Novel TG‐FGFR1 and TRIM33‐NTRK1 transcript fusions in papillary thyroid carcinoma

Abstract

Papillary thyroid carcinoma (PTC) is most common among all thyroid cancers. Multiple genomic alterations occur in PTC, and gene rearrangements are one of them. Here we screened 14 tumors for novel fusion transcripts by RNA‐Seq. Two samples harboring RET/PTC1 and RET/PTC3 rearrangements were positive controls whereas the remaining ones were negative regarding the common PTC alterations. We used Sanger sequencing to validate potential fusions. We detected 2 novel potentially oncogenic transcript fusions: TG‐FGFR1 and TRIM33‐NTRK1 . We detected 4 novel fusion transcripts of unknown significance accompanying the TRIM33‐NTRK1 fusion: ZSWIM5‐TP53BP2 , TAF4B‐WDR1 , ABI2‐MTA3 , and ARID1B‐PSMA1 . Apart from confirming the presence of RET/PTC1 and RET/PTC3 in positive control samples, we also detected known oncogenic fusion transcripts in remaining samples: TFG‐NTRK1 , ETV6‐NTRK3 , MKRN1‐BRAF , EML4‐ALK , and novel isoform of CCDC6‐RET .

NTRK Fusion Genes in Thyroid Carcinomas: Clinicopathological Characteristics and Their Impacts on Prognosis

“…Molecular markers, such as the BRAF V600E mutation or the TERT mutation, have been well studied in large cohorts, and the management of thyroid nodules harboring these mutations has also been recommended in the American and the European Thyroid Association Guidelines [ 18 , 19 ]. However, data on NTRK fusion genes in TC are very limited due to their rare occurrence, and therefore there are only small cohorts of NTRK fusion-positive samples that are described and characterized [ 10 , 11 , 12 , 15 , 20 , 21 , 22 , 23 , 24 ]. Another reason is their more expensive and challenging accurate testing requiring RNA of suitable quality.…”

Complete response to larotrectinib treatment in a patient with papillary thyroid cancer harboring an ETV6‐NTRK3 gene fusion

“…In addition, a recent study reported a patient with ETV6‐NTRK secretory thyroid carcinoma who had a long‐lasting response (21 months) to larotrectinib with complete resolution of the radiologically detectable tumor, and a patient with TPR‐NTRK1 PTC who had a 33% decrease in tumor burden and stable disease for 15 months 34 . NTRK gene fusions occur relatively frequently in thyroid cancer—in 2‐15% of adult patients, with the highest levels observed in post‐Chernobyl reactor accident cases, and in 2‐26% of pediatric patients with thyroid cancer 34‐40 . A number of NTRK gene rearrangements have been observed in thyroid carcinomas, including ETV6‐NTRK3 , TPR‐NTRK1 , RBPMS‐NTRK3 , SQSTM1‐NTRK1/3 , and EML4‐NTRK3 34 .…”

“…34 NTRK gene fusions occur relatively frequently in thyroid cancer-in 2-15% of adult patients, with the highest levels observed in post-Chernobyl reactor accident cases, and in 2-26% of pediatric patients with thyroid cancer. [34][35][36][37][38][39][40] A number of NTRK gene rearrangements have been observed in thyroid carcinomas, including ETV6-NTRK3, TPR-NTRK1, 34 As demonstrated in this case, NTRK-rearranged thyroid cancer is clinically aggressive with a high rate of metastatic spread, but with low mortality when treated with TRK inhibitor therapy. 34 Due to the prevalence and actionability of NTRK gene fusions, upfront molecular testing should be recommended for patients with advanced or metastatic RAI-R DTC, if feasible.…”

Next generation sequencing based detection of 15 target genes mutations in papillary thyroid carcinoma

“…5,6 Recently, published literature increasingly suggested that somatic mutations in BRAF, HRAS, KRAS, NRAS, TERT, RET, PIK3CA, PTEN, TP53, CTNNB1,AKT1, GNAS, PAX8/PPARγ, NTRK1, and TSHR genes have been associated with diagnosis and treatment of TC. [7][8][9][10][11][12][13][14][15][16] Next generation sequencing (NGS) is a newlydeveloped technique offered a cost-effective approach for detecting multiple genetic alterations and provided quantitative assessment of mutation frequency. 17,18 Therefore, a panel designed to these 15 target genes was used to detect molecular alterations by NGS in PTC.…”

“…In the past, single gene assays, such as BRAF V600E mutation, have been commonly used for finding molecular alterations by Sanger sequence, immunohistochemistry, and real time PCR in PTC 5,6 . Recently, published literature increasingly suggested that somatic mutations in BRAF, HRAS, KRAS, NRAS, TERT, RET, PIK3CA, PTEN, TP53, CTNNB1,AKT1, GNAS, PAX8/PPARγ, NTRK1, and TSHR genes have been associated with diagnosis and treatment of TC 7‐16 . Next generation sequencing (NGS) is a newly‐developed technique offered a cost‐effective approach for detecting multiple genetic alterations and provided quantitative assessment of mutation frequency 17,18 .…”