Introduction

Rhabdoid tumor predisposition syndrome type 1 (RTPS1) is caused by germline, or hereditary, heterozygous loss-of-function pathogenic variants in the SMARCB1gene on chromosome 22q11. Individuals with RTPS1 are at an increased risk of developing both central nervous system (CNS) and non-CNS rhabdoid tumors, including atypical teratoid/rhabdoid tumors (AT/RTs), malignant rhabdoid tumors (MRTs) of the kidney, and extrarenal rhabdoid tumors. These tumors tend to require multimodal treatment such as surgery, chemotherapy, and possibly radiation therapy. These tumors occur most frequently in early childhood, often before the age of 3 years.

References

1. Sévenet N, Sheridan E, Amram D, et al.: Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 65 (5): 1342-8, 1999.
2. Biegel JA, Zhou JY, Rorke LB, et al.: Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59 (1): 74-9, 1999.
3. Versteege I, Sévenet N, Lange J, et al.: Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394 (6689): 203-6, 1998.

Nomenclature

Individuals who harbor a germlinepathogenic variant in SMARCB1 are said to have rhabdoid tumor predisposition syndrome type 1 (RTPS1). Individuals who harbor a germline pathogenic variant in SMARCA4 are said to have rhabdoid tumor predisposition syndrome type 2 (RTPS2). Nomenclature in genetic disorders continues to evolve, and future terminology for these disorders may reflect the proposed dyadic naming approach, incorporating both gene and phenotype.

References

1. Samples, Phenotypes and Ontologies Team: Rhabdoid Tumor Predisposition Syndrome 1. Ontology Lookup Service European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), 2023. Available online. Last accessed October 17, 2023.
2. Samples, Phenotypes and Ontologies Team: Rhabdoid Tumor Predisposition Syndrome 2. Ontology Lookup Service European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), 2023. Available online. Last accessed October 17, 2023.
3. Biesecker LG, Adam MP, Alkuraya FS, et al.: A dyadic approach to the delineation of diagnostic entities in clinical genomics. Am J Hum Genet 108 (1): 8-15, 2021.

Genetics

Molecular Genetics

The SMARCB1gene encodes the SMARCB1 protein (also called INI1 or BAF47), a member of the SWI/SNF chromatin remodeling complex, which helps control gene transcription. Rhabdoid tumors develop when both copies of the SMARCB1 gene are inactivated, or in some cases, when both copies of the SMARCA4 gene are inactivated. Individuals with germlineSMARCA4variants have a diagnosis of rhabdoid tumor predisposition syndrome type 2. Loss of SMARCB1/INI1 expression (detected by immunohistochemistry) is included in the diagnostic criteria for rhabdoid tumors.

In individuals with rhabdoid tumor predisposition syndrome type 1 (RTPS1), tumor development follows the Knudsen two-hit hypothesis. The first hit is caused by the inactivation of one copy of SMARCB1, typically by a truncating variant, copy-number change, or structural variant. The second hit is typically due to chromosomaldeletion or loss of heterozygosity. It is estimated that approximately 25% to 35% of rhabdoid tumor cases are associated with a germline variant in SMARCB1. Higher rates have been reported in certain subgroups, including patients diagnosed at younger than 6 months (55%) and patients with multifocal tumors (78%). It is recommended that all patients diagnosed with rhabdoid tumors consider genetic evaluation. Whole- and partial-gene deletions, nonsense, and frameshift variants are seen most commonly, frequently affecting exons 2 through 7 of the SMARCB1 gene. Point mutations, duplications, and splice-site variants occur more rarely. A case of ring chromosome 22 has also been reported in an individual with RTPS1.

Inheritance

RTPS1 is inherited in an autosomal dominant manner. Penetrance is reported as greater than 90% for most types of truncating variants in SMARCB1. However, these estimates are based on a modest number of observations and ascertainment of affected individuals and families. Most cases appear to be de novo, and individuals with rhabdoid tumors are often the first person in the family to be affected. This may be due to the aggressive nature of rhabdoid tumors. However, incomplete penetrance and late-onset tumors, including schwannoma and meningioma, have been reported in a small subset of families who are unaffected by rhabdoid tumors and carry a germline SMARCB1 variant. Gonadal mosaicism in a parent has been well documented in RTPS1. Therefore, negative genetic testing of parental blood cannot rule out the risk that more than one child may inherit the pathogenic variant and have a diagnosis of RTPS1. Genetic counseling has been suggested to discuss topics like prenatal testing and potential reproductive recurrence risk relevant to gonadal mosaicism.

Related Disorders

Germline alterations in the SMARCB1 gene are primarily associated with two additional hereditary conditions, schwannomatosis and Coffin-Siris syndrome (CSS). Cases of schwannoma have been reported in RTPS1 kindreds. However, rhabdoid tumors have not been reported in individuals with CSS. Generally, SMARCB1 variants associated with CSS are missense variants that cluster in the first and last exons of the gene. In patients with schwannomatosis, variants are often nontruncating and occur in the 3’ untranslated (UTR) region of SMARCB1. However, nonsenseSMARCB1 variants or deletions/duplications of the whole gene/multiple exons are more often associated with rhabdoid tumors. While these patterns represent the common genotype-phenotype correlations, they are not final, and overlap can be seen. However, exon-spanning deletions appear to occur exclusively in patients with RTPS1. While genotype-phenotype correlations exist across these three disorders, there is limited information regarding genotype-phenotype correlations specific to RTPS1.

References

1. Roberts CW, Biegel JA: The role of SMARCB1/INI1 in development of rhabdoid tumor. Cancer Biol Ther 8 (5): 412-6, 2009.
2. Reisman D, Glaros S, Thompson EA: The SWI/SNF complex and cancer. Oncogene 28 (14): 1653-68, 2009.
3. Foulkes WD, Kamihara J, Evans DGR, et al.: Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome. Clin Cancer Res 23 (12): e62-e67, 2017.
4. Biegel JA, Zhou JY, Rorke LB, et al.: Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59 (1): 74-9, 1999.
5. Eaton KW, Tooke LS, Wainwright LM, et al.: Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 56 (1): 7-15, 2011.
6. Bourdeaut F, Lequin D, Brugières L, et al.: Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res 17 (1): 31-8, 2011.
7. Frühwald MC, Nemes K, Boztug H, et al.: Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group. Fam Cancer 20 (4): 305-316, 2021.
8. Nemes K, Johann PD, Steinbügl M, et al.: Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population. Cancers (Basel) 14 (9): , 2022.
9. Pinto EM, Hamideh D, Bahrami A, et al.: Malignant rhabdoid tumors originating within and outside the central nervous system are clinically and molecularly heterogeneous. Acta Neuropathol 136 (2): 315-326, 2018.
10. Druker H, Zelley K, McGee RB, et al.: Genetic Counselor Recommendations for Cancer Predisposition Evaluation and Surveillance in the Pediatric Oncology Patient. Clin Cancer Res 23 (13): e91-e97, 2017.
11. Holsten T, Bens S, Oyen F, et al.: Germline variants in SMARCB1 and other members of the BAF chromatin-remodeling complex across human disease entities: a meta-analysis. Eur J Hum Genet 26 (8): 1083-1093, 2018.
12. Kordes U, Mautner VF, Oyen F, et al.: Evidence for a low-penetrant extended phenotype of rhabdoid tumor predisposition syndrome type 1 from a kindred with gain of SMARCB1 exon 6. Pediatr Blood Cancer 68 (10): e29185, 2021.
13. Byers HM, Adam MP, LaCroix A, et al.: Description of a new oncogenic mechanism for atypical teratoid rhabdoid tumors in patients with ring chromosome 22. Am J Med Genet A 173 (1): 245-249, 2017.
14. Biegel JA, Tan L, Zhang F, et al.: Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res 8 (11): 3461-7, 2002.
15. Nemes K, Clément N, Kachanov D, et al.: The extraordinary challenge of treating patients with congenital rhabdoid tumors-a collaborative European effort. Pediatr Blood Cancer 65 (6): e26999, 2018.
16. Gigante L, Paganini I, Frontali M, et al.: Rhabdoid tumor predisposition syndrome caused by SMARCB1 constitutional deletion: prenatal detection of new case of recurrence in siblings due to gonadal mosaicism. Fam Cancer 15 (1): 123-6, 2016.
17. Bruggers CS, Bleyl SB, Pysher T, et al.: Clinicopathologic comparison of familial versus sporadic atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system. Pediatr Blood Cancer 56 (7): 1026-31, 2011.
18. Smith MJ, Wallace AJ, Bowers NL, et al.: SMARCB1 mutations in schwannomatosis and genotype correlations with rhabdoid tumors. Cancer Genet 207 (9): 373-8, 2014.

Cancer Risks, Spectrum, and Characteristics

As a class, copy-number(deletion) and truncating variants in SMARCB1 are associated with increased risk of tumor predisposition, although there are no known SMARCB1genotypes that can predict whether a tumor (or type of tumor) will develop. A meta-analysis of 185 carriers of SMARCB1variants found that the most common tumor type was atypical teratoid/rhabdoid tumors (AT/RTs), followed by rhabdoid tumors of the kidney and soft tissue. Multifocal tumors were common. Other tumors found included meningiomas, malignant peripheral nerve sheath tumors, chondrosarcomas, epithelioid sarcomas, leiomyosarcomas, leiomyomas, and myoepitheliomas. Anatomical locations of the tumors varied, especially in the brain. Tumors can also be synchronous or metachronous.

In patients with rhabdoid tumor predisposition syndrome type 1 (RTPS1), tumor onset typically occurs in very early childhood (often in infancy), and tumors may even be detected pre- or perinatally. There are rare case reports of adults developing SMARCB1-associated tumors. As next-generation sequencing of tumors has become more prevalent, alterations in the SMARCB1gene may require investigation for an underlying germline predisposition. However, the absence of a genetic alteration in the SMARBC1 gene does not rule out an underlying cancer predisposition syndrome. Second primary tumors have developed up to 15 years after the first primary tumor diagnosis, suggesting that lifetime surveillance is needed for patients with this syndrome.

References

1. Holsten T, Bens S, Oyen F, et al.: Germline variants in SMARCB1 and other members of the BAF chromatin-remodeling complex across human disease entities: a meta-analysis. Eur J Hum Genet 26 (8): 1083-1093, 2018.
2. Nemes K, Johann PD, Steinbügl M, et al.: Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population. Cancers (Basel) 14 (9): , 2022.
3. Frühwald MC, Nemes K, Boztug H, et al.: Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group. Fam Cancer 20 (4): 305-316, 2021.
4. Bruggers CS, Linscott L, Lee JC, et al.: Molecular characterization of metachronous atypical teratoid rhabdoid tumors occurring in a young man 15 years apart. Pediatr Blood Cancer 70 (1): e29836, 2023.
5. Bhatt MD, Al-Karmi S, Druker H, et al.: Second rhabdoid tumor 8 years after treatment of atypical teratoid/rhabdoid tumor in a child with germline SMARCB1 mutation. Pediatr Blood Cancer 66 (3): e27546, 2019.

Management

Genetic Counseling

Experts in the field of cancer genetics recommend a referral for genetic counseling or genetic evaluation for children who have been diagnosed with atypical teratoid/rhabdoid tumors (AT/RTs), malignant rhaboid tumors (MRTs), or any other SMARCB1-deficient tumors. These recommendations are based on the American Association for Cancer Research's (AACR) Childhood Cancer Predisposition Workshop and the European Society for Paediatric Oncology's (SIOPE) Host Genome Working Group guidelines. In the event that a child with an AT/RT or MRT died before completing the evaluation, counseling may be provided to parents and siblings.

Rhabdoid Tumor Predisposition and Fertility Preservation

Treatments for AT/RTs and MRTs may reduce fertility in boys and girls. Therefore, the medical team may offer fertility preservation to these patients. Parents of children with AT/RTs and MRTs who undergo fertility preservation should be advised that if a germlineSMARCB1 truncating variant is found, 50% of children derived from preserved gonadal tissue will inherit a SMARCB1 pathogenic variant and have a risk of developing rhabdoid tumors. Prenatal genetic counseling is advised for individuals with RTPS1.

Outcomes and Treatment Modification

In patients with AT/RTs or extracranial rhabdoid tumors, germline SMARCB1 variants are associated with poor outcomes. The risk of metastasis may also be associated with a germline variant. Despite intensive therapy, fewer than half of children with rhabdoid tumor predisposition syndrome type 1 (RTPS1) become long-term survivors. There are no data suggesting that treatment of patients with AT/RTs or MRTs should be modified because of a germline RTPS1 diagnosis.

For information about the treatment of AT/RTs, see Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment. For information about the treatment of MRTs, see the Rhabdoid Tumors of the Kidney section in Wilms Tumor and Other Childhood Kidney Tumors Treatment and the Rhabdoid Tumor NOS (Extrarenal) section in Childhood Soft Tissue Sarcoma Treatment.

Surveillance

In 2017, a group of experts in childhood cancer genetics created the first recommendations for cancer surveillance for patients with RTPS1. Since children with germline SMARCB1 truncating variants have an increased risk of developing AT/RTs in early childhood, screening recommendations include brain magnetic resonance imaging (MRI) every 3 months until age 5 years, after which surveillance ceases. Because of the risk of MRTs of the kidney, abdominal ultrasonography is recommended every 3 months from birth, with no upper age limit to stop surveillance. Whole-body MRI may also be considered until age 5 years. Screening is not recommended for children with a germline missensepathogenic variant in the SMARCB1gene because the risk of tumor development is very low.

In 2021, the SIOPE Host Genome Working Group published guidelines for clinical surveillance and genetic testing in patients with RTPS1. These guidelines recommend an age-based approach to surveillance. Central nervous system (CNS) and abdominal imaging occur every 1 to 3 months for patients younger than 6 months, every 2 to 3 months for patients aged 7 to 18 months, and every 3 months for patients aged 19 months to 5 years. Yearly whole-body MRI is recommended for patients aged 5 years and older.

Surveillance in Survivorship

For children with tumors and SMARCB1 truncating variants, surveillance should be ongoing to detect primary disease recurrence. Survivors of AT/RTs will continue to require abdominal ultrasonography to screen for MRTs. Conversely, children with MRTs of the kidney will continue to undergo CNS surveillance for AT/RTs until age 5 years if they have a germline truncating variant in SMARCB1.

Level of evidence: 5

References

1. Druker H, Zelley K, McGee RB, et al.: Genetic Counselor Recommendations for Cancer Predisposition Evaluation and Surveillance in the Pediatric Oncology Patient. Clin Cancer Res 23 (13): e91-e97, 2017.
2. Frühwald MC, Nemes K, Boztug H, et al.: Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group. Fam Cancer 20 (4): 305-316, 2021.
3. Mulder RL, Font-Gonzalez A, Green DM, et al.: Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 22 (2): e57-e67, 2021.
4. Mulder RL, Font-Gonzalez A, Hudson MM, et al.: Fertility preservation for female patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 22 (2): e45-e56, 2021.
5. Reddy AT, Strother DR, Judkins AR, et al.: Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333. J Clin Oncol 38 (11): 1175-1185, 2020.
6. Nemes K, Bens S, Kachanov D, et al.: Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK). Eur J Cancer 142: 112-122, 2021.
7. Foulkes WD, Kamihara J, Evans DGR, et al.: Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome. Clin Cancer Res 23 (12): e62-e67, 2017.

Latest Updates to This Summary (03/05/2024)

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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics, cancer risks, and management of rhabdoid tumor predisposition syndrome type 1. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board and the PDQ Pediatric Treatment Editorial Board, which are editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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• Julia Meade, MD
• Sarah Scollon, MS, CGC (Baylor College of Medicine & Texas Children's Hospital)
• Douglas Stewart, MD (National Cancer Institute)

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