PMID- 26855057 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20161230 IS - 1878-0849 (Electronic) IS - 1769-7212 (Linking) VI - 59 IP - 3 DP - 2016 Mar TI - Acute lymphoblastic leukemia in the context of RASopathies. PG - 173-8 LID - S1769-7212(16)30003-9 [pii] LID - 10.1016/j.ejmg.2016.01.003 [doi] AB - Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients. CI - Copyright (c) 2016 Elsevier Masson SAS. All rights reserved. FAU - Cave, Helene AU - Cave H AD - INSERM UMR_S1131, Institut Universitaire d'Hematologie, Universite Paris Diderot, Sorbonne-Paris-Cite, Paris, France; Assistance Publique des Hopitaux de Paris (AP-HP), Hopital Robert Debre, Departement de Genetique, Paris, France. Electronic address: helene.cave@aphp.fr. FAU - Caye, Aurelie AU - Caye A AD - INSERM UMR_S1131, Institut Universitaire d'Hematologie, Universite Paris Diderot, Sorbonne-Paris-Cite, Paris, France; Assistance Publique des Hopitaux de Paris (AP-HP), Hopital Robert Debre, Departement de Genetique, Paris, France. FAU - Strullu, Marion AU - Strullu M AD - INSERM UMR_S1131, Institut Universitaire d'Hematologie, Universite Paris Diderot, Sorbonne-Paris-Cite, Paris, France; Assistance Publique des Hopitaux de Paris (AP-HP), Hopital Robert Debre, Departement de Genetique, Paris, France. FAU - Aladjidi, Nathalie AU - Aladjidi N AD - Hopital Pellegrin, Hopital des Enfants, Unite d'Hemato-Oncologie Pediatrique, Bordeaux, France. FAU - Vignal, Cedric AU - Vignal C AD - Assistance Publique des Hopitaux de Paris (AP-HP), Hopital Robert Debre, Departement de Genetique, Paris, France. FAU - Ferster, Alice AU - Ferster A AD - Hopital Universitaire des Enfants Reine Fabiola (ULB), Department of Pediatric Onco-Hematology, Brussels, Belgium. FAU - Mechinaud, Francoise AU - Mechinaud F AD - The Royal Children's Hospital Melbourne, Children's Cancer Centre, Victoria, Australia. FAU - Domenech, Carine AU - Domenech C AD - Institut d'Hemato-Oncologie Pediatrique (IHOP), Departement d'Immunologie et Hematologie Pediatrique Lyon, France. FAU - Pierri, Filomena AU - Pierri F AD - Assistance Publique des Hopitaux de Paris (AP-HP), Hopital Armand-Trousseau, Service d'Hematologie Oncologie Pediatrique, France. FAU - Contet, Audrey AU - Contet A AD - Hopital d'Enfants de Brabois, Service d'Onco-Hematologie pediatrique, Vandoeuvre les Nancy, France. FAU - Cacheux, Valere AU - Cacheux V AD - CHU de Montpellier, Hopital Saint-Eloi, Laboratoire d'Hematologie, Paris, France. FAU - Irving, Julie AU - Irving J AD - Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK. FAU - Kratz, Christian AU - Kratz C AD - Pediatric Hematology and Oncology, Hannover, Medical School, Hannover, Germany. FAU - Clavel, Jacqueline AU - Clavel J AD - National Registry of Childhood Cancers, Villejuif, France; Descartes University Center of Research in Epidemiology and Statistics Sorbonne Paris Cite (CRESS-UMR1153), Paris, France. FAU - Verloes, Alain AU - Verloes A AD - Assistance Publique des Hopitaux de Paris (AP-HP), Hopital Robert Debre, Departement de Genetique, Paris, France; INSERM UMR 1141, Universite Paris Diderot, Sorbonne-Paris-Cite, Paris, France. LA - eng PT - Journal Article DEP - 20160205 PL - Netherlands TA - Eur J Med Genet JT - European journal of medical genetics JID - 101247089 RN - 0 (SOS1 Protein) RN - EC 3.1.3.48 (PTPN11 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Adolescent MH - Child MH - Child, Preschool MH - Female MH - Genotype MH - Humans MH - Infant MH - Infant, Newborn MH - Male MH - Mutation MH - Neoplasms, Second Primary/etiology MH - Noonan Syndrome/complications/genetics/metabolism MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*epidemiology/*etiology/therapy MH - Prevalence MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics MH - SOS1 Protein/genetics MH - ras Proteins/*genetics/metabolism OTO - NOTNLM OT - Acute lymphoblastic leukemia OT - Noonan syndrome OT - PTPN11 OT - RASopathies OT - SHP2 OT - SOS1 EDAT- 2016/02/09 06:00 MHDA- 2016/12/15 06:00 CRDT- 2016/02/09 06:00 PHST- 2015/12/24 00:00 [received] PHST- 2016/01/13 00:00 [accepted] PHST- 2016/02/09 06:00 [entrez] PHST- 2016/02/09 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - S1769-7212(16)30003-9 [pii] AID - 10.1016/j.ejmg.2016.01.003 [doi] PST - ppublish SO - Eur J Med Genet. 2016 Mar;59(3):173-8. doi: 10.1016/j.ejmg.2016.01.003. Epub 2016 Feb 5.