results from genetic alterations that are either sporadic or inherited. The majority of ATRT diagnoses are sporadic, meaning the genetic change is confined only to the tumor cells. This is known as a somatic mutation, which happens after conception and is not present in the parents’ germline. In sporadic cases, the tumor-forming cell randomly acquires inactivating mutations in both copies of the \(SMARCB1\) gene during the child’s lifetime. Since this mutation is only found within the tumor tissue, parents and future children are not at an increased risk.
Approximately 25 to 35 percent of ATRT patients have a germline mutation in \(SMARCB1\). A germline mutation is present in the sperm or egg cell at conception, meaning it is found in every cell of the child’s body. This inherited mutation provides the first “hit” toward cancer development, making the child highly susceptible to ATRT or other related tumors.
The Family Implications of Rhabdoid Tumor Predisposition Syndrome
A germline mutation in the \(SMARCB1\) gene causes Rhabdoid Tumor Predisposition Syndrome (RTPS). Individuals with RTPS have a significantly increased lifetime risk of developing aggressive cancers collectively called rhabdoid tumors. These include ATRT in the brain, Malignant Rhabdoid Tumor of the Kidney (MRTK), and extrarenal extracranial rhabdoid tumors.
RTPS is inherited in an autosomal dominant pattern, meaning only one altered copy of the gene is needed for the predisposition. A parent carrying the \(SMARCB1\) mutation has a 50 percent chance of passing the variant to each child, even if the parent has never developed a tumor. The risk for tumor development is concentrated in early childhood, typically before age three. In many cases, the germline mutation is de novo, meaning it occurred for the first time in the affected child and was not inherited. If the child survives to adulthood, they carry the mutation in their germline and have a 50 percent chance of passing it to their own children.
Genetic Counseling and Screening Protocols
Following an ATRT diagnosis, genetic testing is strongly recommended for all patients to determine if the mutation is somatic or germline. Testing compares DNA from the tumor tissue to DNA found in a non-cancerous sample, usually blood. Identifying a germline mutation confirms Rhabdoid Tumor Predisposition Syndrome and carries significant implications for the entire family. Genetic counseling provides families with a clear explanation of the inheritance patterns and the risks for other family members, including siblings and parents. If a germline mutation is identified in the child, testing is offered to the parents to determine if one is a carrier, and testing can also be offered to siblings and extended family members.
For high-risk carriers of the \(SMARCB1\) germline mutation, specialized surveillance protocols are put in place for early detection, as early treatment offers the best chance of a positive outcome. This usually includes regular neurological examinations, routine magnetic resonance imaging (MRI) of the brain and spine, and abdominal ultrasounds to check for tumors in the kidney. The frequency of this intensive surveillance is highest in the first five years of life when the risk is greatest.