Human Cancer Biology Frequent hSNF5/INI1 Germline Mutations in Patients with Rhabdoid Tumor Franck Bourdeaut 1,2 , Delphine Lequin 3 , Laurence Brugieres 4 , Stephanie Reynaud 3 , Christelle Dufour 4 , Fran¸ cois Doz 5,6 , Nicolas Andre 7 , Jean-Louis Stephan 8,9 , Yves Perel 10,11 , Odile Oberlin 4 , Daniel Orbach 5 , Christophe Bergeron 12 , Xavier Rialland 13 , Paul Freneaux 14 , Dominique Ranchere 15 , Dominique Figarella-Branger 16 , Georges Audry 17,18 , Stephanie Puget 6,19 , D. Gareth Evans 20 , Joan Carles Ferreres Pinas 21 , Valeria Capra 22 ,Veronique Mosseri 23 , Isabelle Coupier 24 , Marion Gauthier-Villars 25 , Ga€ elle Pierron 3 , and Olivier Delattre 2,3 Abstract Purpose: Germline hSNF5/INI1 mutations are responsible for hereditary cases of rhabdoid tumors (RT) that constitute the rhabdoid predisposition syndrome (RPS). Our study provides the first precise overview of the prevalence of RPS within a large cohort of RT. Experimental Design: hSNF5/INI1 coding exons were investigated by sequencing and by multiplex ligation-dependent probe amplification. Results: Seventy-four constitutional DNAs from 115 apparently sporadic RT were analyzed from 1999 to 2009. Germline mutations were found in 26 patients (35%). Data from 9 individuals from 5 RPS families (siblings) were also studied. The median age at diagnosis was much lower (6 months) in patients with germline mutation (P < 0.01) than in patients without (18 months). Nevertheless, 7 of 35 patients with germline mutation (20%) developed the disease after 2 years of age. The mutation could be detected in only 1 parent whereas germline blood DNA was wild type in the 20 other parent pairs, therefore indicating the very high proportion of germ-cell mosaicism or of de novo mutations in RPS. The former hypothesis could be clearly documented in 1 case in which prenatal diagnosis was positive in a new pregnancy. Finally, the 2 years’ overall survival was 7% in mutated and 29% in wild-type patients, mainly due to the worse outcome of RT in younger patients. Conclusions: Our results show a high proportion of germline mutations in patients with RT that can be found at any age and up to 60% in the youngest patients. Genetic counseling is recommended given the low but actual risk of familial recurrence. Clin Cancer Res; 17(1); 31–8. Ó2011 AACR. Introduction Rhabdoid tumors (RT) are rare and aggressive tumors of children, initially characterized by the presence of undifferentiated cells with eosinophilic cytoplasmic inclusions, uncondensed chromatin, and large nucleo- lus, defining the rhabdoid phenotype (1). Miscellaneous anatomic locations can be involved. Beckwith et al. first described rhabdoid cells in aggressive renal tumors, therefore individualizing rhabdoid tumors of the kidney (RTK) from Wilms’ tumors (1). Tsuneyoshi et al. extended the observation of a rhabdoid phenotype in soft-part undifferentiated tumors, which were subse- quently named extrarenal malignant rhabdoid tumors (ER-MRT; ref. 2). Finally, Rorke et al. described central nervous system (CNS) tumors of early onset, with high aggressiveness and also harboring rhabdoid cells. Because of their pleomorphic aspect, these CNS tumors were designated as atypical/teratoid rhabdoid tumors (ATRT; ref. 3). Although affecting different parts of the Authors' Affiliations: 1 CHU Nantes, Service d’hemato-oncologie pediatrique, Nantes, 2 INSERM U830, Laboratoire de genetique et biologie des cancers, Paris, 3 Institut Curie, Unite de genetique somatique, Paris, 4 Institut Gustave Roussy, Departement de pediatrie, Villejuif, 5 Institut Curie, Departement de pediatrie, Paris, 6 Universite Paris 5 Rene Descartes, Paris, 7 La Timone, Service d’oncologie pediatrique, Marseille, 8 CHU St Etienne, Service d’hemato-oncologie pediatrique, Hôpital Nord, Saint- Etienne, 9 Universite Saint-Etienne, St-Etienne, 10 CHU Bordeaux, Service d’hemato-oncologie pediatrique, Hôpital Pellegrin, Bordeaux, 11 Universite Bordeaux 2, Bordeaux, 12 Centre Leon Berard, Departement de pediatrie, Loyn, 13 CHU Angers, Service d’hemato-oncologie pediatrique, Angers, 14 Institut Curie, Departement de Pathologie, Paris, 15 Centre Leon Berard, Departement d’anatomie pathologique, Lyon, 16 La Timone, Service d’ana- tomie pathologique, Marseille, 17 Aix-Marseille Universite, Inserm U911, Marseille, 17 Hôpital Armand Trousseau, Service de chirurgie infantile, Paris, 18 Universite Paris 6, Paris, 19 Hôpital Necker-Enfants Malades, Service de neurochirurgie infantile, Paris, France; 20 Genetic Medicine, MAHSC, St Mary's Hospital, Manchester, United Kingdom; 21 Servei d’Anatomia pato- lògica, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 22 U.O. Neu- rochirurgia, Instituto G.Gaslini, Genoa, Italy; 23 Institut Curie, Departement de Biostatistiques, Paris, 24 CHU Montpellier, Service de genetique, Mon- tpellier, and 25 Institut Curie, Departement d’oncogenetique, Paris Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Olivier Delattre, INSERM U830, Laboratoire de genetique et biologie des cancers, Institut Curie, 75248 Paris, Cedex 05, France. Phone: 33156246679; Fax: 33156246630; E-mail: olivier.delattre@curie.fr. doi: 10.1158/1078-0432.CCR-10-1795 Ó2011 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 31 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/17/1/31/1995295/31.pdf by guest on 14 June 2022