Integrative proteogenomic characterization reveals therapeutic targets in poorly differentiated and anaplastic...

Area of Science:

• Oncology
• Genomics
• Proteomics

Background:

• Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are aggressive and heterogeneous, posing treatment challenges.
• Deep-scale analyses are crucial for understanding the complex biology of these virulent thyroid cancers.

Purpose of the Study:

• To perform deep-scale genomic, proteomic, and phosphoproteomic analyses of PDTC and ATC.
• To identify common hallmarks, molecular subtypes, and potential therapeutic targets for PDTC and ATC.

Main Methods:

• Analysis of 348 thyroid cancer and 119 tumor-adjacent samples.
• Genomic, proteomic, and phosphoproteomic data integration.
• Proteomic clustering to identify distinct tumor subtypes.

Main Results:

• TP53, TERT promoter, and BRAF mutations are frequent in PDTC and ATC.
• Ribosome biogenesis is a common hallmark of ATC; RRP9 silencing inhibits tumor growth.
• Three PDTC/ATC subtypes were identified: Pro-I (insulin signaling, low immune infiltration), Pro-II (DNA repair signaling), and Pro-III (TP53/BRAF mutations, myeloid infiltration).
• Targeting C5AR1 synergistically enhances PD-1 blockade efficacy.

Conclusions:

• These findings offer systematic insights into PDTC and ATC tumor biology.
• Identification of subtypes and C5AR1 targeting presents opportunities for precision therapy development in aggressive thyroid cancers.