{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T23:33:23Z","timestamp":1767915203558,"version":"3.49.0"},"reference-count":33,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T00:00:00Z","timestamp":1733443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ricerca Finalizzata","award":["GR-2019-12368592"],"award-info":[{"award-number":["GR-2019-12368592"]}]},{"name":"Ricerca Finalizzata","award":["PNC0000003"],"award-info":[{"award-number":["PNC0000003"]}]},{"name":"National Plan for NRRP Complementary Investments","award":["GR-2019-12368592"],"award-info":[{"award-number":["GR-2019-12368592"]}]},{"name":"National Plan for NRRP Complementary Investments","award":["PNC0000003"],"award-info":[{"award-number":["PNC0000003"]}]},{"name":"research initiatives for technologies and innovative trajectories in the health and care sectors","award":["GR-2019-12368592"],"award-info":[{"award-number":["GR-2019-12368592"]}]},{"name":"research initiatives for technologies and innovative trajectories in the health and care sectors","award":["PNC0000003"],"award-info":[{"award-number":["PNC0000003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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., RAS 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 RAS-mutant [RAS-mut] and n = 55 RAS-wild type [RAS-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 RAS-mut as compared to RAS-wt NIFTPs. These proteins could serve as readily accessible markers in morphologically borderline cases showing RAS mutations. Additionally, our findings may provide insights into the distinct pathogenic pathways through which RAS-mut and RAS-wt NIFTPs arise, highlighting the pivotal role of constitutive RAS\u2013mitogen-activated protein kinase (MAPK) pathway activation in the development and progression of RAS-mut tumors.<\/jats:p>","DOI":"10.3390\/ijms252313115","type":"journal-article","created":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T06:25:16Z","timestamp":1733466316000},"page":"13115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Spatially Resolved Molecular Characterization of Noninvasive Follicular Thyroid Neoplasms with Papillary-like Nuclear Features (NIFTPs) Identifies a Distinct Proteomic Signature Associated with RAS-Mutant Lesions"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6373-689X","authenticated-orcid":false,"given":"Vanna","family":"Denti","sequence":"first","affiliation":[{"name":"Proteomics and Metabolomics Unit, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Greco","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0686-6203","authenticated-orcid":false,"given":"Antonio Maria","family":"Alviano","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8178-2440","authenticated-orcid":false,"given":"Giulia","family":"Capitoli","sequence":"additional","affiliation":[{"name":"Bicocca Bioinformatics Biostatistics and Bioimaging Research Centre\u2014B4, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"},{"name":"Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Monza","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Unit, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6530-6113","authenticated-orcid":false,"given":"Andrew","family":"Smith","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Unit, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Pilla","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Maggioni","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7636-1000","authenticated-orcid":false,"given":"Mariia","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, European Institute of Oncology IRCCS, 20141 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantinos","family":"Venetis","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, European Institute of Oncology IRCCS, 20141 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4554-8956","authenticated-orcid":false,"given":"Fausto","family":"Maffini","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, European Institute of Oncology IRCCS, 20141 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattia","family":"Garancini","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela Ida","family":"Pincelli","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1504-7242","authenticated-orcid":false,"given":"Stefania","family":"Galimberti","sequence":"additional","affiliation":[{"name":"Bicocca Bioinformatics Biostatistics and Bioimaging Research Centre\u2014B4, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"},{"name":"Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8663-0374","authenticated-orcid":false,"given":"Fulvio","family":"Magni","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Unit, Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9101-9131","authenticated-orcid":false,"given":"Nicola","family":"Fusco","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, European Institute of Oncology IRCCS, 20141 Milan, Italy"},{"name":"Department of Oncology & Hemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-2998","authenticated-orcid":false,"given":"Vincenzo","family":"L\u2019Imperio","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9625-1637","authenticated-orcid":false,"given":"Fabio","family":"Pagni","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"152282","DOI":"10.1016\/j.anndiagpath.2024.152282","article-title":"Evaluation of the Follicular Patterned Thyroid Lesions Based on the WHO 2022 Criteria with an Emphasis on the Grey-Zone 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