Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai–Dorfman disease

Abstract

Rosai-Dorfman disease is a histiocytic disorder with a poorly-defined pathogenesis. Recent molecular studies have revealed recurrent mutations involving genes in the MAPK/ERK pathway in Langerhans cell histiocytosis and Erdheim-Chester disease. However, cases of Rosai-Dorfman disease have rarely been assessed. We performed next-generation sequencing to assess 134 genes on 21 cases of Rosai-Dorfman disease, including 13 women and 8 men with a median age of 43 years (range, 3–82). Thirteen had extranodal, 5 had nodal, and 3 had coexistent nodal and extranodal disease. The head and neck region was the most common area involved (n=7). Mutation analysis detected point mutations in 7 (33%) cases, including KRAS (n=4) and MAP2K1 (n=3). No mutations were identified in ARAF, BRAF, PIK3CA, or any other genes assessed. Immunohistochemistry demonstrated p-ERK overexpression in 3 cases, all harboring MAP2K1 mutations. Patients carrying mutated genes were younger (median age, 10 versus 53 years, p=0.0347) with more pediatric patients (4/7 versus 1/14, p=0.0251). The presence of mutations correlated with location being more common in the head and neck region; 6/7 (86%) mutated versus 1/14 (7%) unmutated cases (p=0.0009). All 5 (100%) mutated cases with available staging information had a multifocal presentation, whereas only 3/11 (27%) unmutated patients had multifocal disease (p=0.0256). Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3). With a median follow-up of 84 months (range, 7–352), 7 remained in clinical remission and 3 had persistent disease. No correlation between mutation status and clinical outcome was noted. In summary, we detected mutually exclusive KRAS and MAP2K1 mutations in one third of cases of Rosai-Dorfman disease suggesting this subgroup are clonal and involve activation of MAPK/ERK pathway. Our data contributes to the understanding of the biology of Rosai-Dorfman disease and points to potential diagnostic and therapeutic targets.

Cyclin D1 expression and novel mutational findings in Rosai‐Dorfman disease

“…Case 1 carried five distinct mutations, three of which involve the MAPK pathway (Table ). Identical mutations in MAP2K1 have been reported in two cases of LCH, with a different mutation at the same residue (c.157T>G p.F53V) previously reported in a single case of RDD (Brown et al , ; Garces et al , ). Nonsense mutations are among the most common types of disease‐associated mutation involving NF1 , with mutations occurring around codon 1152 known to be pathogenic (Ars et al , ).…”

“…This exact variant is a known driver mutation in human colorectal carcinoma (Edkins et al , ). A different mutation at the same residue (c.436G>A, p.A146T) was previously reported in a single case of RDD (Garces et al , ). Case 4 harboured a KRAS c.182A>G p.Q61R mutation (AF = 17%).…”

“…Based on the recent discovery of MAPK pathway mutations in some Rosai‐Dorfman disease (RDD) cases (Garces et al , ), we aimed to determine whether they also express CCND1 by immunohistochemistry. This would not only lend support to the neoplastic nature of RDD and shed light on its pathogenesis, but also provide a useful diagnostic marker for histopathologists, particularly in small biopsies where the diagnostic morphological features may not be fully represented.…”

Sirolimus—A targeted therapy for Rosai‐Dorfman disease

“…Histocytic disorders such as Erdheim‐Chester disease have also shown stabilization with sirolimus therapy . Recent studies have identified KRAS , MAP2K1 , NRAS , and ARAF mutations in patients with RDD, thus implicating a complex pathophysiology, and thus making various targeted therapies for RDD possible …”

Emperipolesis and S100 expression may be seen in cutaneous xanthogranulomas: A multi‐institutional observation

“…O'Malley et al have recently evaluated clonal abnormalities and genetic gains and/or losses in LCH and RDD coexistence, and highlight that these diseases may belong to a spectrum linked by clonal abnormalities 19. Mutually exclusive KRAS and MAP2K1 mutations have been detected in approximately one-third of RDD cases, suggesting MAPK/ERK pathway activation and clonal origin 23. Recently, Ozkaya et al describe the same MAP2K1 mutation detected in a RDD-like testis lesion and Erdheim-Chester disease-like tongue lesion of a patient with known…”