Germline nonsense-mutations of the SMARCB1 gene in Russian patients with rhabdoid renal tumors

The malignant rhabdoid tumor (RT) is one of the most aggressive childhood neoplasm. RTs are characterized by the presence of inactivating mutations in the SMARCB1 (hSNF5/INI1/BAF47) gene – a tumor suppressor localized in 22q11.2. Up to 30 % of RTs caused by germline mutations of this gene, to date those cases are considered as a manifestation of the rhabdoid tumor predisposition syndrome type 1 (RTPS1). We have analyzed the SMARCB1 mutations by polymerase chain reaction and subsequent Sanger sequencing in 18 patients with RT in different localizations for improving of genetic laboratory diagnostics of the RTPS1, as well as searching of genotype-phenotype correlations in this disease. Three patients had de novo nonsense-mutations c.157C→T (p.R53*), c.669_670del (p.C223*) and c.843G→A (p.W281*), confirming RTPS1, which were associated with RT in the kidney, early age at diagnosis (median 2.6 months) and poor prognosis. Identification of germline SMARCB1 mutations in the patients with RTs is essential to assess the risk of metachronous tumors and for genetic counseling of other family members.

malignant rhabdoid tumor, SMARCB1 gene, nonsense-mutation, sequencing, renal tumor

1. Van den Heuvel-Eibrink M.M., van Tinteren H., Rehorst H. et al. Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: a report of the SIOP renal tumour study group. Pediatr Blood Cancer 2011;56(5):733–7. DOI: 10.1002/pbc.22922. PMID: 21370404.

2. Heck J.E., Lombardi C.A., Cockburn M. et al. Epidemiology of rhabdoid tumors of early childhood. Pediatr Blood Cancer 2013;60(1):77–81. DOI: 10.1002/pbc.24141. PMID: 22434719.

3. Fernandez C., Bouvier C., Sevenet N. et al. Congenital disseminated malignant rhabdoid tumor and cerebellar tumor mimicking medulloblastoma in monozygotic twins. pathologic and molecular diagnosis. Am J Surg Pathol 2002;26(2):266–70. PMID: 11812951.

4. Kieran M.W., Roberts C.W., Chi S.N. et al. Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors. Pediatr Blood Cancer 2012;59(7):1155–7. DOI: 10.1002/pbc.24315. PMID: 22997201.

5. Witkowski L., Lalonde E., Zhang J. et al. Familial rhabdoid tumor “avant la lettre” – from pathology review to exome sequencing and back again. J Pathol 2013;231(1):35–43. DOI: 10.1002/path.4225. PMID: 23775540.

6. Schneppenheim R., Fruhwald M.C., Gesk S. et al. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 2010;86(2):279–84. DOI: 10.1016/j.ajhg.2010.01.013. PMID: 20137775.

7. Biegel J.A., 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 2002;8(11):3461–7. PMID: 12429635.

8. Bourdeaut F., Lequin D., Brugieres L. et al. Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res 2011;17(1):31–8. DOI: 10.1158/1078-0432.CCR-10-1795. PMID: 21208904.

9. Teplick A., Kowalski M., Biegel J.A., Nichols K.E. Educational paper: screening in cancer predisposition syndromes: guidelines for the general pediatrician. Eur J Pediatr 2011;170(3):285–94. DOI: 10.1007/s00431-010-1377-2. PMID: 21210147.

10. Gigante L., Paganini I., Frontali M. et al. Rhabdoid tumor predisposition syndrome caused by SMARCB1constitutional deletion: prenatal detection of new case of recurrence in siblings due to gonadal mosaicism. Fam Cancer 2016;15(1):123–6. DOI: 10.1007/s10689-015-9836-6. PMID: 26342593.

11. Biegel J.A., Busse T.M., Weissman B.E. SWI/SNF chromatin remodeling complexes and cancer. Am J Med Genet C Semin Med Genet 2014;166C(3):350–66. DOI: 10.1002/ajmg.c.31410. PMID: 25169151.

12. Johansson G., Andersson U., Melin B. Recent developments in brain tumor predisposing syndroms. Acta Oncol 2016;55(4):401–11. DOI: 10.3109/0284186X.2015.1107190. PMID: 26634384.

13. Bartelheim K., Sumerauer D., Behrends U. et al. Clinical and genetic features of rhabdoid tumors of the heart registered with the European Rhabdoid Registry (EU-RHAB). Cancer Genet 2014;207(9):379–83. DOI: 10.1016/j.cancergen.2014.04.005. PMID: 24972932.

14. Sredni S.T., Tomita T. Rhabdoid tumor predisposition syndrome. Pediatr Dev Pathol 2015;18(1):49–58. DOI: 10.2350/14-07-1531-MISC.1. PMID: 25494491.

15. Dagar V., Chow C.W., Ashley D.M., Algar E.M. Rapid detection of SMARCB1 sequence variation using high resolution melting. BMC Cancer 2009;9:437. DOI: 10.1186/1471-2407-9-437. PMID: 20003390.

16. Fujisawa H., Takabatake Y., Fukusato T. et al. Molecular analysis of the rhabdoid predisposition syndrome in a child: a novel germline hSNF5/INI1 mutation and absence of c-myc amplification. J Neurooncol 2003;63(3):257–62. PMID: 12892231.

17. Hasselblatt M., Isken S., Linge A. et al. High-resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors. Genes Chromosomes Cancer 2013;52(2):185–90. DOI: 10.1002/gcc.22018. PMID: 23074045.

18. Eaton K.W., Tooke L.S., Wainwright L.M. et al. Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 2011;56(1):7–15. DOI: 10.1002/pbc.22831. PMID: 21108436.

19. Sevenet N., Lellouch-Tubiana A., Schofield D. et al. Spectrum of hSNF5/ INI1 somatic mutations in human cancer and genotype-phenotype correlations. Hum Mol Genet 1999;8(13):2359–68. PMID: 10556283.

20. Jackson E.M., Sievert A.J., Gai X. et al. Genomic analysis using high-density single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors. Clin Cancer Res 2009;15(6):1923–30. DOI: 10.1158/1078-0432.CCR-08-2091. PMID: 19276269.

21. Kim K.H., Roberts C.W. Mechanisms by which SMARCB1 loss drives rhabdoid tumor growth. Cancer Genet 2014;207(9):365–72. DOI: 10.1016/j.cancergen.2014.04.004. PMID: 24853101.