Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Oral Dis. 2020 Mar;26(2):334-340. doi: 10.1111/odi.13241. Epub 2019 Dec 19.
To investigate the molecular pathogenesis of implant-associated peripheral giant cell granuloma (IA-PGCG).
A convenience sample of 15 IA-PGCG cases was selected. Hotspot mutations of KRAS, FGFR1, and TRPV4 genes, previously reported in conventional giant cell lesions of the jaws, were investigated by Sanger sequencing. As these mutations could activate MAPK/ERK pathway, the expression of phospho-ERK1/2 was also evaluated by immunohistochemistry.
KRAS mutations were detected in 8/15 (53.4%) samples. Similar to conventional peripheral giant cell granuloma, the KRAS mutations most frequently occurred in codon 146 (p.A146V, n = 3), followed by codon 12 (p.G12A and p.G12D, n = 1 each) and codon 14 (p.V14L, n = 1). Variants of unknown significance (VUS) were also detected in two cases, affecting codons 37 (p.E37K) and 127 (p.T127I). All samples showed wild-type (WT) sequences for FGFR1 and TRPV4 genes. Consistent with MAPK/ERK pathway activation, all mononuclear cells of the lesion showed strong staining for phospho-ERK1/2 protein in the immunohistochemical analysis.
KRAS mutations and activation of the MAPK-ERK signaling pathway occur in IA-PGCG. This is the first study to demonstrate cancer-associated gene mutations in a non-neoplastic reactive condition associated with dental implants.
研究种植体相关外周性巨大细胞肉芽肿（IA-PGCG）的分子发病机制。
选择 15 例 IA-PGCG 病例进行研究。通过 Sanger 测序，研究了先前在颌骨常规巨细胞瘤中报道的 KRAS、FGFR1 和 TRPV4 基因热点突变。由于这些突变可以激活 MAPK/ERK 通路，还通过免疫组织化学评估磷酸化 ERK1/2 的表达。
在 15 个样本中有 8 个（53.4%）检测到 KRAS 突变。与常规外周性巨大细胞肉芽肿相似，KRAS 突变最常发生在密码子 146（p.A146V，n=3），其次是密码子 12（p.G12A 和 p.G12D，n=1 个）和密码子 14（p.V14L，n=1）。两个病例还检测到了意义不明的变异（VUS），影响密码子 37（p.E37K）和 127（p.T127I）。所有样本均显示 FGFR1 和 TRPV4 基因的野生型（WT）序列。与 MAPK/ERK 通路激活一致，在免疫组织化学分析中，病变的所有单核细胞均显示磷酸化 ERK1/2 蛋白强染色。
IA-PGCG 中存在 KRAS 突变和 MAPK-ERK 信号通路的激活。这是第一项在与牙种植体相关的非肿瘤性反应性条件中证明癌症相关基因突变的研究。
