Atypical Teratoid Rhabdoid tumors (AT/RT) are rare, highly malignant embryonal tumors of the Central Nervous System (CNS). They are genetically characterized by inactivating mutations of the INI1/SMARCB1/hSNF5/BAF47 gene located at chromosome 22q11. These tumors are associated with poor outcomes regardless of surgery, chemotherapy and radiation therapy. Recently, intensive multimodal treatment has provided some improvement in survival, but treatment-related toxicity is high.
A better understanding of the biology of these aggressive tumors is needed in order to find new treatments, improve patient survival, and lower therapy-related toxicity. Several major biological questions involving this entity are still to be answered. For example, the cell of origin is still not known. Additionally, we do not understand how INI1/SMARCB1 mutation alters cell biology to result in this tumor type. Furthermore, some unique clinical scenarios may provide an opportunity to enhance our knowledge – for example, AT/RTs are typically diagnosed in early childhood, but these tumors can develop in older patients, too, and familial forms have been described. Similarly, this tumor can develop also outside the CNS. In these situations, they are named Malignant Rhabdoid Tumors (MRT).
The mission of iSTAR AT/RT is to leverage state of the art multidisciplinary scientific approaches aiming to gain a better understanding of AT/RT biology, uncovering markers of prognosis, and making discoveries that will drive new therapeutic development. The creation of iSTAR AT/RT is a direct consequence of the work done at Stanley Manne Children's Research Institute in the last 5 years. What started as a modest individual research initiative evolved into an internal and external collaborative effort. Our overall long-term goal is to contribute to quality-of-life improvement of children with AT/RT by effectively stratifying patients at the time of diagnosis and uncovering more effective and less toxic targets for therapeutic intervention.
Rhabdoid Tumor Predisposition Syndrome - RTPS
RTPS is a hereditary cancer syndrome, which presents with a constitutional loss or inactivation in one allele of the SMARCB1/INI1 gene. This results in an increased risk of developing rhabdoid tumors: atypical teratoid rhabdoid tumors (AT/RT) of the brain, rhabdoid tumors of the kidney (RTK) or malignant rhabdoid tumors (MRT) of other locations. The vast majority of rhabdoid tumors present with “defects” (or mutations) in a gene called SMARCB1/INI1. The SMARCB1/INI1 gene is a tumor suppressor gene.
In all of our cells, we each have two copies of each gene: One that we receive from our mom and the other from our dad. Tumor suppressor genes control cell division and “suppress” tumor formation. When both copies of a tumor suppressor gene are damaged (or mutated) the gene no longer “suppresses" tumor formation, and a tumor may develop.
Most rhabdoid tumors (AT/RTs, RTKs and MRTs) develop sporadically. A sporadic tumor is a tumor in which development is not related to a family history. In sporadic rhabdoid tumors “defects” (or mutations) of the SMARCB1/INI1 gene occur only in the tumor, but not in other cells in the rest of the body.
In rhabdoid tumor predisposition syndrome, a child may receive a “defective” copy of the SMARCB1/INI1 gene from one of his/her parents. As a result, the child will have one “defective” copy of the gene in every cell in the body. If the other copy of the gene remains “healthy” and functional, the gene will do its job “suppressing” tumor formation, and the child won’t develop a tumor. However, if one extra mutation occurs in the “healthy” copy of the gene, a tumor may develop.
If a mutation in the “healthy” copy of the gene never occurs, the child won’t develop a tumor. However, he/she will be a carrier of the mutation and when the time comes; he/she may pass the mutated gene to his/her children.
In RTPS, the child does not always inherit the mutated SMARCB1/INI1 gene from one of the parents. The child can instead develop the mutation during embryonic development (during the child's formation in the womb). This type of mutation is called de novo. In these cases, the child will also have one “defective” copy of the gene in all of the cells in the body, but parents and siblings won’t have it.
If your child has a rhabdoid tumor (AT/RT, RTK or MRT) and has been tested for SMARCB1/INI1 mutations, there are 4 possible scenarios:
If the mutation was detected only in the tumor, but not in the blood, the tumor is sporadic. This means that there is no increased risk for your other children to be affected by the disease.
If the mutation was detected in the tumor and in the blood of the patient, parents should also be tested for the mutation in their blood.
If the mutation is not detected in parents, this means that the mutation occurred while the child was developing in the uterus (de novo) and therefore the siblings of the affected child are also not at increased risk to develop a tumor.
If the mutation is detected in one of the parents, siblings need to be tested as well. The reason is that siblings may also have inherited the mutated gene. If this is the case, there is an increased risk of tumor development and/or transmission of the mutated gene to the next generation.
It is still not known if patients with RTPS have a better or worse outcome than children with sporadic rhabdoid tumors. However, in RTPS, genetic counseling is recommended to the families and should be facilitated by clinicians and institutions.