Abstract
The genetic landscape of medullary thyroid cancer (MTC) is not yet fully understood, although some oncogenic mutations have been identified. To explore genetic profiles of MTCs, formalin-fixed, paraffin-embedded tumor tissues from MTC patients were assayed on the Ion AmpliSeq Cancer Panel v2. Eighty-four sporadic MTC samples and 36 paired normal thyroid tissues were successfully sequenced. We discovered 101 hotspot mutations in 18 genes in the 84 MTC tissue samples. The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3). We also evaluated anaplastic lymphoma kinase (ALK) rearrangement by immunohistochemistry and break-apart fluorescence in situ hybridization (FISH). Two of 98 screened cases were positive for ALK FISH. To identify the genomic breakpoint and 5’ fusion partner of ALK, customized targeted cancer panel sequencing was performed using DNA from tumor samples of the two patients. Glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-ALK and echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions were identified. Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1-ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion. Notably, a metastatic MTC case harboring the EML4-ALK fusion showed a dramatic response to an ALK inhibitor, crizotinib. In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC. Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors. Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular target therapy.
Highlights
Many cancer gene profiling studies have recently been published, describing genetic trends that are not limited to specific cancers
Little is known about the molecular biology of medullary thyroid cancer (MTC), which is a rare disease
Anaplastic lymphoma kinase (ALK) rearrangements were detected in MTC: one case with a glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-anaplastic lymphoma kinase (ALK) fusion, and another case with an echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion
Summary
Many cancer gene profiling studies have recently been published, describing genetic trends that are not limited to specific cancers. Next-generation sequencing (NGS) is an important tool for detecting genetic alterations in many kinds of cancers, as it allows for millions of nucleic acid sequences to be simultaneously sequenced within a short period of time and is more costeffective than older methods. Medullary thyroid cancer (MTC) is a rare malignancy that accounts for up to 3–5% of thyroid cancers. It is derived from calcitonin-secreting para-follicular C cells and can arise in a familial (25%) or sporadic (75%) pattern. Genetic and epigenetic alterations play important roles in the progression and prognosis of MTC [1,2,3]. The RET mutation is believed to be a causative event in both familial and sporadic MTC [6, 7]. In the Mitogen-activated protein kinase (MAPK) pathway, the RAS mutation is another genetic rearrangement that is prevalent in sporadic MTC and other types of thyroid cancer [2] but the prevalence and significance of other genetic mutations including BRAF in MTC remain unclear
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