Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumour

14 Jan 2011

Malignant rhabdoid tumour is a rare and aggressive type of paediatric cancer characterised by the presence of large, undifferentiated cells with abundant, eosinophilic cytoplasm and large nucleoli. It often affects the kidneys, and was originally classified as a type of Wilms tumour, but is now known to occur in other parts of the body including the CNS. Prognosis is generally poor, particularly so when the disease is diagnosed during the first months of life.

In more than 80% of analysed cases, this cancer arises from the inactivation of the tumour suppressor gene hSNF5/INI1. Although most cases appear sporadic, a familial rhabdoid predisposition syndrome (RPS) has been identified and linked to the germline inactivation of one copy of this gene.

A large group of mainly French researchers, led by Olivier Delattre at the Institut Curie in Paris, has now investigated the prevalence of this germline mutation in a large cohort of apparently sporadic rhabdoid tumour patients.

The cohort sampled was derived from 115 rhabdoid tumours with no familial link and known loss of hSNF5/INI1expression, sent to the Institut Curie for analysis since 1999. Constitutional DNA and informed consent was available in seventy-four cases, which were used for further analysis.

DNA was extracted from frozen tumour samples and peripheral blood, and the hSNF5/INI1 region sequenced using the Sanger method. Mutation type and the presence or absence of constitutional mutations was correlated with clinical data including age at diagnosis, tumour location and outcome.

The inactivation of both copies of the hSNF5/INI1gene was confirmed in all the 74 cases studied, and a single germline mutation was detected in 26 (35%) of these: a higher proportion than had previously been assumed. DNA samples from forty of the parents of these patients with germline mutations were tested, and no mutations were found. Genetic counseling and prenatal testing was offered in 13 subsequent pregnancies of parents of germline mutation carriers, with one fetus testing positive for a mutation.

The parents in three families with more than one affected sibling not included in the original sample were also tested, and a germline mutation was discovered in one unaffected mother. Including these familial cases in the statistical analysis, children with germline mutations were found to have been diagnosed at an earlier age (median 6 months) than those without (median 11 months), although with some outliers: one germline case was diagnosed at over twenty years of age. There was no statistically significant difference in tumour location between the cases with germline mutations and those without.

Overall, two-year survival was poorer in the cases with germline mutations, but this difference was mainly due to the previously documented difference in prognosis with age at diagnosis.

Delattre and his colleagues conclude that germline mutations in this cancer are relatively frequent, and that although these are most often found in patients diagnosed at very young ages, this is not invariable. They suggest that DNA testing and genetic counseling should be made available to all families with affected children, and that prenatal testing should be considered in subsequent pregnancies if a germline mutation is found.


Bourdeaut, F., Lequin, D., Brugières, L. and 23 others (2011) Frequent hSNF5/INI1 Germline Mutations in Patients with Rhabdoid Tumor Clin Cancer Res 17: 31-38 doi:10.1158/1078-0432.CCR-10-1795