title: Acute lymphoblastic leukemia in the context of RASopathies.
abstract: 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.
authors: INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne-Paris-Cité, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France. Electronic address: helene.cave@aphp.fr.
authors: Hélène
authors: H
authors: Cavé
authors: INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne-Paris-Cité, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France.
authors: Aurélie
authors: A
authors: Caye
authors: INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne-Paris-Cité, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France.
authors: Marion
authors: M
authors: Strullu
authors: Hôpital Pellegrin, Hôpital des Enfants, Unité d'Hémato-Oncologie Pédiatrique, Bordeaux, France.
authors: Nathalie
authors: N
authors: Aladjidi
authors: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France.
authors: Cédric
authors: C
authors: Vignal
authors: Hôpital Universitaire des Enfants Reine Fabiola (ULB), Department of Pediatric Onco-Hematology, Brussels, Belgium.
authors: Alice
authors: A
authors: Ferster
authors: The Royal Children's Hospital Melbourne, Children's Cancer Centre, Victoria, Australia.
authors: Françoise
authors: F
authors: Méchinaud
authors: Institut d'Hémato-Oncologie Pédiatrique (IHOP), Département d'Immunologie et Hématologie Pédiatrique Lyon, France.
authors: Carine
authors: C
authors: Domenech
authors: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Armand-Trousseau, Service d'Hématologie Oncologie Pédiatrique, France.
authors: Filomena
authors: F
authors: Pierri
authors: Hôpital d'Enfants de Brabois, Service d'Onco-Hématologie pédiatrique, Vandoeuvre lès Nancy, France.
authors: Audrey
authors: A
authors: Contet
authors: CHU de Montpellier, Hôpital Saint-Eloi, Laboratoire d'Hématologie, Paris, France.
authors: Valère
authors: V
authors: Cacheux
authors: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors: Julie
authors: J
authors: Irving
authors: Pediatric Hematology and Oncology, Hannover, Medical School, Hannover, Germany.
authors: Christian
authors: C
authors: Kratz
authors: National Registry of Childhood Cancers, Villejuif, France; Descartes University Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS-UMR1153), Paris, France.
authors: Jacqueline
authors: J
authors: Clavel
authors: Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Département de Génétique, Paris, France; INSERM UMR 1141, Université Paris Diderot, Sorbonne-Paris-Cité, Paris, France.
authors: Alain
authors: A
authors: Verloes
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D016609:Neoplasms, Second Primary / Q000209:etiology; D009634:Noonan Syndrome / Q000150:complications / Q000235:genetics / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology* / Q000209:etiology* / Q000628:therapy; D015995:Prevalence; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D020837:SOS1 Protein / Q000235:genetics; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020837:SOS1 Protein; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D018631:ras Proteins
keywords: Acute lymphoblastic leukemia; Noonan syndrome; PTPN11; RASopathies; SHP2; SOS1