• Sourat Darabi, Tolulope Adeyelu, Andrew Elliott, Ammar Sukari, Kurt Hodges, Farah Abdulla, Carlos E Zuazo, Trisha Wise-Draper, Thomas Wang, and Michael J Demeure.
• Hoag Memorial Hospital, Newport Beach, CA, Cancer Institute.
• J. Am. Coll. Surg. 2024 Apr 23.

BackgroundAbout 75% of medullary thyroid cancers (MTCs) are sporadic with 45-70% being driven by a RET mutation. Selpercatinib is an approved treatment for RET-mutated (mutRET) MTC, however, treatments are needed for wild-type RET MTC (wtRET). Genomic alterations and transcriptomic signatures of wtRET MTC may reveal new therapeutic insights.MethodsWe did a retrospective analysis of MTC samples submitted for DNA/RNA sequencing and PD-L1 expression using IHC at a CLIA/CAP-certified lab. Tumor microenvironment immune cell fractions were estimated using RNA deconvolution (quanTIseq). Transcriptomic signatures of inflammation and MAP kinase pathway activation scores (MPAS) were calculated. Mann-Whitney U, chi-square, and Fisher exact tests were applied (p-values adjusted for multiple comparisons).ResultsThe 160-patient cohort included 108 mutRET and 52 wtRET MTC samples. wtRET tumors frequently harbored MAPK pathway mutations, including HRAS (42.31%), KRAS (15.7%), NF1 (6.7%), and BRAF (2%) whereas only one MAPK pathway mutation (NF1) was identified among mutRET MTC. Recurrent mutations seen in wtRET MTC included MGA, VHL, APC, STK11, and NFE2L2. Increased transcriptional activation of the MAPK pathway was observed in wtRET patients harboring mutations in MAPK genes. While the frequency of PD-L1 expression was similar in wtRET and mutRET (10.2% vs 7.0%, p=0.531), wtRET tumors were more often TMB-high (7.7% vs 0.0%, p=0.011), and wtRET MTC exhibited higher expression of immune checkpoint genes.ConclusionsWe identified molecular alterations and immune-related features that distinguish wtRET from mutRET MTC. While RET mutation drives MTC in the absence of other alterations, we showed that wtRET MTC frequently harbors MAPK pathway mutations. These findings may indicate a potential basis for MAPK-targeted therapy, possibly in combination with oncology immune-oncology agents for selected patients with wtRET MTC.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Surgeons.

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