Genomic and Transcriptomic Landscape of RET Wild-Type Medullary Thyroid Cancer and Potential Use of Mitogen-Activated Protein Kinase-Targeted Therapy

Abstract

BACKGROUND: About 75% of medullary thyroid cancers (MTCs) are sporadic with 45% to 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. STUDY DESIGN: We did a retrospective analysis of MTC samples submitted for DNA/RNA sequencing and programmed cell death ligand 1 expression using immunohistochemistry at a Clinical Laboratory Improvement Amendments/College of American Pathologists-certified laboratory. Tumor microenvironment immune cell fractions were estimated using RNA deconvolution (quanTIseq). Transcriptomic signatures of inflammation and MAP kinase pathway activation scores were calculated. Mann-Whitney U, chi-square, and Fisher’s exact tests were applied (p values adjusted for multiple comparisons). RESULTS: The 160-patient cohort included 108 mutRET and 52 wtRET MTC samples. wtRET tumors frequently harbored mitogen-activated protein kinase (MAPK) pathway mutations, including HRAS (42.31%), KRAS (15.7%), NF1 (6.7%), and BRAF (2%), whereas only 1 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 patients with wtRET harboring mutations in MAPK genes. Although the frequency of programmed cell death ligand 1 expression was similar in wtRET and mutRET (10.2% vs 7%, p = 0.531), wtRET tumors were more often tumor mutational burden high (7.7% vs 0%, p = 0.011), and wtRET MTC exhibited higher expression of immune checkpoint genes. CONCLUSIONS: We identified molecular alterations and immune-related features that distinguish wtRET from mutRET MTC. Although 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 immuno-oncology agents for selected patients with wtRET MTC.