Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
Mod Pathol. 2019 Jun;32(6):799-806. doi: 10.1038/s41379-018-0194-4. Epub 2019 Jan 14.
Adenomatoid odontogenic tumor is a benign encapsulated epithelial odontogenic tumor that shows an indolent clinical behavior. We have reported in a few adenomatoid odontogenic tumors mutations in KRAS, which is a proto-oncogene frequently mutated in cancer such as lung, pancreas, and colorectal adenocarcinomas. We aimed to assess KRAS mutations in the hotspot codons 12, 13, and 61 in a large cohort of adenomatoid odontogenic tumors and to test the association of these mutations with clinical (age, site, tumor size, follicular/extrafollicular subtypes) and histopathological parameters. Thirty eight central cases were studied. KRAS codon 12 mutations were assessed by TaqMan allele-specific qPCR (p.G12V/R) and/or Sanger sequencing, and codon 13 and 61 mutations were screened by Sanger. Histological tumor capsule thickness was evaluated by morphometric analysis. Additionally, the phosphorylated form of the MAPK downstream effector ERK1/2 was investigated. Statistical analysis was carried out to test the association of KRAS mutations with clinicopathological parameters. KRAS c.35 G >T mutation, leading to p.G12V, was detected in 15 cases. A novel mutation in adenomatoid odontogenic tumor, c.34 G >C, leading to p.G12R, was detected in 12 cases and the other 11 were wild-type. Codon 12 mutations were not associated with the clinicopathological parameters tested. RAS mutations are known to activate the MAPK pathway, and we show that adenomatoid odontogenic tumors express phosphorylated ERK1/2. In conclusion, a high proportion of adenomatoid odontogenic tumors (27/38, 71%) have KRAS codon 12 mutations, which occur independently of the clinicopathological features evaluated. Collectively, these findings indicate that KRAS mutations and MAPK pathway activation are the common features of this tumor and some cancer types. Although it is unclear why different codon 12 alleles occur in different disease contexts and the complex interactions between tumor genotype and phenotype need clarification, on the basis of our results the presence of KRAS p.G12V/R favors the adenomatoid odontogenic tumor diagnosis in challenging oral neoplasm cases.
腺牙源性肿瘤是一种良性包膜上皮性牙源性肿瘤，具有惰性的临床行为。我们曾报道过少数腺牙源性肿瘤中 KRAS 突变，KRAS 是一种原癌基因，在肺癌、胰腺癌和结直肠癌等癌症中经常发生突变。我们旨在评估大样本腺牙源性肿瘤中 KRAS 热点密码子 12、13 和 61 的突变，并检测这些突变与临床（年龄、部位、肿瘤大小、滤泡/滤泡外亚型）和组织病理学参数的相关性。研究了 38 例中央病例。通过 TaqMan 等位基因特异性 qPCR（p.G12V/R）和/或 Sanger 测序评估 KRAS 密码子 12 突变，通过 Sanger 筛选密码子 13 和 61 突变。通过形态计量分析评估组织学肿瘤包膜厚度。此外，还研究了 MAPK 下游效应物 ERK1/2 的磷酸化形式。进行统计学分析以检测 KRAS 突变与临床病理参数的相关性。在 15 例中检测到导致 p.G12V 的 KRAS c.35 G > T 突变。在 12 例中检测到腺牙源性肿瘤的新突变 c.34 G > C，导致 p.G12R，而其他 11 例为野生型。密码子 12 突变与检测的临床病理参数无关。众所周知，RAS 突变会激活 MAPK 途径，我们表明腺牙源性肿瘤表达磷酸化 ERK1/2。总之，高比例的腺牙源性肿瘤（38/38，71%）具有 KRAS 密码子 12 突变，这些突变独立于评估的临床病理特征发生。总的来说，这些发现表明 KRAS 突变和 MAPK 途径激活是这种肿瘤和一些癌症类型的共同特征。尽管尚不清楚为什么不同的密码子 12 等位基因出现在不同的疾病环境中，以及肿瘤基因型和表型之间的复杂相互作用需要澄清，但基于我们的结果，KRAS p.G12V/R 的存在有利于在具有挑战性的口腔肿瘤病例中诊断腺牙源性肿瘤。
