PMID- 26295973 OWN - NLM STAT- MEDLINE DCOM- 20160510 LR - 20211203 IS - 1553-7404 (Electronic) IS - 1553-7390 (Print) IS - 1553-7390 (Linking) VI - 11 IP - 8 DP - 2015 Aug TI - Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer. PG - e1005467 LID - 10.1371/journal.pgen.1005467 [doi] LID - e1005467 AB - 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. FAU - Ji, Jun Ho AU - Ji JH AD - Division of Hematology and Oncology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea. FAU - Oh, Young Lyun AU - Oh YL AD - Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. FAU - Hong, Mineui AU - Hong M AD - Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. FAU - Yun, Jae Won AU - Yun JW AD - Samsung Genome Institute, Samsung Medical Center, Seoul, Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea. FAU - Lee, Hyun-Woo AU - Lee HW AD - Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. FAU - Kim, DeokGeun AU - Kim D AD - Molecular Translational Research Center, Samsung Biomedical Research Institute, Seoul, Korea. FAU - Ji, Yongick AU - Ji Y AD - Molecular Translational Research Center, Samsung Biomedical Research Institute, Seoul, Korea. FAU - Kim, Duk-Hwan AU - Kim DH AD - Molecular Translational Research Center, Samsung Biomedical Research Institute, Seoul, Korea. FAU - Park, Woong-Yang AU - Park WY AD - Samsung Genome Institute, Samsung Medical Center, Seoul, Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea. FAU - Shin, Hyun-Tae AU - Shin HT AD - Samsung Genome Institute, Samsung Medical Center, Seoul, Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea. FAU - Kim, Kyoung-Mee AU - Kim KM AD - Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. FAU - Ahn, Myung-Ju AU - Ahn MJ AD - Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. FAU - Park, Keunchil AU - Park K AD - Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. FAU - Sun, Jong-Mu AU - Sun JM AD - Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. LA - eng PT - Journal Article DEP - 20150821 PL - United States TA - PLoS Genet JT - PLoS genetics JID - 101239074 RN - 0 (EML4-ALK fusion protein, human) RN - 0 (MAS1 protein, human) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (Proto-Oncogene Mas) RN - EC 2.6.1.16 (GFPT1 protein, human) RN - EC 2.6.1.16 (Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Alk protein, rat) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret) RN - EC 2.7.10.1 (RET protein, human) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - Thyroid cancer, medullary SB - IM MH - Adult MH - Anaplastic Lymphoma Kinase MH - Base Sequence MH - Carcinoma, Neuroendocrine/*genetics MH - DNA Mutational Analysis MH - Female MH - Genetic Predisposition to Disease MH - Genome, Human MH - Genome-Wide Association Study MH - Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)/genetics MH - Humans MH - Male MH - Middle Aged MH - Oncogene Proteins, Fusion/genetics MH - Proto-Oncogene Mas MH - Proto-Oncogene Proteins c-ret/genetics MH - Receptor Protein-Tyrosine Kinases/*genetics MH - Thyroid Neoplasms/*genetics MH - Young Adult PMC - PMC4546689 COIS- The authors have declared that no competing interest exist. EDAT- 2015/08/22 06:00 MHDA- 2016/05/11 06:00 PMCR- 2015/08/21 CRDT- 2015/08/22 06:00 PHST- 2015/04/10 00:00 [received] PHST- 2015/07/24 00:00 [accepted] PHST- 2015/08/22 06:00 [entrez] PHST- 2015/08/22 06:00 [pubmed] PHST- 2016/05/11 06:00 [medline] PHST- 2015/08/21 00:00 [pmc-release] AID - PGENETICS-D-15-00884 [pii] AID - 10.1371/journal.pgen.1005467 [doi] PST - epublish SO - PLoS Genet. 2015 Aug 21;11(8):e1005467. doi: 10.1371/journal.pgen.1005467. eCollection 2015 Aug.