Recurrent Alterations in the MAPK pathway in Sporadic Pyogenic Granuloma of Childhood
Keywords:pyogenic granuloma, targeted sequencing, MAPK pathway
Pyogenic granuloma is one of the most common vascular tumours. The cause of pyogenic granuloma was previously thought to be an inflammatory reaction with consecutive stimulation of endothelial cell proliferation. However, recent studies suggest that pyogenic granuloma may be driven by constitutive activation of the mitogen-activated protein kinase pathway. The aim of this study was to investigate the molecular profile of sporadic pyogenic granuloma of childhood, using a systematic approach scrutinizing potential aberrations within different oncogenic pathways. Within a retrospective setting pyogenic granuloma of 15 patients was analysed by targeted next generation sequencing using the Oncomine Focus Assay, which includes genes of key tumorigenic signalling pathways. Activating mutations were found in 4 out of 15 cases (27%). Two HRAS hotspot mutations (p.Gly13Arg, p.Ala59Thr), 1 BRAF (p.Val600Glu) mutation and a novel, previously not reported, MAP2K1 hotspot mutation (p.Glu203Lys) were identified. It is notable that all of these genes are involved in constitutive mitogen- activated protein kinase signalling. This study increases the range of underlying genetic alterations in pyogenic granuloma by identifying novel oncogenic mutations in crucial mitogen-activated protein kinase pathway genes. The results provide supporting evidence that activated mitogen-activated protein kinase signalling is a key driver in the pathogenesis of pyogenic granuloma, which might be exploited by targeted treatment approaches for selected cases.
Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, et al. Vascular anomalies classification: recommendations From the International Society for the Study of Vascular Anomalies. Pediatrics 2015; 136: e203-e214.
Patrice SJ, Wiss K, Mulliken JB. Pyogenic granuloma (lobular capillary hemangioma): a clinicopathologic study of 178 cases. Pediatr Dermatol 1991; 8: 267-276.
Chen D, Hu XJ, Lin XX, Ma G, Jin YB, Chen H, et al. Nodules arising within port-wine stains: a clinicopathologic study of 31 cases. Am J Dermatopathol 2011; 33: 144-151.
Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 2013; 368: 1971-1979.
Groesser L, Peterhof E, Evert M, Landthaler M, Berneburg M, Hafner C. BRAF and RAS mutations in sporadic and secondary pyogenic granuloma. J Invest Dermatol 2016; 136: 481-486.
Lim YH, Douglas SR, Ko CJ, Antaya RJ, McNiff JM, Zhou J, et al. Somatic activating RAS mutations cause vascular tumors including pyogenic granuloma. J Invest Dermatol 2015; 135: 1698-1700.
Pereira T, de Amorim LSD, Pereira NB, Vitório JG, Duarte-Andrade FF, Guimarães LM, et al. Oral pyogenic granulomas show MAPK/ERK signaling pathway activation, which occurs independently of BRAF, KRAS, HRAS, NRAS, GNA11, and GNA14 mutations. J Oral Pathol Med 2019; 48: 906-910.
Nguyen V, Hochman M, Mihm MC, Jr., Nelson JS, Tan W. The pathogenesis of port wine stain and Sturge Weber syndrome: complex interactions between genetic alterations and aberrant MAPK and PI3K activation. Int J Mol Sci 2019; 20: 2243.
Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 2011; 4: 51.
Cheraghlou S, Lim Y, Choate K. Genetic investigation of childhood vascular tumor biology reveals pathways for therapeutic intervention. F1000Res 2019; 8: 590.
Zeng H, Zhao D, Yang S, Datta K, Mukhopadhyay D. Heterotrimeric G alpha q/G alpha 11 proteins function upstream of vascular endothelial growth factor (VEGF) receptor-2 (KDR) phosphorylation in vascular permeability factor/VEGF signaling. J Biol Chem 2003; 278: 20738-20745.
Lim YH, Bacchiocchi A, Qiu J, Straub R, Bruckner A, Bercovitch L, et al. GNA14 somatic mutation causes congenital and sporadic vascular tumors by MAPK activation. Am J Hum Genet 2016; 99: 443-450.
Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 2017; 23: 703-713.
Lacal JC, Srivastava SK, Anderson PS, Aaronson SA. Ras p21 proteins with high or low GTPase activity can efficiently transform NIH/3T3 cells. Cell 1986; 44: 609-617.
Liau JY, Lee JC, Tsai JH, Chen CC, Chung YC, Wang YH. High frequency of GNA14, GNAQ, and GNA11 mutations in cherry hemangioma: a histopathological and molecular study of 85 cases indicating GNA14 as the most commonly mutated gene in vascular neoplasms. Mod Pathol 2019; 32: 1657-1665.
Patel M, Smyth E, Chapman PB, Wolchok JD, Schwartz GK, Abramson DH, et al. Therapeutic implications of the emerging molecular biology of uveal melanoma. Clin Cancer Res 2011; 17: 2087-2100.
Li Y, Shi J, Yang J, Ge S, Zhang J, Jia R, et al. Uveal melanoma: progress in molecular biology and therapeutics. Ther Adv Med Oncol 2020; 12: 1758835920965852.
Gao Y, Chang MT, McKay D, Na N, Zhou B, Yaeger R, et al. Allele-specific mechanisms of activation of MEK1 mutants determine their properties. Cancer Discov 2018; 8: 648-661.
Nikolaev SI, Rimoldi D, Iseli C, Valsesia A, Robyr D, Gehrig C, et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat Genet 2011; 44: 133-139.
Maik-Rachline G, Hacohen-Lev-Ran A, Seger R. Nuclear ERK: mechanism of translocation, substrates, and role in cancer. Int J Mol Sci 2019; 20: 1194.
Meadows KN, Bryant P, Vincent PA, Pumiglia KM. Activated Ras induces a proangiogenic phenotype in primary endothelial cells. Oncogene 2004; 23: 192-200.
Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell 2018; 173: 321-37.e10.
Jansen P, Müller H, Lodde GC, Zaremba A, Möller I, Sucker A, et al. GNA14, GNA11, and GNAQ mutations are frequent in benign but not malignant cutaneous vascular tumors. Front Genet 2021; 12: 663272.
Zhu H, Blake S, Kusuma FK, Pearson RB, Kang J, Chan KT. Oncogene-induced senescence: from biology to therapy. Mech Ageing Dev 2020; 187: 111229.
Li G, Adams E, Eshleman JR, Eberhart CG. No BRAF V600E mutation identified in 28 periocular pyogenic granuloma. Ophthalmic Plast Reconstr Surg 2018; 34: 525-527.
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Copyright (c) 2022 Katharina Strobel, Katja Maurus, Henning Hamm, Sabine Roth, Matthias Goebeler, Andreas Rosenwald, Marion Wobser
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