Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus
| العنوان: | Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus |
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| المؤلفون: | Jeeyun Lee, Sora Kim, Hyo Song Kim, Hyun Cheol Chung, Siraj M. Ali, Byoung Chul Cho, Sangwoo Kim, Hyunki Kim, Jin-Hee Ahn, Sun Min Lim, Joel R. Greenbowe, Hyung Soon Park, In Seok Yang, Yoon-Koo Kang, Joo Hang Kim, Hye Ryun Kim, Nak Jung Kwon, Jae-Lyun Lee, Min Hee Ryu, Yong Wha Moon, Min Goo Lee |
| المصدر: | Oncotarget ResearcherID |
| بيانات النشر: | Impact Journals LLC, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Oncology, Male, Somatic cell, Tuberous Sclerosis Complex 1 Protein, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Class Ib Phosphatidylinositol 3-Kinase, Genetics, Aged, 80 and over, BAP1, Neurofibromin 1, TOR Serine-Threonine Kinases, Lacrimal Apparatus, High-Throughput Nucleotide Sequencing, Sarcoma, Middle Aged, Kidney Neoplasms, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, mTOR, Female, medicine.drug, Research Paper, Adult, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, Antineoplastic Agents, Adenocarcinoma, Polymorphism, Single Nucleotide, DNA sequencing, 03 medical and health sciences, Young Adult, Stomach Neoplasms, Internal medicine, Tuberous Sclerosis Complex 2 Protein, medicine, Humans, Everolimus, Thyroid Neoplasms, Carcinoma, Renal Cell, PI3K/AKT/mTOR pathway, Predictive biomarker, Aged, business.industry, Tumor Suppressor Proteins, Head and neck cancer, Cancer, medicine.disease, TSC1, 030104 developmental biology, NF1, Drug Resistance, Neoplasm, Mutation, next-generation sequencing, Tumor Suppressor Protein p53, business |
| الوصف: | // Sun Min Lim 1,2,* , Hyung Soon Park 3,* , Sangwoo Kim 4 , Sora Kim 4 , Siraj M. Ali 5 , Joel R. Greenbowe 5 , In Seok Yang 4 , Nak-Jung Kwon 6 , Jae Lyun Lee 7 , Min-Hee Ryu 7 , Jin-Hee Ahn 7 , Jeeyun Lee 8 , Min Goo Lee 3 , Hyo Song Kim 1 , Hyunki Kim 9 , Hye Ryun Kim 1 , Yong Wha Moon 1,2 , Hyun Cheol Chung 1 , Joo-Hang Kim 2 , Yoon-Koo Kang 7 and Byoung Chul Cho 1 1 Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea 2 Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea 3 Department of Pharmacology and Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea 4 Severance Biomedical Science Institute and Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea 5 Foundation Medicine Inc, Cambridge, MA, USA 6 MacroGen Inc., Seoul, Korea 7 Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea 8 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 9 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Yoon-Koo Kang, email: // Byoung Chul Cho, email: // Keywords : everolimus, NF1, TSC1, mTOR, next-generation sequencing Received : November 27, 2015 Accepted : January 25, 2016 Published : February 07, 2016 Abstract Background: Given the modest responses to everolimus, a mTOR inhibitor, in multiple tumor types, there is a pressing need to identify predictive biomarkers for this drug. Using targeted ultra-deep sequencing, we aimed to explore genomic alterations that confer extreme sensitivity to everolimus. Results: We collected formalin-fixed paraffin-embedded tumor/normal pairs from 39 patients (22 with exceptional clinical benefit, 17 with no clinical benefit) who were treated with everolimus across various tumor types (13 gastric cancers, 15 renal cell carcinomas, 2 thyroid cancers, 2 head and neck cancer, and 7 sarcomas). Ion AmpliSeq TM Comprehensive Cancer Panel was used to identify alterations across all exons of 409 target genes. Tumors were sequenced to a median coverage of 552x. Cancer genomes are characterized by 219 somatic single-nucleotide variants (181 missense, 9 nonsense, 7 splice-site) and 22 frameshift insertions/deletions, with a median of 2.1 mutations per Mb (0 to 12.4 mutations per Mb). Overall, genomic alterations with activating effect on mTOR signaling were identified in 10 of 22 (45%) patients with clinical benefit and these include MTOR, TSC1, TSC2, NF1 , PIK3CA and PIK3CG mutations. Recurrently mutated genes in chromatin remodeling genes ( BAP1; n = 2, 12%) and receptor tyrosine kinase signaling ( FGFR4; n = 2, 12%) were noted only in patients without clinical benefit. Conclusions: Regardless of different cancer types, mTOR-pathway-activating mutations confer sensitivity to everolimus. Targeted sequencing of mTOR pathway genes facilitates identification of potential candidates for mTOR inhibitors. |
| اللغة: | English |
| تدمد: | 1949-2553 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::029b1d948f0ecf95f7548daf9ddc13d6Test http://europepmc.org/articles/PMC4891139Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....029b1d948f0ecf95f7548daf9ddc13d6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19492553 |
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