Genomic characterization of high-recurrence risk papillary thyroid carcinoma in a southern Chinese population

Abstract

Background: The objective of this study was to investigate genetic variations and the relationships between these genetic variations and clinicopathological features of high-recurrence risk papillary thyroid carcinoma in a southern Chinese population. Methods: One hundred sixty-eight patients of high-recurrence risk papillary thyroid carcinoma were recruited for this study from 2017 to 2018. Formalin-fixed paraffin-embedded tissue and the data of clinicopathological characteristics were all collected and analyzed from these patients. We used next-generation sequencing technology to investigate the targeted gene mutations and gene fusions of the pathology specimens. Results: The frequency of candidate tumor driver gene mutation was 85.1% in 143 patients, including BRAF V600E mutation in 119 patients(70.8%), RET fusion in 13 patients(7.7%), TERT promoter mutations in 11 patients(6.5%), RAS (HRAS, NRAS, KRAS) gene mutations in 10 patients(6.0%), and other mutations involving TP53, PIK3CA, AKT1, PTEN and NTRK1. Concomitant presence of more than two genetic aberrations was seen in 27 patients (16.1%). Our study showed that BRAF V600E mutation is highly correlated with conventional PTC (p < 0.001), BRAF V600E and TERT promoter mutation duet was associated with older patient age (> 45, p = 0.003) and higher disease stage of III or IV (p = 0.002). RAS gene and BRAF V600E co-mutations were only seen in multifocal PTC (p = 0.015). Conclusion: In our high-recurrence risk PTC cohort, most patients had more than one driver gene aberration. Coexistence of BRAF V600E with TERT promoter mutations or with RAS mutations were significantly correlated with worse clinicopathological characteristics.

Yield and costs of molecular diagnostics on thyroid cytology slides in the Netherlands, adapting the Bethesda classification

“…44,52 TERT promoter variants, concurrent TERT and RAS variants or TERT and BRAF V600E gene variants are also reported to indicate a more aggressive nature with worse prognosis. [53][54][55][56][57] In case of GLIS translocations (modification to Bethesda V), a lobectomy is the appropriate treatment, for this translocation is highly specific for hyalinizing trabecular tumour (a benign lesion). 58,59 Ultimately, according to histopathologic assessment of the diagnostic hemithyroidectomy, a completing thyroidectomy may be performed in case of proven carcinoma.…”

“… 44 , 52 TERT promoter variants, concurrent TERT and RAS variants or TERT and BRAF V600E gene variants are also reported to indicate a more aggressive nature with worse prognosis. 53 , 54 , 55 , 56 , 57 …”

“…Some gene variants including TP53 , TERT and TERT gene fusions (indicated with * in Figure 1) are rather not specific for a follicular lesion per se, and may be found in various types of thyroid lesion, so, on its own, may justify the modification of a Bethesda III to Bethesda V. GLIS gene fusions are associated with hyalinizing trabecular tumours and may modify the Bethesda class as Bethesda V. Concurrent EIF1AX and RAS variants are reported to occur in advanced thyroid carcinomas promoting tumorigenesis 51 ; however, also NIFTP cases have been described harbouring concurrent EIF1AX and RAS variants 44,52 . TERT promoter variants, concurrent TERT and RAS variants or TERT and BRAF V600E gene variants are also reported to indicate a more aggressive nature with worse prognosis 53–57 …”

Somatic Mutation Profiling of Papillary Thyroid Carcinomas by Whole-exome Sequencing and Its Relationship with Clinical Characteristics

“…We also identified TP53, EP300, KRAS, and PTEN were the major core genes of the interaction network in our study, a large number of studies have confirmed the importance of these key genes in the pathogenesis of tumors, and PTC is no exception 6 , 55 - 61 . Mutations in TP53 in PTCs have been reported in many studies 62 - 64 , and they are significantly associated with the monitored tumor characteristics. Moreover, the TP53 mutation is thought to play a critical role in the transformation of differentiated thyroid cancer into anaplastic thyroid cancer 65 , 66 .…”

Molecular testing in fine‐needle aspiration of thyroid nodules

“…TERT promoter mutations often co-occur with BRAF V600E mutation and have an aggressive clinical course. 27,29,43,44,50,[52][53][54] The combination of TERT promoter mutations with RAS mutations appear to be associated with FTC, PDTC, and ATC. 49,55 TERT copy number alterations are more frequent in later stages of disease and is associated with promoter mutations.…”