Simone Treiger Sredni MD, PhD
Research Assistant Professor, Pediatric Neurosurgery
Department of Surgery - Ann & Robert H. Lurie Children's Hospital of Chicago
Northwestern University Feinberg School of Medicine
Tadanori Tomita MD
Yeager Professor in Pediatric Neurosurgery, Head of the Division of Pediatric Neurosurgery
Director, Falk Brain Tumor Center
Ann & Robert H. Lurie Children’s Hospital of Chicago
Professor and Vice-chair, Department of Neurosurgery
Northwestern University Feinberg School of Medicine
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).
iSTAR AT/RT mission is to leverage state of the art multidisciplinary scientific approaches aiming to gain 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.
Read Dr. Sredni's blog here.
What is Rhabdoid Tumor Predisposition Syndrome?
Rhabdoid Tumor Predisposition Syndrome (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: atipical teratoid rhabdoid tumors (AT/RT) of the brain, rhabdoid tumors of the kidney (RTK) or malignant rhabdoid tumors (MRT) of other locations.
In other words:
The vast majority of rhabdoid tumors present with “defects” (or mutations) in a gene calledSMARCB1/INI1. The SMARCB1/INI1 gene is a tumor suppressor gene.
What 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 SMARB1/INI1 gene occur only in the tumor, but not in other cells in the rest of the body.
What if the parents carry the mutation?
In rhabdoid tumor predisposition syndrome, a child may receive a “defective” copy of theSMARCB1/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 patient doesn’t always inherit the mutated SMARCB1/INI1 gene from parents.
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.
How do we know if a child has RTPS and if the mutation was inherited or “de novo”?
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:
(1) 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.
(2) 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.
(3) 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.
(4) 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.
Biegel, J. A. (2006). Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurgical focus 20, E11.
Biegel, J. A., Fogelgren, B., Wainwright, L. M., Zhou, J. Y., Bevan, H. and Rorke, L. B. (2000). Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes, chromosomes & cancer 28, 31-37.
Bourdeaut, F., Lequin, D., Brugieres, L., Reynaud, S., Dufour, C., Doz, F., Andre, N., Stephan, J. L., Perel, Y., Oberlin, O., et al. (2011). Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clinical cancer research : an official journal of the American Association for Cancer Research 17, 31-38.
Bruggers, C. S., Bleyl, S. B., Pysher, T., Barnette, P., Afify, Z., Walker, M. and Biegel, J. A. (2011). Clinicopathologic comparison of familial versus sporadic atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system. Pediatric blood & cancer 56, 1026-1031.
Eaton, K. W., Tooke, L. S., Wainwright, L. M., Judkins, A. R. and Biegel, J. A. (2011). Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatric blood & cancer 56, 7-15.
Want to Get Involved?
If you have a child with a Rhabdoid tumor and want to learn how to participate in our studies, please contact Dr. Sredni directly at email@example.com / firstname.lastname@example.org.
If you would like to contribute, please contact Johanna Wheaton at email@example.com.
Sredni ST, Patel K, Costa FD, Bonaldo MF. Activation of ErbB2- ErbB3 signaling pathway supports potential therapeutic activity of ErbB inhibitors in AT/RT. J Neurooncol. 2014 Feb 27. [Epub ahead of print]
Sredni ST, Halpern AL, Hamm CA, Bonaldo Mde F, Tomita T. Histone deacetylases expression in atypical teratoid rhabdoid tumors. Childs Nerv Syst. 2013 Jan;29(1):5-9. Epub 2012 Nov 10.
Sredni ST, Huang CC, Bonaldo Mde F, Tomita T. MicroRNA expression profiling for molecular classification of pediatric brain tumors. Pediatr Blood Cancer. 2011 Jul 15;57(1):183-4. Epub 2011 Mar 21.
Gadd S*, Sredni ST*, Huang CC, Perlman EJ; Renal Tumor Committee of the Children's Oncology Group. Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. Lab Invest. 2010 May;90(5):724-38. Epub 2010 Mar 8. *Shared first authorship.
Sredni ST, Bonaldo Mde F, Costa FF, Huang CC, Hamm CA, Rajaram V, Tomita T, Goldman S, Bischof JM, Soares MB. Upregulation of mir-221 and mir-222 in atypical teratoid/rhabdoid tumors: potential therapeutic targets. Childs Nerv Syst. 2010 Mar;26(3):279-83. Epub 2009 Dec 10.
Grupenmacher AT, Halpern AL, Bonaldo MD, Huang CC, Hamm CA, de Andrade A, Tomita T, Sredni ST. Study of the gene expression and microRNA expression profiles of malignant rhabdoid tumors originated in the brain (AT/RT) and in the kidney (RTK). Childs Nerv Syst. 2013 Sep 3.
Sredni ST, Huang CC, Halpern AL, Pundy T, Andrade A, Bonaldo MF, Tomita T. A Gene Signature to Identify Long-Survival Atypical Teratoid/Rhabdoid Tumors (AT/RT). To the 45th Congress of the International Society for Pediatric Oncology (SIOP) – Hong Kong 2013. Best Poster Award.
Sredni ST, Halpern AL, Huang CC, Costa FA, Bezerra SM, Hamm CA, Szany EV, Chou PM, Soares FA, Bonaldo MF, Tomita T. Activation of ErBb2-Erbb3 Signaling Pathway in Atypical Teratoid/Rhabdoid Tumors (AT/RT): Potential Therapeutic Targets. To the 45th Congress of the International Society for Pediatric Oncology (SIOP) – Hong Kong 2013
Sredni ST, Bonaldo MF, Grupenmacher AT, Goldman S, Soares MB, Tomita T. New potential therapeutic targets for Atypical Theratoid Rahbdoid Tumors (AT/RT). In: 44th meeting of the International Society for Pediatric Oncology (SIOP) – London October 2012. Pediatric Blood and Cancer 59 (6):1080.
Grupenmacher AT, Huang CC, Bonaldo MF, Andrade A, Soares MB, Tomita T, Sredni ST. Study of the gene expression and microRNA expression profiles of Malignant Rhabdoid Tumors originated in the kidney (RTK) and in the brain (AT/RT). In: the XXVII Congresso de la Sociaedad Latinoamericana de Patologia (Congress of the Latin-American Society of pathology). Maceió, Brazil (October, 2011) – Best research project award. Also presented at CMRC’s Research Scholar’s Day (April 26, 2012)
Halpern AL, Bonaldo MF, Hamm CA, Huang CC, Andrade A, Costa FF, Bischoff J, Goldman S, Soares MB, Tomita T, Sredni ST. Study of the gene expression and microRNA expression profiles of a case of Atypical Teratoid Rhabdoid Tumor (AT/RT) that initially responded to therapy. In: the XXVII Congresso de la Sociaedad Latinoamericana de Patologia (Congress of the Latin-American Society of pathology). Maceió, Brazil (October, 2011). Also presented at the 8th Northwestern University’s Annual Lewis Landsberg Research day (April 5, 2012) and at CMRC’s Research Scholar’s Day (April 26, 2012)
Sredni ST, Costa F, Hamm CA, Huang CC, Bonaldo MF, Bishop J, Tomita T, Goldman S, Rajaram V, Soares MB. Regulation of the cell-cycle inhibitor p27KIP1 by mir-221 and mir-222 in Pediatric Brain Tumors. Annual meeting of the Society for Pediatric Pathology (March, 2009 – Boston, MA). Modern Pathol 22(2):S22,2009
Sredni ST, Gadd S, Huang CC, Perlman EJ and the Renal Tumor Committee of The Children’s Oncology Group. Rhabdoid Tumors: Gene Expression Patterns Provide Clues to the Cell of Origin, Pathogenesis and Potential Therapeutic Targets. In: 13th International Symposium of Pediatric Neuro-Oncology (ISPNO) – Chicago, IL. USA. 06/29/2008 to 07/02/2008. Neuro-Oncology, 10(3), p388, 2008
Sredni ST, Costa F, Huang CC, Bonaldo MF, Bischof J, Tomita T, Goldman S, Rajaram V, Soares MB. Study of expression pattern from 365 microRNAs in Atypical Teratoid-Rhabdoid tumors. A comparison with Medulloblastomas. In: 40th Meeting of the International Society of Pediatric Oncology (SIOP) – Berlin, Germany. From 10/02/2008 to 10/06/2008
Sredni ST. Searching new therapeutic targets for Malignant Rhabdoid Tumors. XV International Conference on Investigative Pathology. São Paulo, Brazil (August 08-11, 2012
Sredni ST. Advanced Molecular Pathology: Epigenetic mechanisms of regulation of aggressive behavior in Malignant Rhabdoid Tumors. XXVII Congresso de la Sociaedad Latinoamericana de Patologia (Congress of the Latin-American Society of Pathology). Maceió, Brazil (October, 2011)
Book chapter on AT/RT
Sredni ST, Lulla RR. Atypical Teratoid/Rhabdoid Tumors. In: Tumors of the Central Nervous System. (Ed) Hayat MA, Springer Company, New York, NY. Chapter 2 (p13-25).