Cutaneous epithelioid haemangiomas show somatic mutations in the mitogen‐activated protein kinase pathway

Abstract

Summary Background Epithelioid haemangioma (EH) arising from the skin is a benign vascular tumour with marked inflammatory cell infiltration, which exhibits a high tendency to persist and frequently recurs after resection. So far, the underlying pathogenesis is largely elusive. Objectives To identify genetic alterations by next‐generation sequencing and/or droplet digital polymerase chain reaction (ddPCR) in cutaneous EH. Methods DNA and RNA from an EH lesion of an index patient were subjected to whole‐genome and RNA sequencing. Multiplex PCR‐based panel sequencing of genomic DNA isolated from archival formalin‐fixed paraffin‐embedded tissue of 18 patients with cutaneous EH was performed. ddPCR was used to confirm mutations. Results We identified somatic mutations in genes of the mitogen‐activated protein kinase (MAPK) pathway (MAP2K1 and KRAS) in cutaneous EH biopsies. By ddPCR we could confirm the recurrent presence of activating, low‐frequency mutations affecting MAP2K1. In total, nine out of 18 patients analysed showed activating MAPK pathway mutations, which were mutually exclusive. Comparative analysis of tissue areas enriched for lymphatic infiltrate or aberrant endothelial cells, respectively, revealed an association of these mutations with the presence of endothelial cells. Conclusions Taken together, our data suggest that EH shows somatic mutations in genes of the MAPK pathway which might contribute to the formation of this benign tumour.

VEGF Pathway Gene Expression Profile of Proliferating versus Involuting Infantile Hemangiomas: Preliminary Evidence and Review of the Literature

“…Most of other MAPK family members were downregulated for both involuting and proliferating hemangioma except MAP2K1 which was found to be upregulated for both types of our hemangioma. Compared with the previously discussed upregulated genes (AKT1 and MAPK14) which have not yet been reported as having an involvement in hemangioma pathogenesis, MAP2K1 is highly present in several papers focused on vascular malformations [ 39 , 40 , 41 ] as a gene having somatic mutation associated with vascular malformation. Most of the papers reporting MAP2K1 somatic mutation frequently associated KRAS mutation [ 39 , 40 , 41 ] and HRAS mutation [ 42 ].…”

“…Compared with the previously discussed upregulated genes (AKT1 and MAPK14) which have not yet been reported as having an involvement in hemangioma pathogenesis, MAP2K1 is highly present in several papers focused on vascular malformations [ 39 , 40 , 41 ] as a gene having somatic mutation associated with vascular malformation. Most of the papers reporting MAP2K1 somatic mutation frequently associated KRAS mutation [ 39 , 40 , 41 ] and HRAS mutation [ 42 ]. We also found an upregulation of KRAS and HRAS genes for both involuting and proliferating hemangioma.…”

From FOS fusions to somatic mutations in the MAPK pathway, heterogeneous genetic abnormalities cause distinct pathophysiology among subsets of epithelioid haemangiomas

“…In this issue of the BJD , Maurus et al . report various somatic mutations in MAP2K1 and KRAS in cutaneous EH, which resulted in an enhanced MAPK pathway 8 . These somatic mutations may account for distinct pathological mechanisms underlying the development of cutaneous EH where FOS gene fusions are absent.…”

“…These mutations occur in 50% of patients across all three EH subsets: typical, cellular and ALHE. The mutation allele frequency ranged from 1·5% to 6·2% 8 . As a pathological readout of these mutations, a strong activation of the MAPK pathway and subsequently morphological changes in endothelial cells was observed 8 …”

“…Maurus et al . suggest that epithelioid endothelial cells carry the mutations but lymphocytes do not 8 . As a result of the low frequencies of these mutations, it is reasonably posited that only a very few epithelioid endothelial cells carry the mutations.…”