title: Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease.
abstract: Erdheim-Chester disease (ECD) is a rare histiocytic disorder that is challenging to diagnose and treat. We performed molecular analysis of BRAF in the largest cohort of ECD patients studied to date followed by N/KRAS, PIK3CA, and AKT1 mutational analysis in BRAF wild-type patients. Forty-six of 80 (57.5%) of patients were BRAFV600E-mutant. NRAS mutations were detected in 3 of 17 ECD BRAFV600E wild-type patients. PIK3CA mutations (p.E542K, p.E545K, p.A1046T, and p.H1047R) were detected in 7 of 55 patients, 4 of whom also had BRAF mutations. Mutant NRAS was present in peripheral blood CD14(+) cells, but not lymphoid cells, from an NRASQ61R mutant patient. Our results underscore the central role of RAS-RAF-MEK-ERK activation in ECD and identify an important role of activation of RAS-PI3K-AKT signaling in ECD. These results provide a rationale for targeting mutant RAS or PI3K/AKT/mTOR signaling in the subset of ECD patients with NRAS or PIK3CA mutations.
authors.affiliation: Unité de Recherche EA 4340, Versailles University, Boulogne, France; Pathology Department, Ambroise Paré Hospital, Assistance Publique - Hôpitaux de Paris, Boulogne, France;
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Eli L
authors.initials: EL
authors.lastname: Diamond
authors.affiliation: Unité de Recherche EA 4340, Versailles University, Boulogne, France; Pathology Department, Ambroise Paré Hospital, Assistance Publique - Hôpitaux de Paris, Boulogne, France;
authors.forename: Zofia
authors.initials: Z
authors.lastname: Hélias-Rodzewicz
authors.affiliation: Department of Internal Medicine & French Reference Center for Rare Auto-immune & Systemic Diseases, Hôpital Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; Pierre and Marie Curie University, Paris, France;
authors.forename: Fleur
authors.initials: F
authors.lastname: Cohen-Aubart
authors.affiliation: Pierre and Marie Curie University, Paris, France; Department of Pathology, Hôpital Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris, France;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charlotte
authors.affiliation: Experimental Therapeutics Unit and.
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Minal
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel;
authors.forename: Chezi
authors.initials: C
authors.lastname: Ganzel
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Shlomzion
authors.initials: S
authors.lastname: Aumann
authors.affiliation: Unité de Recherche EA 4340, Versailles University, Boulogne, France; Pathology Department, Ambroise Paré Hospital, Assistance Publique - Hôpitaux de Paris, Boulogne, France;
authors.forename: Gladwys
authors.initials: G
authors.lastname: Faucher
authors.affiliation: Unité de Recherche EA 4340, Versailles University, Boulogne, France; Pathology Department, Ambroise Paré Hospital, Assistance Publique - Hôpitaux de Paris, Boulogne, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Le Gall
authors.affiliation: Université Paris-Est Créteil, Créteil, France; Department of Pathology, Hospital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France;
authors.forename: Karen
authors.initials: K
authors.lastname: Leroy
authors.affiliation: Department of Pathology and.
authors.forename: Magali
authors.initials: M
authors.lastname: Colombat
authors.affiliation: Department of Internal Medicine, Foch Hospital, Suresne, France;
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Kahn
authors.affiliation: Department of Internal Medicine, Ambroise Paré Hospital, Assistance Publique - Hôpitaux de Paris, Boulogne, France;
authors.forename: Salim
authors.initials: S
authors.lastname: Trad
authors.affiliation: Université Paris Sorbonne Cité, INSERM, Paris, France; and.
authors.forename: Philippe
authors.initials: P
authors.lastname: Nizard
authors.affiliation: Unité de Recherche EA 4340, Versailles University, Boulogne, France; Department of Pediatrics & French Reference Center for Langerhans Cell Histiocytosis, Trousseau Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Donadieu
authors.affiliation: Université Paris Sorbonne Cité, INSERM, Paris, France; and.
authors.forename: Valérie
authors.initials: V
authors.lastname: Taly
authors.affiliation: Department of Internal Medicine & French Reference Center for Rare Auto-immune & Systemic Diseases, Hôpital Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; Pierre and Marie Curie University, Paris, France;
authors.forename: Zahir
authors.initials: Z
authors.lastname: Amoura
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Omar
authors.identifier: http://orcid.org/0000-0002-3907-6171
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Department of Internal Medicine & French Reference Center for Rare Auto-immune & Systemic Diseases, Hôpital Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; Pierre and Marie Curie University, Paris, France;
authors.forename: Julien
authors.initials: J
authors.lastname: Haroche
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D031249:Erdheim-Chester Disease / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D006644:Histiocytes / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012008:Recurrence; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins