biostudies-literatureShi XNational Key R&D Program of ChinaNatural Science Foundation of ShanghaiNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)Natural Science Foundation of Shanghai (Natural Science Foundation of Shanghai Municipality)120https://www.ebi.ac.uk/biostudies/studies/S-EPMC9640541biostudies-literatureUnknown8(1)Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy derived from parafollicular cells (C cells) of the thyroid. Here we presented a comprehensive multi-omics landscape of 102 MTCs through whole-exome sequencing, RNA sequencing, DNA methylation array, proteomic and phosphoproteomic profiling. Integrated analyses identified BRAF and NF1 as novel driver genes in addition to the well-characterized RET and RAS proto-oncogenes. Proteome-based stratification of MTCs revealed three molecularly heterogeneous subtypes named as: (1) Metabolic, (2) Basal and (3) Mesenchymal, which are distinct in genetic drivers, epigenetic modification profiles, clinicopathologic factors and clinical outcomes. Furthermore, we explored putative therapeutic targets of each proteomic subtype, and foundCell discoveryIntegrated proteogenomic characterization of medullary thyroid carcinoma.PMC96405418200283019ZR14109008177285420YF14082008207295122ZR1412800Zhang FJiao LShi RZhu ZGeng XYu PLu ZHuang NShen CGuo TWei WShi XGe SGuo LQu NLiao TWang WWang YChen TGu YGuan HLi PSun YLi YHuang SZhang TJi QLv GHu JZhang ZZhang YXu TPu WQin GXu WfalseIntegrated proteogenomic characterization of medullary thyroid carcinoma.Medullary thyroid carcinoma (MTC) is a rare neuroendocrine malignancy derived from parafollicular cells (C cells) of the thyroid. Here we presented a comprehensive multi-omics landscape of 102 MTCs through whole-exome sequencing, RNA sequencing, DNA methylation array, proteomic and phosphoproteomic profiling. Integrated analyses identified BRAF and NF1 as novel driver genes in addition to the well-characterized RET and RAS proto-oncogenes. Proteome-based stratification of MTCs revealed three molecularly heterogeneous subtypes named as: (1) Metabolic, (2) Basal and (3) Mesenchymal, which are distinct in genetic drivers, epigenetic modification profiles, clinicopathologic factors and clinical outcomes. Furthermore, we explored putative therapeutic targets of each proteomic subtype, and found2022-01-01T00:00:00Z2022 Nov2025-04-04T19:27:33.86Z2025-04-04T19:27:33.86ZS-EPMC96405413634450910.1038/s41421-022-00479-y