Thyroid cancer is the most common type of endocrine malignancy. Papillary thyroid
carcinoma (PTC) is its predominant subtype, which is responsible for the vast majority
of cases. It is true that PTC is a malignant tumor with a very good prognosis due
to effective primary therapeutic approaches such as thyroidectomy and radioiodine
(RAI) therapy. However, we are often required to indicate second-line treatments to
eradicate the tumor properly. In these scenarios, molecular therapies are promising
alternatives, especially if specifically targetable mutations are present. Many of
these targetable gene alterations originate from gene fusions, which can be found
using molecular diagnostics like next-generation sequencing (NGS). Nonetheless, molecular
profiling is far from being a routine procedure in the initial phase of PTC diagnostics.
As a result, the mutation status, except for BRAF V600E mutation, is not included
in risk classification algorithms either. This study aims to provide a comprehensive
analysis of fusion mutations in PTC and their associations with clinicopathological
variables in order to underscore certain clinical settings when molecular diagnostics
should be considered earlier, and to demonstrate yet unknown molecular–clinicopathological
connections. We conducted a retrospective fusion mutation screening in formalin-fixed
paraffin-embedded (FFPE) PTC tissue samples of 100 patients. After quality evaluation
by an expert pathologist, RNA isolation was performed, and then NGS was applied to
detect 23 relevant gene fusions in the tumor samples. Clinicopathological data were
collected from medical and histological records. To obtain the most associations from
the multivariate dataset, we used the d-correlation method for our principal component
analysis (PCA). Further statistical analyses, including Chi-square tests and logistic
regressions, were performed to identify additional significant correlations within
certain subsets of the data. Fusion mutations were identified in 27% of the PTC samples,
involving nine distinct genes: RET, NTRK3, CCDC6, ETV6, MET, ALK, NCOA4, EML4, and
SQSTM1. RET and CCDC6 fusions were associated with type of thyroidectomy, RAI therapy,
smaller tumor size, and history of Hashimoto’s disease. NCOA4 fusion correlated with
sex, multifocality, microcarcinoma character, history of goiter, and obstructive pulmonary
disease. EML4 fusion was also linked with surgical procedure type and smaller tumor
size, as well as the history of hypothyroidism. SQSTM1 fusion was associated with
multifocality and a medical history of thyroid/parathyroid adenoma. NTRK3 and ETV6
fusions showed significant associations with Hashimoto’s disease, and ETV6, also with
endometriosis. Moreover, fusion mutations were linked to younger age at the time of
diagnosis, particularly the fusion of ETV6. The frequent occurrence of fusion mutations
and their associations with certain clinicopathological metrics highlight the importance
of integrating molecular profiling into routine PTC management. Early detection of
fusion mutations can inform surgical decisions and therapeutic strategies, potentially
improving clinical outcomes.
