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This study aimed to utilize a sensitive proteomic method, data-independent mass spectrometry (DIA-MS), to extensively analyze the LARC proteome, seeking individuals with favorable initial responses suitable for a watch-and-wait approach. This research addresses the unmet need to understand the response to treatment, potentially guiding personalized strategies for LARC patients. Post-treatment assessment included MRI scans and proctoscopy. This research involved 97 LARC patients treated with intense chemoradiotherapy, comprising radiation and chemotherapy. Out of 97 LARC included in this study, we selected 20 samples with the most different responses to nCRT for proteome profiling (responders vs. non-responders). This proteomic approach shows extensive proteome coverage in LARC samples. The analysis identified a significant number of proteins compared to a prior study. A total of 915 proteins exhibited differential expression between the two groups, with certain signaling pathways associated with response mechanisms, while top candidates had good predictive potential. Proteins encoded by genes SMPDL3A, PCTP, LGMN, SYNJ2, NHLRC3, GLB1, and RAB43 showed high predictive potential of unfavorable treatment outcome, while RPA2, SARNP, PCBP2, SF3B2, HNRNPF, RBBP4, MAGOHB, DUT, ERG28, and BUB3 were good predictive biomarkers of favorable treatment outcome. The identified proteins and related biological processes provide promising insights that could enhance the management and care of LARC patients.<\/jats:p>","DOI":"10.3390\/ijms242015412","type":"journal-article","created":{"date-parts":[[2023,10,21]],"date-time":"2023-10-21T12:59:01Z","timestamp":1697893141000},"page":"15412","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Data-Independent Acquisition Mass Spectrometry Analysis of FFPE Rectal Cancer Samples Offers In-Depth Proteomics Characterization of the Response to Neoadjuvant Chemoradiotherapy"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9179-2856","authenticated-orcid":false,"given":"Aleksandra","family":"Stanojevic","sequence":"first","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9952-0636","authenticated-orcid":false,"given":"Martina","family":"Samiotaki","sequence":"additional","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 166 72 Vari, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1555-1326","authenticated-orcid":false,"given":"Vasiliki","family":"Lygirou","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mladen","family":"Marinkovic","sequence":"additional","affiliation":[{"name":"Clinic for Radiation Oncology and Diagnostics, Department of Radiation Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Nikolic","sequence":"additional","affiliation":[{"name":"Clinic for Medical Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana","family":"Stojanovic-Rundic","sequence":"additional","affiliation":[{"name":"Clinic for Radiation Oncology and Diagnostics, Department of Radiation Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radmila","family":"Jankovic","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3284-5713","authenticated-orcid":false,"given":"Antonia","family":"Vlahou","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Panayotou","sequence":"additional","affiliation":[{"name":"Institute for Bioinnovation, Biomedical Sciences Research Center \u201cAlexander Fleming\u201d, Fleming 34, 166 72 Vari, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2076-5521","authenticated-orcid":false,"given":"Remond J. A.","family":"Fijneman","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergi","family":"Castellv\u00ed-Bel","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, Fundaci\u00f3 Cl\u00ednic per la Recerca Biom\u00e8dica-Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (FRCB-IDIBAPS), C\/del Rossell\u00f3, 149, 08036 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd) Almagro, 3, 28029 Madrid, Spain"},{"name":"Hospital Cl\u00ednic, University of Barcelona, C\/del Villarroel, 170, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4557-3430","authenticated-orcid":false,"given":"Jerome","family":"Zoidakis","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece"},{"name":"Department of Biology, National and Kapodistrian University of Athens, Panepistim\u00edou 30, 106 79 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7604-9295","authenticated-orcid":false,"given":"Milena","family":"Cavic","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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