{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:33Z","timestamp":1787028513228,"version":"build-2736575974"},"reference-count":34,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["17-75-30027"],"award-info":[{"award-number":["17-75-30027"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>RET-kinase-activating gene rearrangements occur in approximately 1\u20132% of non-small-cell lung carcinomas (NSCLCs). Their reliable detection requires next-generation sequencing (NGS), while conventional methods, such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) or variant-specific PCR, have significant limitations. We developed an assay that compares the level of RNA transcripts corresponding to 5\u2032- and 3\u2032-end portions of the RET gene; this test relies on the fact that RET translocations result in the upregulation of the kinase domain of the gene and, therefore, the 5\u2032\/3\u2032-end expression imbalance. The present study included 16,106 consecutive NSCLC patients, 14,449 (89.7%) of whom passed cDNA quality control. The 5\u2032\/3\u2032-end unbalanced RET expression was observed in 184 (1.3%) tumors, 169 of which had a sufficient amount of material for the identification of translocation variants. Variant-specific PCR revealed RET rearrangements in 155\/169 (91.7%) tumors. RNA quality was sufficient for RNA-based NGS in 10 cases, 8 of which carried exceptionally rare or novel (HOOK1::RET and ZC3H7A::RET) RET translocations. We also applied variant-specific PCR for eight common RET rearrangements in 4680 tumors, which emerged negative upon the 5\u2032\/3\u2032-end unbalanced expression test; 33 (0.7%) of these NSCLCs showed RET fusion. While the combination of the analysis of 5\u2032\/3\u2032-end RET expression imbalance and variant-specific PCR allowed identification of RET translocations in approximately 2% of consecutive NSCLCs, this estimate approached 120\/2361 (5.1%) in EGFR\/KRAS\/ALK\/ROS1\/BRAF\/MET-negative carcinomas. RET-rearranged tumors obtained from females, but not males, had a decreased level of expression of thymidylate synthase (p &lt; 0.00001), which is a known predictive marker of the efficacy of pemetrexed. The results of our study provide a viable alternative for RET testing in facilities that do not have access to NGS due to cost or technical limitations.<\/jats:p>","DOI":"10.3390\/ijms241310530","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T01:42:32Z","timestamp":1687743752000},"page":"10530","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Rapid and Cost-Efficient Detection of RET Rearrangements in a Large Consecutive Series of Lung Carcinomas"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0157-5952","authenticated-orcid":false,"given":"Vladislav I.","family":"Tiurin","sequence":"first","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7800-013X","authenticated-orcid":false,"given":"Elena V.","family":"Preobrazhenskaya","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"},{"name":"Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0179-3191","authenticated-orcid":false,"given":"Natalia V.","family":"Mitiushkina","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6549-8378","authenticated-orcid":false,"given":"Aleksandr A.","family":"Romanko","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"},{"name":"Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra A.","family":"Anuskina","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rimma S.","family":"Mulkidjan","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeniya S.","family":"Saitova","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8499-4409","authenticated-orcid":false,"given":"Elena A.","family":"Krivosheyeva","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7898-7405","authenticated-orcid":false,"given":"Elena D.","family":"Kharitonova","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail P.","family":"Shevyakov","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8995-8417","authenticated-orcid":false,"given":"Ilya A.","family":"Tryakin","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana N.","family":"Aleksakhina","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aigul R.","family":"Venina","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana N.","family":"Sokolova","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7690-8328","authenticated-orcid":false,"given":"Aleksandr S.","family":"Martianov","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"},{"name":"Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna D.","family":"Shestakova","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandr O.","family":"Ivantsov","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"},{"name":"Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aglaya G.","family":"Iyevleva","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"},{"name":"Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4529-7891","authenticated-orcid":false,"given":"Evgeny N.","family":"Imyanitov","sequence":"additional","affiliation":[{"name":"Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St.-Petersburg, Russia"},{"name":"Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St.-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"562480","DOI":"10.3389\/fmed.2020.562480","article-title":"Practical Considerations Relating to Routine Clinical Biomarker Testing for Non-small Cell Lung Cancer: Focus on Testing for RET Fusions","volume":"7","author":"Herbst","year":"2021","journal-title":"Front. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1056\/NEJMoa2005653","article-title":"Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer","volume":"383","author":"Drilon","year":"2020","journal-title":"N. Engl. J. 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