Integrated Genomic Characterization of Papillary Thyroid Carcinoma

TLDR

Papillary thyroid carcinoma is the most common type of thyroid cancer. The study describes the genomic landscape of 496 papillary thyroid carcinoma cases. The analysis identified a low frequency of somatic alterations, expanded the list of driver genes to include EIF1AX, PPM1D, and CHEK2, reduced the proportion of cases with unknown drivers to 3.5%, revealed that distinct driver groups and BRAF‑mutant subtypes correspond to different pathologies and signaling pathways, and suggested a molecular reclassification that could improve thyroid cancer diagnosis and treatment.

Abstract

<h2>Summary</h2> Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include <i>EIF1AX</i>, <i>PPM1D</i>, and <i>CHEK2</i> and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of <i>BRAF</i>-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.