Heterogenous nature of gene expression patterns in BRAF-like papillary thyroid carcinomas with BRAF^V600E

Purpose: Papillary thyroid cancers (PTCs) are the most common type of thyroid cancers, in which BRAF^V600E is the most prevalent driver mutation. It is known that BRAF^V600E-positive PTCs are clinically and molecularly heterogenous in terms of aggressiveness and prognosis. The molecular mechanisms of this heterogeneity were evaluated.

Methods: The publicly available RNA-seq data for 26 classical (c) and 5 follicular variant (fv) PTCs with BRAF^V600E mutation and the BRAF-like expression signature in the BRAF^V600E-RAS score (BRS) and their respective normal adjacent tissues were downloaded, and analyzed for differentially expressed genes (DEGs). The DEGs were then analyzed with the Gene Ontology annotation and the KEGG pathway dataset.

Results: We found four lines of evidence for heterogeneity of cPTCs. First, the cluster dendrogram and principle component analyses could not completely distinguish the cancer tissues from normal tissues. Second, the DEGs identified in each sample were highly diverse from one another. Third, although the DEGs were enriched in many terms containing the word "extracellular" ("extracellular region", "extracellular space", and so on) when analyzed as groups, the degree of this enrichment was variable when analyzed individually. Fourth, there are only a few intersections in the over-/underexpressed genes annotated with the terms containing the word "extracellular" among the samples examined. Essentially same results were obtained with BRAF-like, fvPTCs with BRAF^V600E. Nevertheless, some frequently over-/underexpressed genes were detected, of which LIPH (lipase H) expression was found to be prognostic and its high expression was favorable for PTCs.

Conclusion: Groups of BRAF-like, BRAF^V600E-positive cPTCs and fvPTCs that are homogenous in regard to histopathology, driver mutation and BRS were found to be highly heterogenous in terms of gene expression patterns. Yet, among the genes that were annotated with the terms containing the word "extracellular" and frequently over-/underexpressed, LIPH is a favorable prognostic marker for PTCs.