title: Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer.
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.
authors: Division of Hematology and Oncology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea.
authors: Jun Ho
authors: JH
authors: Ji
authors: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Young Lyun
authors: YL
authors: Oh
authors: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Mineui
authors: M
authors: Hong
authors: Samsung Genome Institute, Samsung Medical Center, Seoul, Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors: Jae Won
authors: JW
authors: Yun
authors: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Hyun-Woo
authors: HW
authors: Lee
authors: Molecular Translational Research Center, Samsung Biomedical Research Institute, Seoul, Korea.
authors: DeokGeun
authors: D
authors: Kim
authors: Molecular Translational Research Center, Samsung Biomedical Research Institute, Seoul, Korea.
authors: Yongick
authors: Y
authors: Ji
authors: Molecular Translational Research Center, Samsung Biomedical Research Institute, Seoul, Korea.
authors: Duk-Hwan
authors: DH
authors: Kim
authors: Samsung Genome Institute, Samsung Medical Center, Seoul, Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors: Woong-Yang
authors: WY
authors: Park
authors: Samsung Genome Institute, Samsung Medical Center, Seoul, Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors: Hyun-Tae
authors: HT
authors: Shin
authors: Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Kyoung-Mee
authors: KM
authors: Kim
authors: Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Myung-Ju
authors: MJ
authors: Ahn
authors: Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Keunchil
authors: K
authors: Park
authors: Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Jong-Mu
authors: JM
authors: Sun
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D001483:Base Sequence; D018278:Carcinoma, Neuroendocrine / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: C522504:EML4-ALK fusion protein, human; C000715470:MAS1 protein, human; D015514:Oncogene Proteins, Fusion; D000090063:Proto-Oncogene Mas; C497511:GFPT1 protein, human; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases