Denti Vanna, Greco Angela, Alviano Antonio Maria, Capitoli Giulia, Monza Nicole, Smith Andrew, Pilla Daniela, Maggioni Alice, Ivanova Mariia, Venetis Konstantinos, Maffini Fausto, Garancini Mattia, Pincelli Angela Ida, Galimberti Stefania, Magni Fulvio, Fusco Nicola, L'Imperio Vincenzo, Pagni Fabio
Proteomics and Metabolomics Unit, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy.
Department of Medicine and Surgery, Pathology, Center of Digital Medicine, University of Milano-Bicocca, Fondazione IRCCS San Gerardo dei Tintori, Via Cadore 48, 20900 Monza, Italy.
Int J Mol Sci. 2024 Dec 6;25(23):13115. doi: 10.3390/ijms252313115.
Follicular-patterned thyroid neoplasms comprise a diverse group of lesions that pose significant challenges in terms of differential diagnosis based solely on morphologic and genetic features. Thus, the identification of easily testable biomarkers complementing microscopic and genetic analyses is a highly anticipated advancement that could improve diagnostic accuracy, particularly for noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs). These tumors exhibit considerable morphological and molecular heterogeneity, which may complicate their distinction from structurally similar neoplasms, especially when genetic analyses reveal shared genomic alterations (e.g., mutations). Here, we integrated next-generation sequencing (NGS) with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to perform a proteogenomic analysis on 85 NIFTPs (n = 30 -mutant [-mut] and n = 55 -wild type [-wt]), with the aim to detect putative biomarkers of RAS-mut lesions. Through this combined approach, we identified four proteins that were significantly underexpressed in -mut as compared to RAS-wt NIFTPs. These proteins could serve as readily accessible markers in morphologically borderline cases showing mutations. Additionally, our findings may provide insights into the distinct pathogenic pathways through which -mut and -wt NIFTPs arise, highlighting the pivotal role of constitutive RAS-mitogen-activated protein kinase (MAPK) pathway activation in the development and progression of -mut tumors.
滤泡型甲状腺肿瘤包含一组多样的病变，仅基于形态学和遗传学特征进行鉴别诊断时面临重大挑战。因此，鉴定易于检测的生物标志物以补充显微镜检查和基因分析，是一项备受期待的进展，有望提高诊断准确性，特别是对于具有乳头状核特征的非侵袭性滤泡性甲状腺肿瘤（NIFTPs）。这些肿瘤表现出相当大的形态学和分子异质性，这可能使它们与结构相似的肿瘤区分开来变得复杂，尤其是当基因分析揭示共享的基因组改变（例如突变）时。在这里，我们将下一代测序（NGS）与基质辅助激光解吸/电离质谱成像（MALDI-MSI）相结合，对85个NIFTPs（n = 30 -突变体[-mut]和n = 55 -野生型[-wt]）进行蛋白质基因组分析，旨在检测RAS突变病变的假定生物标志物。通过这种联合方法，我们鉴定出四种蛋白质，与RAS野生型NIFTPs相比，它们在突变体中显著低表达。这些蛋白质可作为形态学临界病例中显示突变的易于获取的标志物。此外，我们的发现可能为突变体和野生型NIFTPs产生的不同致病途径提供见解，突出组成型RAS丝裂原活化蛋白激酶（MAPK）途径激活在突变体肿瘤发生和发展中的关键作用。
