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13 High Prevalence of Epigenetic Mutations in Histiocytic and Dendritic Cell Disorders: Results from Molecular Analysis of a Large Cohort from Histiocytosis Working Group

Program: Oral and Poster Abstracts
Type: Oral
Session: 201. Granulocytes, Monocytes, and Macrophages II
Hematology Disease Topics & Pathways:
Research, adult, Translational Research, genomics, bioinformatics, Diseases, Biological Processes, Technology and Procedures, Study Population, Human
Saturday, December 10, 2022: 9:30 AM

Gaurav Goyal, MD1,2, Jithma P. Abeykoon, MD3, Aldo A. Acosta Medina, MD4, Karen Rech, MD5*, Saurabh Zanwar3, Aishwarya Ravindran, MBBS3,6, Gordon Ruan, MD3*, Matthew Koster, MD7*, W. Oliver Tobin, MB BCh8*, Robert Vassallo, MD9*, Jay Ryu, MD9*, N. Nora Nora Bennani, MD3, Mithun V. Shah, MD, PhD3, Liuyan Jiang, MD10, Lucinda Gruber, MD11*, Caroline J Davidge-Pitts, MBBCh12*, Xiaosheng Wu, MD3*, Jason R. Young, MD13*, Colton M McNinch14*, Ronald Go, MD3 and Surendra Dasari, PhD15*

1Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
2Research Collaborator (limited-tenure), Division of Hematology, Mayo Clinic, Birmingham, AL
3Division of Hematology, Mayo Clinic, Rochester, MN
4Department of Internal Medicine, Mayo Clinic, Rochester, MN
5Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
6Division of Laboratory Medicine, University of Alabama at Birmingham, Birmingham, AL
7Division of Rheumatology, Mayo Clinic, Rochester, MN
8Department of Neurology, Mayo Clinic, Rochester, MN
9Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
10Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL
11Endocrinology and Metabolism, Mayo Clinic, Rochester, MN
12Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN
13Department of Radiology, Mayo Clinic, Jacksonville, FL
14Mayo Clinic, Rochester, MN
15Department of Quantitative Health Sciences, Rochester


Over the last decade, recurrent oncogenic alterations in the MAPK/ERK pathway have been discovered in various histiocytic and dendritic cell disorders, especially Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD). These discoveries have led to the successful use of targeted BRAF- and MEK-inhibitors. However, most data are derived from small institutional studies mostly focusing on ECD and LCH, which leaves room for a comprehensive evaluation of the molecular underpinnings in a large cohort.


Formalin-fixed paraffin embedded tumor biopsies from various histiocytic/dendritic cell disorders seen at a tertiary institution from 2001-2021 were subjected to whole exome sequencing (WES) using one of two assays: in-house SureSelectXT AllExon V5+UTR or commercially available Tempus xT assay. Identified variants were filtered to remove polymorphic, low coding impact and low read coverage variants. A variant was then selected for further analysis if it met one of the following criteria: 1) observed as somatic in ≥1 tumor-germline pairs or COSMIC database or 2) observed in at least three samples with an allele frequency of ≥10% in ≥1 sample. Cases were clustered into mutually exclusive groups based on their primary driver mutational profile using the following funneling order: BRAF-V600E (BRAF-V600E mutations), BRAF*/NRAS/KRAS (BRAF non-V600E, KRAS, or NRAS mutations), CSF1R (CSF1R mutations), MAPK (MAPK/MEK mutations), and PI3K (AKT3, INPP4B, MTOR, PIK3CA, PIK3R1, PIK3R2, PIK3R3, PPP2R1A, MTR mutations). A cancer specific pathway enrichment was performed on the unknown cases, which identified epigenetic mutations as major pathway alterations observed in the cohort. We also correlated the presence of epigenetic mutations with clinical features and outcomes.


We included 114 cases with histiocytic and dendritic cell disorders in the study. Median age at diagnosis was 51y (IQR 37-64). The disease distribution was as follows: 46 LCH, 20 ECD, 17 RDD, 8 follicular dendritic cell sarcoma (FDCS), 1 adult xanthogranuloma, 12 malignant histiocytosis (MH; including histiocytic and Langerhans cell sarcoma), and 10 multicentric reticulohistiocytosis (MRH). Based on the known driver mutations in histiocytoses, the following 5 molecular groups were identified: BRAF-V600E (n= 19, 17%), BRAF*/KRAS/NRAS (n=17, 15%), MAPK (n=14, 12%), PI3K (n=8, 7%), CSF1R (n=2, 2%) (Figure 1). A large proportion (n=48, 42%) did not have any of the known driver mutations, while 6 cases (5%) had no alterations identified. Cancer-specific enrichment analysis in the entire cohort revealed mutations in epigenetic genes in 47 (41%) cases, including 30 (26%) cases with identifiable driver mutations and 17 (15%) cases without known driver mutations. Median number of epigenetic mutations was 1 (range 1-11); 21% cases had 2 and 10% cases had 3 epigenetic mutations, respectively. The most common epigenetic mutations included those in KMT2C (34%), KMT2D (23%), and ARID1A (19%).

The mutational groups with highest prevalence of epigenetic mutations were CSF1R (100%), MAPK (71%), and PI3K (63%), while lowest prevalence of these alterations was found in BRAF-V600E group (16%; p=0.0003). The epigenetic gene mutations were seen more commonly in MRH (90%) and MH (50%) compared with ECD (45%), RDD (41%), FDCS (38%), and LCH (33%; p=0.037). There was no association between epigenetic gene mutations and age at diagnosis or organ involvement. The median overall survival (OS) was not significantly different between those with epigenetic mutations and those without such alterations (22y vs. 17y, p=0.89).


In this large study of patients with diverse histiocytic and dendritic cell disorders, we found a high prevalence of mutations in epigenetic genes (41%). These mutations were specifically enriched in tumors with non-BRAF-V600E mutations, and in MRH/MH. These data shed light on additional mechanisms of disease pathogenesis, and with available epigenetic therapies, warrant further investigation.

Disclosures: Goyal: UpToDate: Patents & Royalties; SeaGen: Research Funding; 2nd.MD: Consultancy; Viracta Therapeutics: Research Funding; Sutro Biopharma: Research Funding. Vassallo: Bristol Myers Squibb: Research Funding; Sun Pharma: Research Funding; Pfizer: Research Funding. Shah: Astellas: Research Funding; Celgene: Research Funding; Marker Therapeutics: Research Funding.

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