Rhabdoid Tumor Predisposition Syndrome

Rhabdoid tumors are aggressive tumors that may occur sporadically or as part of a hereditary cancer syndrome known as Rhabdoid Tumor Predisposition syndrome (RTPS). Rhabdoid tumors usually develop in infants and young children, with the most common locations being in the central nervous system and the kidney.

Individuals with RTPS are also at increased risk to develop schwannomas (benign tumors of the peripheral nerves). Approximately 30-35 percent of children who are diagnosed with rhabdoid tumors have RTPS. Children with RTPS have a higher chance of developing multiple tumors and are often diagnosed at a younger age than children with sporadic rhabdoid tumors.

Rhabdoid tumor predisposition syndrome is caused by alterations, also known as mutations, at specific areas within an individual’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as “genes.” Genes provide the necessary instructions that our cells require to perform different functions within our bodies.

There is a specific gene known as INI1 (also known as SMARCB1), located on chromosome 22, which is altered in individuals with RTPS. With the exception of egg and sperm cells, each cell of the body normally has two working copies of the INI1 gene. In individuals with RTPS, however, each cell contains only one working copy of INI1. While the second copy is present, it is mutated so it does not function properly.

The protein produced by the INI1 gene acts as a “tumor suppressor," which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death. If the second copy of the INI1 gene is altered or lost in a cell of the body, the affected cell can grow and divide in an abnormal fashion, which can ultimately lead to tumor formation.

How is RTPS inherited?

Some individuals with rhabdoid tumor predisposition syndrome inherit an altered copy of the INI1 gene from a parent who also carries the same genetic mutation. In most cases, however, RTPS results from the development of a “new” mutation in one of the father’s sperm, mother’s eggs, or in a cell of the developing fetus. In the latter scenarios, the affected individuals will be the first ones in their family to carry this genetic change.

Individuals who carry an alteration in one copy of the INI1 gene in all the cells of their body have a 50 percent chance of passing this same alteration onto each of his or her children. Children who inherit the altered gene copy will have RTPS and therefore be at an increased risk of developing rhabdoid tumors and/or multiple schwannomas.

Some individuals may develop RTPS due to a deletion of DNA that encompasses one copy of the INI1 gene and sometimes additional genes. These individuals may have certain physical features, including heart and other birth defects, as well as developmental delays and/or intellectual disabilities, depending on the size and number of genes that are deleted. Thus far, deletions that include the INI1 gene have only been associated with the development of rhabdoid tumors and not schwannomas.

Additionally, in one study, three out of six individuals with a complete deletion of one copy of the INI1 gene developed rhabdoid tumors at a later age, suggesting that larger deletions including INI1 may be associated with an older age of onset compared to other individuals with RTPS.

The diagnosis of RTPS should be considered in any individual with a personal or family history of rhabdoid tumors and/or schwannomas, especially individuals with who have multiple primary tumors.

A careful and detailed review of a person's medical and family history is important when attempting to make a diagnosis of RTPS. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that shows which members of the family have developed cancer, the types of cancer, and their ages when the cancer first occurred.

Testing for RTPS

To confirm — on a molecular level — that an individual has RTPS, he or she can undergo the process of genetic testing. Genetic testing usually involves the collection of a sample of blood, from which the white blood cells are isolated and used as a source of DNA. Subsequently, the two copies of the INI1 gene are analyzed using a variety of methods to look for possible changes in the normal lettering of one of the two copies of the INI1 gene. If a change in one of the two INI1 gene copies is identified, it can be further analyzed to determine if it is causative of RTPS or simply a normal variation in the gene.

Genetic testing for RTPS is most effective when tumor tissue from an affected individual is available. In these cases, DNA is isolated from the tumor sample and the two copies of the INI1 gene are evaluated using a variety of methods. These genetic analyses are performed on the tumor tissue first to identify the two INI1 alterations that are present within the cells of the tumor and presumably led to its formation.

Subsequently, DNA from a sample of blood is screened for the presence of one of the two INI1 gene alterations found in the tumor. The presence of an INI1 mutation in the blood confirms the diagnosis of RTPS. In contrast, the absence of an INI1 abnormality most likely indicates that an affected individual’s rhabdoid tumor or schwannoma developed sporadically.

A person with RTPS who is concerned about passing this disorder onto future children has several options regarding prenatal genetic testing. In these cases, the familial INI1 mutation must be identified before prenatal testing can be performed. Current options regarding prenatal genetic testing include:

• Prenatal diagnosis: DNA is obtained from the cells of the embryo through chorionic villus sampling (CVS) or amniocentesis. The DNA is analyzed for alterations in the INI1 gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or end the pregnancy.
• Preimplantation genetic diagnosis (PGD): For couples using in vitro fertilization (IVF) to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the INI1 gene would be implanted.

Individuals with RTPS are primarily at increased risk to develop rhabdoid tumors. This risk is highest in childhood and decreases after age 5. Older children and adults with RTPS are at increased risk to develop schwannomas.

While the risk that an individual with RTPS will develop one or more tumors is increased compared to individuals who do not have RTPS, it is less than 100 percent. For example, some individuals with an INI1 mutation never develop tumors. It is not yet understood why some individuals with RTPS develop rhabdoid tumors while others develop schwannomas. Similarly, it is not well understood why some individuals with the condition never develop a tumor. There are likely other genetic and environmental factors that contribute to these differences, but currently these remain unknown. It is important to note that RTPS has only been described recently and further studies may clarify or expand our current knowledge of the tumor risks associated with germline INI1 mutations.

Tumor screening protocols

Standard screening guidelines for Rhabdoid Tumor Predisposition Syndrome (RTPS) have not yet been established. However, it has been suggested that screening guidelines could include baseline brain MRI examinations and renal ultrasounds as soon as a diagnosis of RTPS is established. A screening protocol should be discussed with a physician familiar with RTPS to determine the best methods and frequency of screening as well as the benefits, risks, and limitations of screening.

Bourdeaut F, et al. 2011. Frequent hSNF5/INI1 Germline Mutations in Patients with Rhabdoid Tumor. Clin Cancer Res, 17, 31-38.

Eaton KW, et al. 2011. Spectrum of SMARCB1/INI1 Mutations in Familial and Sporadic Rhabdoid Tumors. Pediatr Blood Cancer, 56, 7-15.

Jackson EM, et al. 2007. High-density single nucleotide polymorphism array analysis in patients with germline deletions of 22q11.2 and malignant rhabdoid tumor. Hum Genet, 122, 117-127.