Rosai–Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation

Shanmugam, Vignesh; Margolskee, Elizabeth; Kluk, Michael J.; Giorgadze, Tamara; Orazi, Attilio

doi:10.1007/s12105-016-0709-6

Cited by 61 publications

(30 citation statements)

References 41 publications

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“…Recently, Diamond et al interrogated 37 patients with BRAF V600E-wild type, non-Langerhans cell histiocytosis histiocytoses by whole exome sequencing and/or RNA sequencing and demonstrated recurrent activating mutations in MAP2K1 (32%), NRAS (16%), KRAS (11%), PIK3CA (8%), and ARAF (3%) in all types of non- Langerhans cell histiocytosis histiocytoses (21), including 8 patients with Rosai-Dorfman disease where 50% harbored mutually exclusive mutations involving KRAS, NRAS or ARAF (21). Another recent single case report identified a KRAS K117N point mutation in a case of Rosai-Dorfman disease (36). In light of these breakthroughs, we hypothesized that activating mutations in the RAS/RAF/MAPK/ERK or related signaling pathways may play a key role in the pathogenesis of Rosai-Dorfman disease.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Langerhans cell histiocytosis (LCH) and Erdheim–Chester disease (ECD) have been associated with mutations and fusions in genes of the mitogen‐activated (MAP) kinase (MAPK) pathway (also known as the MAPK/ERK [extracellular signal‐regulated kinase] pathway), including BRAF, MAP2K1, ARAF, NRAS , and KRAS . Point mutations affecting KRAS, NRAS, SMAD4, ARAF , or MAP2K1 occur in 33% to 50% of RDD cases …”

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confidence: 99%

BRAF mutation leading to central nervous system rosai‐dorfman disease

Richardson

Wachsmann

Oliver

et al. 2018

Annals of Neurology

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Rosai-Dorfman disease (RDD) is an uncommon histiocytic proliferative disorder that can present in nodal, extranodal, or, extremely rarely, in central nervous system (CNS)-restricted form. RDD is characterized histologically as a non-Langerhans cell histiocytosis composed of atypical CD68 /S-100 /CD1a macrophages demonstrating prominent emperipolesis and effacement of the surrounding tissue. Previously thought to represent a reactive process, recent studies have raised the possibility that RDD and other histiocytic lesions, including Erdheim-Chester and Langerhans cell histiocytosis, are clonal processes linked to somatic mutations in the mitogen-activated protein (MAP) kinase pathway. Herein, we present a fatal case of RDD isolated to the CNS and used a next-generation targeted gene panel and Sanger sequencing to uncover a pathogenic deletion in the β3-αC loop of the kinase domain in exon 12 of BRAF. This mutation, previously described in melanoma and Langerhans cell histiocytosis, represents the first BRAF mutation of this kind identified in RDD. These findings support the idea that RDD is a neoplastic condition and raise the possibility that inhibitors of the MAP kinase pathway may be effective in RDD. Ann Neurol 2018;83:147-152.

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“…Also, p-ERK overexpression was detected by immunohistochemistry in all cases harboring MAP2K1 mutation, indicating that mutations in Rosai-Dorfman disease activate the mitogenactivated protein kinase/extracellular regulated kinase (MAPK/ERK) signaling pathway [19]. Others have reported similar mutations and additional NRAS and ARAF mutations in smaller series and case reports [20][21][22][23]. Overall, these findings suggest that mutated cases of Rosai-Dorfman disease are neoplastic and that these mutations can be targeted for therapy, as shown by others [2,21].…”

Section: Introductionmentioning

confidence: 88%

Focal Rosai–Dorfman disease coexisting with lymphoma in the same anatomic site: a localized histiocytic proliferation associated with MAPK/ERK pathway activation

et al. 2019

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Rosai-Dorfman disease is a rare histiocytic disorder shown to have gene mutations that activate the MAPK/ERK pathway in at least one-third of cases. Most patients with Rosai-Dorfman disease present with bulky lymphadenopathy or extranodal disease, but rarely Rosai-Dorfman disease is detected concomitantly with lymphoma in the same biopsy specimen. The underlying molecular mechanisms of focal Rosai-Dorfman disease occurring in the setting of lymphoma have not been investigated. We report 12 cases of Rosai-Dorfman disease and lymphoma involving the same anatomic site. There were five men and seven women (age, 23 to 77 years) who underwent lymph node (n = 11) or skin (n = 1) biopsy; the lymphomas included nodular lymphocyte predominant Hodgkin lymphoma (n = 6), classical Hodgkin lymphoma (n = 4), small lymphocytic lymphoma (n = 1) and extranodal marginal zone lymphoma (n = 1). The foci of Rosai-Dorfman disease in all cases had S100 protein-positive histiocytes undergoing emperipolesis. No patients had Rosai-Dorfman disease at other anatomic sites at initial diagnosis and at last follow-up (median, 40 months). We performed immunohistochemical analysis to assess activity of the MAPK/ERK pathway in the Rosai-Dorfman disease foci. We also micro-dissected disease foci and analyzed 146 genes using next-generation sequencing in four cases with adequate DNA; the panel included genes previously reported to be mutated in Rosai-Dorfman disease. All cases were negative for gene mutations. Nevertheless, all cases were positive for cyclin D1 and most cases showed pERK expression indicating that the MAPK/ERK pathway is active in the histiocytes of focal Rosai-Dorfman disease. We conclude that focal Rosai-Dorfman disease coexisting with lymphoma is a clinically benign and localized histiocytic proliferation. These data also indicate that the MAPK/ERK pathway is active in focal Rosai-Dorfman disease although we did not identify activating mutations. These findings suggest that the pathogenesis of focal Rosai-Dorfman disease is different from that of usual cases of Rosai-Dorfman disease.

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Rosai–Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation

Cited by 61 publications

References 41 publications

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

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

BRAF mutation leading to central nervous system rosai‐dorfman disease

Focal Rosai–Dorfman disease coexisting with lymphoma in the same anatomic site: a localized histiocytic proliferation associated with MAPK/ERK pathway activation

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