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PLoS Genet
2015 Aug 21;118:e1005467. doi: 10.1371/journal.pgen.1005467.
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Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer.
Ji JH
,
Oh YL
,
Hong M
,
Yun JW
,
Lee HW
,
Kim D
,
Ji Y
,
Kim DH
,
Park WY
,
Shin HT
,
Kim KM
,
Ahn MJ
,
Park K
,
Sun JM
.
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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.
Fig 1. Mutational profiles of medullary thyroid cancer (MTC), as identified by next-generation sequencing.SNP, single-nucleotide polymorphism; DEL, deletion.
Fig 2. Mutational profiles for comparisons between MTC tissues and normal thyroid tissues from the same individual.Samples from 36 individuals were used. SNP, single-nucleotide polymorphism; DEL, deletion.
Fig 3. Anaplastic lymphoma kinase (ALK) staining using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).(A) and (C) ALK staining in tumor cells was detected by IHC. (B) and (D) Results of FISH with the break-apart ALK probe are shown. A single red signal or splitting of the red and green signals was observed (marked with arrows). The cases shown in A/B and C/D exhibited glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-ALK and echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions, respectively.
Fig 4. Gene fusion between GFPT1 and ALK.(A) Schematic representation of the fusion of the 5’ GFPT1 to 3’ ALK. (B) The fusion of GFPT1 to ALK is oriented in the same direction and is located in 2p23. Confirmation of the GFPT1-ALK fusion was carried out by reverse transcription-polymerase chain reaction and Sanger sequencing. GATase_2, glutamine aminotransferases class-II; SIS, Sugar ISomerase domain; MAM, meprin/A5-protein/PTPmu domain; Gly_rich, glycine rich protein; Pkinase_Tyr, protein tyrosine kinase.
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