NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma

Abstract

ContextAnaplastic thyroid carcinoma (ATC) represents one of the most aggressive carcinomas with no consistent survival benefit when treated with conventional radiochemotherapy. Approaches targeting “oncogene addiction” of ATC are increasingly explored and first promising results have been reported in single case studies.ObjectiveTo determine the prevalence of mutations in known thyroid oncogenes and signalling pathways amendable to targeted therapy in a large cohort of ATC.ResultsIn 118 ATC (57 male/ 61 female) a total of 165 mutations were found. Genes involved in the MAPK/ERK and PI3K pathway (BRAF 11.0%, HRAS 4.2%, KRAS 7.6%, NRAS 7.6%, PI3KCA 11.8%) were altered in 33%. Targetable receptor tyrosine kinases were mutated in 11%. The most frequently altered genes were TERT in 86/118 (73%) and p53 in 65/118 (55%) cases. No mutations were found analysing ALK, KIT, MET and mTOR.Materials and MethodsNext generation sequencing (NGS) was performed in FFPE samples from 118 ATC using MiSeq (Illumina) and CLC Cancer Research Workbench (CLCbio; Qiagen) for mutation analysis in: ALK, BRAF, CDKN2A, EGFR, ERBB2, HRAS, KIT, KRAS, MET, mTOR, NRAS, PDGFRA, PI3KCA, p53, RB1, RET and TSC2. Sanger sequencing was used to detect TERT promotor mutations.ConclusionsTo our knowledge this is the largest study analysing mutations for targeted therapy of ATC. We found that 33% of ATC harbour mutations in pathways amendable to targeted therapy. Molecular screening in ATC is suggested for targeted therapies since current conventional treatment for ATC proved mainly futile.

Anaplastic thyroid carcinoma: review of treatment protocols

“…To improve ATC patient treatment in Germany, a therapy protocol was developed that allows standardized therapy with acceptable toxicity including surgery in selected cases, followed by combined radiochemotherapy and mutational screening of known oncogenes with subsequent targeted therapies (Tiedje et al 2015).…”

“…Therefore, it is possible that a subset of ATC arises from DTC. Moreover, histology shows that DTC co-exists in around 30-50% of ATC (Sugitani et al 2012, Zivaljevic et al 2014, Tiedje et al 2017.…”

“…Recent high-throughput sequencing investigations have further elucidated the genetic signature of ATC (Kunstman et al 2015, Landa et al 2016, Latteyer et al 2016a, Tiedje et al 2017. One important characteristic is a high mutational burden due to the accumulation of different somatic mutations (Landa et al 2016).…”

“…Besides TP53 mutations, considered as a genetic hallmark of ATC, several other genetic alterations have been identified to date in ATC e.g. BRAF and RAS mutations that also occur in differentiated thyroid carcinoma (DTC) (Tiedje et al 2017). Therefore, it is possible that a subset of ATC arises from DTC.…”

Anti-hTERT siRNA-Loaded Nanoparticles Block the Growth of Anaplastic Thyroid Cancer Xenograft

“…In the search for novel molecular targets, valid help comes from the genomic analysis of a large number of human tumors. Studies on ATCs have revealed that telomerase reverse transcriptase (TERT) gene alterations are the most frequent event detected in this type of neoplasia (5,(7)(8)(9)(10). In addition, overexpression of TERT has been reported in thyroid carcinomas, lymph node metastases, and, more recently, even in ATCs (11,12).…”