{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T17:04:07Z","timestamp":1785344647940,"version":"3.55.0"},"reference-count":52,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["aao-hnsfjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Otolaryngol.--head neck surg."],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      <jats:italic>NRAS<\/jats:italic>\n                      variants are the most common mutations in thyroid nodules with (B)ethesda III\/IV cytology. This study aims to characterize co\u2010occurring variants, molecular signatures, and hallmarks of cancer pathways in nodules with\n                      <jats:italic>NRAS<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Study Design<\/jats:title>\n                    <jats:p>Retrospective database analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The database of nodules sent for Afirma GSC testing was analyzed for the most common\n                      <jats:italic>NRAS<\/jats:italic>\n                      hotspot mutations, co\u2010occurring mutations,\n                      <jats:italic>BRAF\u2010RAS<\/jats:italic>\n                      score (BRS), thyroid differentiation score (TDS), ERK expression, and activity levels of hallmarks of cancer pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 87,817 Afirma GSC\u2010suspicious or BV\/VI nodules, 12.6% had\n                      <jats:italic>NRAS<\/jats:italic>\n                      mutations. Of those, 79.7% were\n                      <jats:italic>NRAS<\/jats:italic>\n                      p.Q61R and 19.4% were\n                      <jats:italic>NRAS<\/jats:italic>\n                      p.Q61K. 421 nodules (3.8%) had co\u2010occurring mutations,\n                      <jats:italic>EIF1AX<\/jats:italic>\n                      being the most common (1%, about twice the rate seen alone). Of 872 nodules with\n                      <jats:italic>TERT<\/jats:italic>\n                      promoter mutations (\n                      <jats:italic>TERTp<\/jats:italic>\n                      ), 7.8% had concurrent\n                      <jats:italic>NRAS<\/jats:italic>\n                      \u2009+\u2009\n                      <jats:italic>TERT<\/jats:italic>\n                      mutations (more than twice the rate of\n                      <jats:italic>TERT<\/jats:italic>\n                      alone). The presence of\n                      <jats:italic>NRAS<\/jats:italic>\n                      (+\/\u2212 co\u2010mutations) was highly\n                      <jats:italic>RAS\u2010<\/jats:italic>\n                      like on the BRS score. Hallmarks of cancer pathways analyzed across\n                      <jats:italic>NRAS<\/jats:italic>\n                      + nodules, with\n                      <jats:italic>TERTp<\/jats:italic>\n                      profiling, revealed 2 distinct clusters: one with higher inflammatory pathway activity, and another with higher DNA repair, estrogen response, and MYC activity. The latter had a higher rate of BV\/VI nodules.\n                      <jats:italic>NRAS<\/jats:italic>\n                      p.Q61R was equally distributed across the 2 clusters.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>NRAS<\/jats:italic>\n                      p.Q61R\/K comprises 99% of reported NRAS variants.\n                      <jats:italic>TERTp<\/jats:italic>\n                      is the most frequent co\u2010mutation. Among\n                      <jats:italic>NRAS<\/jats:italic>\n                      p.Q61R\/K nodules, there are 2 different clusters of samples based on the activity of hallmarks of cancer pathways. Further studies correlating these clusters with clinical and pathological outcomes are necessary.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ohn.70298","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T15:12:18Z","timestamp":1781709138000},"page":"343-349","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Molecular Heterogeneity of\n                    <i>NRAS<\/i>\n                    Variants in Thyroid Nodules"],"prefix":"10.1002","volume":"175","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1076-1941","authenticated-orcid":false,"given":"Emma De","family":"Ravin","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Thomas Jefferson University Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Alshalalfa","sequence":"additional","affiliation":[{"name":"Veracyte Inc. 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