Integrated proteogenomic analysis of a Chinese cohort of patients with medullary thyroid carcinoma (MTC) revealed 3 molecularly heterogeneous disease subtypes and identified 2 potential prognostic biomarkers, according to a study published in Cell Discovery.

Comprehensive multiomics analysis and unsupervised clustering using whole-exome sequencing, RNA sequencing, DNA methylation array, and proteomic and phosphoproteomic profiling were able to stratify MTC into 3 subtypes, which were labeled as metabolic, basal, and mesenchymal. Each of these subtypes had specific genetic drivers of disease, epigenetic modification profiles, clinicopathology, and clinical outcomes.

The metabolic subtype made up roughly 32.4% of the tumors in the study and was categorized by the enrichment of several cellular metabolism pathways.


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Elevated protein levels of basal factors, including CD44 and a number of keratin genes, such as KRT5, KRT6B, KRT6C, and KRT14, as well as eukaryotic translation initiation factor complex and cytoskeleton members, were present in the basal subtype, which made up 35.3% of tumors.

The mesenchymal subtype had significant upregulation of proteins and pathways associated with the extracellular matrix and included 32.4% of tumors.

Tumors driven by RETM918T mutations were more common in the mesenchymal subtype compared to the metabolic (42.4% vs 18.2%; P =.03), while RAS mutations were more common in the metabolic subtype than the mesenchymal (27.3% vs 3.0%; P =.013). DNA methylation was also significantly higher in the mesenchymal group.

The mesenchymal subtype may also represent more aggressive tumors with more advanced staging (P =.005), increased likelihood of biochemical recurrence/persistent disease (P =.035), and a compromised structural recurrence-free survival (P =.005) than the basal subtype. The metabolic subtype showed a more intermediate degree of malignancy.

In the mesenchymal subtype, 2 members of the tenascin family—tenascin-C (TNC) and tenascin-X (TNXB)—showed increased enrichment. Further investigation revealed that higher TNC or TNXB expression was associated with advanced TNM staging and poorer structural recurrence-free survival in the whole study cohort, indicating that they could be potential prognostic biomarkers.

The study also identified mutations in the BRAF and NF1 genes as novel disease drivers that were mutually exclusive to RET and RAS mutations.

The study included data from 102 patients with MTC collected from 5 hospitals in China. Median age was 50 years, and the cohort had an equal number of males and females.

Reference

Shi, X., Sun, Y., Shen, C. et al. Integrated proteogenomic characterization of medullary thyroid carcinoma. Cell Discov. Published online November 8, 2022. doi:10.1038/s41421-022-00479-y