Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease

J.-F. Emile 1, 2 E. Diamond 3 Z. Helias-Rodzewicz 2, 1 F. Cohen-Aubart 4, 5 F. Charlotte 6 D. Hyman 7 E. Kim 8 R. Rampal 8 M. Patel 8 C. Ganzel 9 S. Aumann 8 G. Faucher 2, 1 C. Le Gall 2, 1 K. Leroy 10 M. Colombat 11 J.-E. Kahn 12 S. Trad 13 P. Nizard 2, 14, 15 J. Donadieu 2 V. Taly 14, 15, * Zahir Amoura 16 O. Abdel-Wahab 8 J. Haroche 17, 5
* Corresponding author
1 Service d'anatomie pathologique
2 Laboratoire épidémiologie et oncogénèse des tumeurs digestives
3 Department of Neurology [New York, NY, USA]
4 Service de médecine interne [CHU Pitié-Salpétrière]
5 Centre de référence français pour les maladies auto-immunes et systémiques rares [Hôpital Pitié-Salpêtrière - APHP]
6 Service d’anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière]
7 Experimental Therapeutics Unit [New York, NY, USA]
8 Human Oncology and Pathogenesis Program and Leukemia Service [New York, NY, USA]
9 Department of Hematology [Jerusalem, Israel]
10 Département de pathologie [Mondor]
11 Service de Pathologie [Hôpital Foch]
12 Service de Médecine Interne [Hôpital Fosh, Suresnes]
13 Service de Médecine Interne [AP-HP Hôpital Ambroise Paré]
14 MEPPOT - U1147 - Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique
15 SU - Sorbonne Université
16 Institut E3M [CHU Pitié-Salpêtrière]
17 Service de Médecine Interne [CHU HEGP]
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.
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UPEC-UPEM | UVSQ | UPMC | UNIV-PARIS5 | USPC | SORBONNE-UNIVERSITE | UPEC

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J.-F. Emile, E. Diamond, Z. Helias-Rodzewicz, F. Cohen-Aubart, F. Charlotte, et al.. Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease. Blood, American Society of Hematology, 2014, 124 (19), pp.3016-3019. ⟨10.1182/blood-2014-04-570937⟩. ⟨inserm-02299579⟩

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