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Blood. 2014 Nov 6;124(19):3016-9. doi: 10.1182/blood-2014-04-570937. Epub 2014 Aug 22.

Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease.

Author information

1
Unité de Recherche EA 4340, Versailles University, Boulogne, France; Pathology Department, Ambroise Paré Hospital, Assistance Publique - Hôpitaux de Paris, Boulogne, France;
2
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY;
3
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;
4
Pierre and Marie Curie University, Paris, France; Department of Pathology, Hôpital Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris, France;
5
Experimental Therapeutics Unit and.
6
Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY;
7
Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel;
8
Université Paris-Est Créteil, Créteil, France; Department of Pathology, Hospital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Créteil, France;
9
Department of Pathology and.
10
Department of Internal Medicine, Foch Hospital, Suresne, France;
11
Department of Internal Medicine, Ambroise Paré Hospital, Assistance Publique - Hôpitaux de Paris, Boulogne, France;
12
Université Paris Sorbonne Cité, INSERM, Paris, France; and.
13
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.

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.

PMID:
25150293
PMCID:
PMC4224196
DOI:
10.1182/blood-2014-04-570937
[Indexed for MEDLINE]
Free PMC Article

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