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<p><i>BRAF</i>, when mutated at V600E, is a well-known potent early oncogenic driver in papillary thyroid carcinoma (PTC), with potential prognostic and therapeutic implications. Non-V600E mutations are less common and without clear functional or therapeutic significance. One class of non-V600E mutations is <i>BRAF</i> gene fusions, which typically involve the C-terminal kinase domain of <i>BRAF</i> joined to a wide repertoire of potential N-terminal fusion partners. The aim of this study was to employ a sequential algorithmic approach to identify patients with <i>BRAF</i> fusions based on an integrated analysis of histologic, immunohistochemistry (IHC), and molecular (NGS) features of <i>BRAF</i>-rearranged PTCs. Nine patients with PTC previously scrutinized as <i>BRAF</i> V600E negative by IHC were analyzed by NGS. The studied 9 cases showed conventional PTC growth; 2 cases displayed a minor high-grade component (tall cell and hobnailing, &lt; 20%), 1 case qualified as high-grade differentiated thyroid carcinoma (presence of necrosis and mitotic activity &gt; 5 MF/ 2 mm<sup>2</sup>; adjacent conventional PTC was present), and 1 case represented neck (lymph node) recurrence after 10&#xa0;years. <i>BRAF</i> fusions were detected in all cases (10 different fusion partners: <i>NRF1</i>, <i>MKRN1</i>, <i>MACF1</i>, <i>MTDH1</i>, <i>ARHGAP26</i>, <i>STRBF</i>, <i>FCHSDH2</i>, <i>POM121C</i>, <i>UBAP2L</i>, <i>SND1</i>). To our knowledge, 7 of these fusions have not been reported so far in PTC (<i>NRF1::BRAF</i>, <i>MTDH1::BRAF</i>, <i>ARHGAP26::BRAF</i>, <i>BRAF::STRBF</i>, <i>FCHSDH2::BRAF</i>, <i>BRAF::POM121C</i>, <i>UBAP2L::BRAF</i>). In 3 PTCs, <i>BRAF</i> fusions were sole genomic events. Concurrent <i>TERT</i> (c.-124C &gt; T) mutations were detected in 3 PTCs; pathogenic <i>IGF2</i> amplification was present in another PTC, in addition to <i>BRAF</i> fusion. Two simultaneous fusions <i>BRAF::STRBF</i> and <i>FCHSDH2::BRAF</i> were found in one case of PTC; two <i>BRAF</i> fusions (<i>BRAF::POM121C</i>; <i>UBAP2L::BRAF</i>) co-existed with 2 <i>FOXO1</i> fusions (<i>FOXO1::TES</i>, <i>YWHAG::FOXO1</i>) in one PTC. In summary, we report 7 new <i>BRAF</i> fusions in PTC <i>BRAF</i> V600E-WT. Additional clinical research is needed to elucidate the behavior of <i>BRAF</i> fusion-driven thyroid carcinomas and the therapeutic utility of <i>MAPK</i> pathway inhibitors.</p>

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Outside canonical BRAF p.V600E Box: 7 novel BRAF gene fusions in BRAF p.V600E WT papillary thyroid carcinoma

  • 期刊论文

  • 发表日期：

    2026年2月16日

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  • Nathan McGrath,
  • Li Liang,
  • Rania Bakkar,
  • Thomas J. Gernon,
  • Ellie Maghami,
  • Michelle Afkhami,
  • Diana Bell

摘要

BRAF, when mutated at V600E, is a well-known potent early oncogenic driver in papillary thyroid carcinoma (PTC), with potential prognostic and therapeutic implications. Non-V600E mutations are less common and without clear functional or therapeutic significance. One class of non-V600E mutations is BRAF gene fusions, which typically involve the C-terminal kinase domain of BRAF joined to a wide repertoire of potential N-terminal fusion partners. The aim of this study was to employ a sequential algorithmic approach to identify patients with BRAF fusions based on an integrated analysis of histologic, immunohistochemistry (IHC), and molecular (NGS) features of BRAF-rearranged PTCs. Nine patients with PTC previously scrutinized as BRAF V600E negative by IHC were analyzed by NGS. The studied 9 cases showed conventional PTC growth; 2 cases displayed a minor high-grade component (tall cell and hobnailing, < 20%), 1 case qualified as high-grade differentiated thyroid carcinoma (presence of necrosis and mitotic activity > 5 MF/ 2 mm2; adjacent conventional PTC was present), and 1 case represented neck (lymph node) recurrence after 10 years. BRAF fusions were detected in all cases (10 different fusion partners: NRF1, MKRN1, MACF1, MTDH1, ARHGAP26, STRBF, FCHSDH2, POM121C, UBAP2L, SND1). To our knowledge, 7 of these fusions have not been reported so far in PTC (NRF1::BRAF, MTDH1::BRAF, ARHGAP26::BRAF, BRAF::STRBF, FCHSDH2::BRAF, BRAF::POM121C, UBAP2L::BRAF). In 3 PTCs, BRAF fusions were sole genomic events. Concurrent TERT (c.-124C > T) mutations were detected in 3 PTCs; pathogenic IGF2 amplification was present in another PTC, in addition to BRAF fusion. Two simultaneous fusions BRAF::STRBF and FCHSDH2::BRAF were found in one case of PTC; two BRAF fusions (BRAF::POM121C; UBAP2L::BRAF) co-existed with 2 FOXO1 fusions (FOXO1::TES, YWHAG::FOXO1) in one PTC. In summary, we report 7 new BRAF fusions in PTC BRAF V600E-WT. Additional clinical research is needed to elucidate the behavior of BRAF fusion-driven thyroid carcinomas and the therapeutic utility of MAPK pathway inhibitors.