Abstract LB414: Characterization of the genomic landscape of <i>BRAF</i>-, <i>RAS</i>-, and fusion-negative thyroid carcinomas underscores the role of tumor suppressor genes

Abstract Background: Most non-medullary thyroid carcinomas (TC) are driven by mutually exclusive BRAF/RAS pathogenic variants or fusions involving RET, NTRK1/3, ALK, BRAF, or PPARG. However, none of these alterations are found in a subset of thyroid carcinomas (hereafter triple-negative TC). Methods: Patients within GENIE AACR (v16.0) with papillary (PTC), follicular (FTC), oncocytic (OTC), poorly-differentiated (PDTC), and anaplastic (ATC) thyroid carcinoma who underwent NGS testing for somatic mutations and fusions were included. We used Fisher exact test to compare the frequency of somatic mutations between (1) BRAF-, RAS-, and fusion-driven TC versus (2) triple-negative TC. P-values were adjusted using Benjamini-Hochberg method. Results: A total of 2,063 cases (1277 PTC, 109 FTC, 112 OTC, 311 PDTC, 254 ATC) were included. Overall, triple-negative TC accounted for 409/2063 (20%) cases. Proportions significantly varied by histology (8% PTC, 35% FTC, 83% OTC, 34% PDTC, 30% ATC; P &amp;lt; 0.001). Mutations affecting tumor suppressor genes (PTEN, NF1, TP53, DAXX, DICER1) were significantly enriched in triple-negative TC (Table 1 Table 1: Frequency of somatic mutations in each group BRAF-, RAS-, Fusion-driven (n=1654) Triple-negative (n=409) Gene Altered (n) Tested (n) (%) Altered (n) Tested (n) (%) P-val Adj. P-val PTEN 30 1654 1.8 70 409 17.1 4.5 x 10-29 1.4 x 10-26 NF1 31 1654 1.9 51 409 12.5 9.7 x 10-18 1.5 x 10-15 TP53 184 1654 11.1 110 409 26.9 1.9 x 10-14 2.0 x 10-12 TERTp 625 1190 52.5 83 295 28.1 3.8 x 10-14 2.9 x 10-12 DAXX 11 1365 0.8 30 338 8.9 1.1 x 10-13 6.5 x 10-12 DICER1 18 1593 1.1 33 395 8.4 1.8 x 10-12 9.1 x 10-11 KEAP1 12 1549 0.8 24 388 6.2 1.1 x 10-9 4.7 x 10-8 STK11 7 1654 0.4 20 409 4.9 1.3 x 10-9 5.1 x 10-8 RB1 15 1654 0.9 21 409 5.1 3.2 x 10-7 1.1 x 10-5 MSH2 9 1495 0.6 14 376 3.7 1.9 x 10-5 6.0 x 10-4 CDKN1A 10 1593 0.6 14 400 3.5 3.8 x 10-5 0.001 KMT2D 64 1599 4.0 36 403 8.9 1.6 x 10-4 0.004 MAP2K1 2 1654 0.1 7 409 1.7 2.9 x 10-4 0.007 JAK1 8 1455 0.5 10 358 2.8 7.7 x 10-4 0.017 POLD1 13 1348 1.0 12 320 3.8 0.001 0.020 ). Among triple-negative TC, some patterns were observed. NF1 and PTEN mutations were usually seen in OTC, PDTC, and ATC, but rarely in PTC or FTC. DICER1 mutations were generally observed in FTC and PDTC, typically from younger patients (median age 38 in DICER1-mutated versus 63 in DICER1-WT) and were mutually exclusive with PTEN (P=0.003), NF1 (P=0.021), and TERT promoter mutations (P&amp;lt;0.001). DAXX mutations co-occurred with CDKN1A (P&amp;lt;0.001) and were mutually exclusive with TERT promoter (P&amp;lt;0.001). DAXX/CDKN1A were strongly enriched in OTC. Conclusions: Our findings shed light into less frequent mechanisms of carcinogenesis that may play a pivotal role in BRAF-, RAS-, and fusion-negative thyroid cancers. Most of these alternative mechanisms involve inactivation of tumor suppressor genes and TC other than PTC. Citation Format: Vicente Rodrigues Marczyk, Sarah Hamidi, Mark Zafereo, Steven G. Waguespack, Ramona Dadu, Naifa L. Busaidy, Priyanka C. Iyer, Anastasios Maniakas, Victoria Banuchi, Maria E. Cabanillas, Jennifer R. Wang. Characterization of the genomic landscape of BRAF-, RAS-, and fusion-negative thyroid carcinomas underscores the role of tumor suppressor genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB414.