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RET fusion

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https://www.readbyqxmd.com/read/28634282/genomic-alterations-in-fatal-forms-of-non-anaplastic-thyroid-cancer-identification-of-med12-and-rbm10-as-novel-thyroid-cancer-genes-associated-with-tumor-virulence
#1
Tihana Ibrahimpasic, Bin Xu, Iñigo Landa, Snjezana Dogan, Sumit Middha, Venkatraman Seshan, Shyamprasad Deraje Vasudeva, Diane Carlson, Jocelyn Migliacci, Jeffrey A Knauf, Brian R Untch, Michael F Berger, Luc Gt Morris, R Michael Tuttle, Timothy A Chan, James A Fagin, Ronald Ghossein, Ian Ganly
Purpose. Patients with anaplastic thyroid cancer have a very high death rate. In contrast, deaths from non-anaplastic thyroid cancer are much less common. The genetic alterations in fatal non-anaplastic thyroid cancers have not been reported. <p>Experimental Design. We performed next-generation sequencing of 410 cancer genes from 57 fatal non-anaplastic thyroid primary cancers. Results were compared to The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC) and to the genomic changes reported in anaplastic thyroid cancer (ATC)...
June 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28615362/drugging-the-catalytically-inactive-state-of-ret-kinase-in-ret-rearranged-tumors
#2
Dennis Plenker, Maximilian Riedel, Johannes Brägelmann, Marcel A Dammert, Rakhee Chauhan, Phillip P Knowles, Carina Lorenz, Marina Keul, Mike Bührmann, Oliver Pagel, Verena Tischler, Andreas H Scheel, Daniel Schütte, Yanrui Song, Justina Stark, Florian Mrugalla, Yannic Alber, André Richters, Julian Engel, Frauke Leenders, Johannes M Heuckmann, Jürgen Wolf, Joachim Diebold, Georg Pall, Martin Peifer, Maarten Aerts, Kris Gevaert, René P Zahedi, Reinhard Buettner, Kevan M Shokat, Neil Q McDonald, Stefan M Kast, Oliver Gautschi, Roman K Thomas, Martin L Sos
Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors...
June 14, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28577945/systematic-identification-of-cancer-related-long-noncoding-rnas-and-aberrant-alternative-splicing-of-quintuple-negative-lung-adenocarcinoma-through-rna-seq
#3
Lu Zhang, Shiyong Li, Yoon-La Choi, Jinseon Lee, Zhuolin Gong, Xiaoqiao Liu, Yunfei Pei, Awei Jiang, Mingzhi Ye, Mao Mao, Xuegong Zhang, Jhingook Kim, Ronghua Chen
OBJECTIVES: Lung adenocarcinoma (LUAD) is a common subtype of non-small cell lung cancer prevalent in Asia. There is a dearth of understanding regarding the transcriptome landscape of LUAD without primary known driver mutations. In this study, LUAD samples without well-known driver mutations occurring in EGFR, KRAS, ALK, ROS1 or RET (quintuple-negative) were used for transcriptome study with a focus on long noncoding RNAs (lncRNAs), alternative splicing and gene fusions. MATERIALS AND METHODS: 24 pairs of LUAD and adjacent normal samples and 13 tumor-only samples derived from 37 quintuple-negative patients were used...
July 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28575860/in-vitro-and-in-vivo-anti-tumor-activity-of-alectinib-in-tumor-cells-with-ncoa4-ret
#4
Sachiko Arai, Kenji Kita, Azusa Tanimoto, Shinji Takeuchi, Koji Fukuda, Hiroshi Sato, Seiji Yano
Rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) accounts for approximately 1-2% of all NSCLCs. To date, RET fusions that involve at least six fusion partners in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1, and ERC1, have been identified. Recent clinical trials for RET fusion-positive NSCLC using vandetanib or cabozantinib demonstrated positive clinical response and considerable differential activities for RET inhibitors among fusion partners. Alectinib, an approved ALK inhibitor, is reported to inhibit KIF5B-RET and CCDC6-RET...
May 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28569245/genetic-diagnosis-of-a-chinese-multiple-endocrine-neoplasia-type-2a-family-through-whole-genome-sequencing
#5
Zhen-Fang DU, Peng-Fei Li, Jian-Qiang Zhao, Zhi-Lie Cao, Feng Li, Ju-Ming Ma, Xiao-Ping Qi
Approximately 98% of patients with multiple endocrine neoplasia type 2A (MEN 2A) have an identifiable RET mutation. Prophylactic or early total thyroidectomy or pheochromocytoma/parathyroid removal in patients can be preventative or curative and has become standard management. The general strategy for RET screening on family members at risk is to sequence the most commonly affected exons and, if negative, to extend sequencing to additional exons. However, different families with MEN 2A due to the same RET mutation often have significant variability in the clinical exhibition of disease and aggressiveness of the MTC, which implies additional genetic loci exsit beyond RET coding region...
June 2017: Journal of Biosciences
https://www.readbyqxmd.com/read/28515244/what-when-and-how-of-biomarker-testing-in-non-small-cell-lung-cancer
#6
Gregory L Riely
Biomarker testing is recommended for all patients diagnosed with non-small cell lung cancer. At a minimum, testing should include the mutations/fusions EGFR, ALK, ROS1, and the protein programmed death ligand-1 (PD-L1), because FDA-approved therapies are available for these alterations. Other actionable molecular findings include RET rearrangements, BRAF(V600E) mutations, and MET exon 14 alterations. If adequate testing was not performed at treatment initiation, molecular testing should be performed before administration of subsequent lines of therapy...
May 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28512242/a-systematic-analysis-of-oncogenic-gene-fusions-in-primary-colon-cancer
#7
Wigard P Kloosterman, Robert R J Coebergh van den Braak, Mark Pieterse, Markus J van Roosmalen, Anieta M Sieuwerts, Christina Stangl, Ronne Brunekreef, Zarina S Lalmahomed, Salo Ooft, Anne van Galen, Marcel Smid, Armel Lefebvre, Fried Zwartkruis, John W M Martens, John A Foekens, Katharina Biermann, Marco J Koudijs, Jan N M IJzermans, Emile E Voest
Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28507274/targeted-next-generation-sequencing-identifies-somatic-mutations-and-gene-fusions-in-papillary-thyroid-carcinoma
#8
Zheming Lu, Yujie Zhang, Dongdong Feng, Jindong Sheng, Wenjun Yang, Baoguo Liu
138 papillary thyroid carcinoma (PTC) samples were assessed for somatic mutation profile and fusion genes by targeted resequencing using a cancer panel (ThyGenCapTM) targeting 244 cancer-related genes and 20 potential fusion genes. At least one genetic alteration (including mutations and fusion genes) was observed in 118/138 (85.5%) samples. The most frequently mutated gene was BRAF V600E (57.2%). Moreover, we identified 11 fusion genes including eight previously reported ones and three novel fusion genes, UEVLD-RET, OSBPL9-BRAF, and SQSTM1-NTRK3...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28502721/met-exon-14-skipping-mutations-in-lung-adenocarcinoma-clinicopathologic-implications-and-prognostic-values
#9
Geun Dong Lee, Seung Eun Lee, Doo-Yi Oh, Dan-Bi Yu, Hae Min Jeong, Jooseok Kim, Sungyoul Hong, Hun Soon Jung, Ensel Oh, Ji-Young Song, Mi-Sook Lee, Mingi Kim, Kyungsoo Jung, Jhingook Kim, Young Kee Shin, Yoon-La Choi, Hyeong Ryul Kim
INTRODUCTION: Response to MET inhibitors in non-small cell lung cancer with MET exon 14 (METex14) skipping has fueled molecular screening efforts and search for optimal therapies. However, further work is needed to refine the clinicopathologic and prognostic implications of METex14 skipping METHODS: Among 795 East-Asian patients who underwent surgery for non-small cell lung cancer, we screened 45 patients with quintuple-negative (EGFR-/KRAS-/ALK-/ROS1-/RET-) lung adenocarcinomas using RT-PCR, and found 17 patients (37...
May 10, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28500237/resistance-to-ret-inhibition-in-ret-rearranged-nsclc-is-mediated-by-reactivation-of-ras-mapk-signaling
#10
Sarah K Nelson-Taylor, Anh T Le, Minjae Yoo, Laura Schubert, Katie M Mishall, Andrea Doak, Marileila Varella-Garcia, Aik-Choon Tan, Robert C Doebele
Oncogenic rearrangements in RET are present in 1-2% of lung adenocarcinoma (LAD) patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent anti-proliferative activity in RET fusion positive LC-2/ad LAD cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose-escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28490045/uterine-inflammatory-myofibroblastic-tumors-frequently-harbor-alk-fusions-with-igfbp5-and-thbs1
#11
Josh D Haimes, Colin J R Stewart, Brian A Kudlow, Brady P Culver, Bo Meng, Eleanor Koay, Ann Whitehouse, Nichola Cope, Jen-Chieh Lee, Tony Ng, W Glenn McCluggage, Cheng-Han Lee
Inflammatory myofibroblastic tumor (IMT) can occur in a number of anatomic sites, including the uterus. Like its soft tissue counterpart, uterine IMT frequently expresses ALK and harbors ALK genetic rearrangements. The aim of this study is to fully characterize the genetic fusions that occur in uterine IMT. We studied 11 uterine IMTs with typical histology and 8 uterine myxoid smooth muscle tumors (5 leiomyomas, 1 smooth muscle tumor of uncertain malignant potential, and 2 leiomyosarcomas) in which the differential of IMT was considered, using a RNA-sequencing-based fusion assay to detect genetic fusions involving ALK, ROS1, RET, NTRK1/3, and other genes...
June 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28471124/multiplex-genomic-test-of-mutation-and-fusion-genes-in-small-biopsy-specimen-of-lung-cancer
#12
Fumihiro Oshita, Rika Kasajima, Yohei Miyagi
We evaluated multiple oncogenic mutations and fusion genes in small specimen obtained by bronchoscopy. Eight patients with lung cancer were recruited, 3 small cell lung cancer, 3 non-small cell lung cancer, 1 adenocarcinoma and 1 squamous cell carcinoma. A median value of extracted RNA and DNA amounts from specimen was 1573 ng (range 367.5 to 8900) and 6700 ng (range 550 to 68000 ng), respectively. We applied amplicon sequencing panels that cover exon regions of 41 genes related to lung tumorigenesis as well as total 61 major variants of ALK, ROS, RET or NTRK1 fusion transcripts...
July 2016: Journal of Experimental Therapeutics & Oncology
https://www.readbyqxmd.com/read/28448556/a-highly-specific-and-sensitive-massive-parallel-sequencer-based-test-for-somatic-mutations-in-non-small-cell-lung-cancer
#13
Yoshiaki Inoue, Jun Shiihara, Hitoshi Miyazawa, Hiromitsu Ohta, Megumi Higo, Yoshiaki Nagai, Kunihiko Kobayashi, Yasuo Saijo, Masanori Tsuchida, Mitsuo Nakayama, Koichi Hagiwara
Molecular targeting therapy for non-small cell lung cancer (NSCLC) has clarified the importance of mutation testing when selecting treatment regimens. As a result, multiple-gene mutation tests are urgently needed. We developed a next-generation sequencer (NGS)-based, multi-gene test named the MINtS for investigating driver mutations in both cytological specimens and snap-frozen tissue samples. The MINtS was used to investigate the EGFR, KRAS, BRAF genes from DNA, and the ERBB2, and the ALK, ROS1, and RET fusion genes from RNA...
2017: PloS One
https://www.readbyqxmd.com/read/28433076/identification-of-ntrk3-fusions-in-childhood-melanocytic-neoplasms
#14
Lu Wang, Klaus J Busam, Ryma Benayed, Robert Cimera, Jiajing Wang, Ryan Denley, Mamta Rao, Ruth Aryeequaye, Kerry Mullaney, Long Cao, Marc Ladanyi, Meera Hameed
Spitzoid neoplasms are a distinct group of melanocytic tumors. Genetically, they lack mutations in common melanoma-associated oncogenes. Recent studies have shown that spitzoid tumors may contain a variety of kinase fusions, including ROS1, NTRK1, ALK, BRAF, and RET fusions. We report herein the discovery of recurrent NTRK3 gene rearrangements in childhood melanocytic neoplasms with spitzoid and/or atypical features, based on genome-wide copy number analysis by single-nucleotide polymorphism array, which showed intragenic copy number changes in NTRK3...
May 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28428274/egfr-mediates-responses-to-small-molecule-drugs-targeting-oncogenic-fusion-kinases
#15
Aria Vaishnavi, Laura Schubert, Uwe Rix, Lindsay A Marek, Anh T Le, Stephen Keysar, Magdalena J Glogowska, Matthew A Smith, Severine L Kako, Natalia J Sumi, Kurtis D Davies, Kathryn E Ware, Marileila Varella-Garcia, Eric B Haura, Antonio Jimeno, Lynn E Heasley, Dara L Aisner, Robert C Doebele
Oncogenic kinase fusions of ALK, ROS1, RET and NTRK1 act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1+ lung cancer patients with oncogene-targeted therapy ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naive cancer cells harboring these oncogene fusions...
April 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28415793/clinical-framework-for-next-generation-sequencing-based-analysis-of-treatment-predictive-mutations-and-multiplexed-gene-fusion-detection-in-non-small-cell-lung-cancer
#16
Kajsa Ericson Lindquist, Anna Karlsson, Per Levéen, Hans Brunnström, Christel Reuterswärd, Karolina Holm, Mats Jönsson, Karin Annersten, Frida Rosengren, Karin Jirström, Jaroslaw Kosieradzki, Lars Ek, Åke Borg, Maria Planck, Göran Jönsson, Johan Staaf
Precision medicine requires accurate multi-gene clinical diagnostics. We describe the implementation of an Illumina TruSight Tumor (TST) clinical NGS diagnostic framework and parallel validation of a NanoString RNA-based ALK, RET, and ROS1 gene fusion assay for combined analysis of treatment predictive alterations in non-small cell lung cancer (NSCLC) in a regional healthcare region of Sweden (Scandinavia). The TST panel was clinically validated in 81 tumors (99% hotspot mutation concordance), after which 533 consecutive NSCLCs were collected during one-year of routine clinical analysis in the healthcare region (~90% advanced stage patients)...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28382399/ccr5-in-recruitment-and-activation-of-myeloid-derived-suppressor-cells-in-melanoma
#17
REVIEW
Viktor Umansky, Carolin Blattner, Christoffer Gebhardt, Jochen Utikal
Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, leading to the accumulation of myeloid-derived suppressor cells (MDSCs). Using ret transgenic mouse melanoma model, we found a significant migration of MDSCs expressing C-C chemokine receptor (CCR)5 into primary tumors and metastatic lymph nodes, which was correlated with tumor progression. An increased CCR5 expression on MDSCs was associated with elevated concentrations of CCR5 ligands in melanoma microenvironment...
April 5, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28351223/identification-of-three-novel-fusion-oncogenes-sqstm1-ntrk3-afap1l2-ret-and-ppfibp2-ret-in-thyroid-cancers-of-young-patients-in-fukushima
#18
Keita Iyama, Michiko Matsuse, Norisato Mitsutake, Tatiana Rogounovitch, Vladimir Saenko, Keiji Suzuki, Mai Ashizawa, Chiyo Ookouchi, Satoshi Suzuki, Hiroshi Mizunuma, Toshihiko Fukushima, Shinichi Suzuki, Shunichi Yamashita
BACKGROUND: The BRAF(V600E) mutation is the most frequent genetic abnormality in adult papillary thyroid carcinomas (PTCs). On the other hand, various chromosomal rearrangements are more prevalent in childhood and adolescent PTCs. The aim of the present study was to identify novel rearrangements in PTCs from young patients. METHODS: Among 63 postoperative specimens of childhood and adolescent PTCs, which had been discovered by the thyroid ultrasound screening program in Fukushima, nine samples without prevalent known oncogenes, BRAF(V600E), RAS, RET/PTC1, RET/PTC3, and ETV6/NTRK3, were analyzed in the current study by quantitative real-time reverse transcription polymerase chain reaction to screen for novel fusion genes by comparing transcript expression between extracellular and kinase domains of ALK, NTRK1, NTRK3, and RET...
June 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28350094/routine-genetic-testing-of-lung-cancer-specimens-derived-from-surgery-bronchoscopy-and-fluid-aspiration-by-next-generation-sequencing
#19
Gou Yamamoto, Mari Kikuchi, Shiho Kobayashi, Yoshiko Arai, Kenji Fujiyoshi, Tomokazu Wakatsuki, Miho Kakuta, Yuki Yamane, Yoshihito Iijima, Hideaki Mizutani, Yuki Nakajima, Junko Sudo, Hiroyasu Kinoshita, Futoshi Kurimoto, Hirohiko Akiyama, Hidetaka Uramoto, Hiroshi Sakai, Yoshito Akagi, Kiwamu Akagi
After the development of EGFR tyrosine kinase inhibitors (TKIs), genetic testing of EGFR became required for effective treatment of lung cancer. Initially, the testing was conducted separately for each mutated region. However, many EGFR mutations have since been identified that determine the efficacy of EGFR-TKIs. Therefore, genetic testing of EGFR by next generation sequencing (NGS) may be a suitable strategy for lung cancer. Here we examined the applicability of the NGS method in regard to sensitivity, time and cost...
May 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28293988/molecular-profiling-of-papillary-thyroid-carcinoma-in-korea-with-a-high-prevalence-of-braf-v600e-mutation
#20
Seung Eun Lee, Tae Sook Hwang, Yoon-La Choi, Wook Youn Kim, Hye Seung Han, So Dug Lim, Wan-Seop Kim, Young Bum Yoo, Suk Kyeong Kim
BACKGROUND: The BRAF(V600E) mutation in papillary thyroid carcinoma (PTC) is particularly prevalent in Korea, and a considerable number of wild-type BRAF PTCs harbor RAS mutations. In addition, subsets of other genetic alterations clearly exist, but their prevalence in the Korean population has not been well studied. Recent increased insight into noninvasive encapsulated follicular variant PTC has prompted endocrine pathologists to reclassify this entity as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP)...
June 2017: Thyroid: Official Journal of the American Thyroid Association
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