title: Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus.
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 AmpliSeqTM 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.
authors: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
authors: Sun Min
authors: SM
authors: Lim
authors: Department of Pharmacology and Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors: Hyung Soon
authors: HS
authors: Park
authors: Severance Biomedical Science Institute and Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors: Sangwoo
authors: S
authors: Kim
authors: Severance Biomedical Science Institute and Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors: Sora
authors: S
authors: Kim
authors: Foundation Medicine Inc, Cambridge, MA, USA.
authors: Siraj M
authors: SM
authors: Ali
authors: Foundation Medicine Inc, Cambridge, MA, USA.
authors: Joel R
authors: JR
authors: Greenbowe
authors: Severance Biomedical Science Institute and Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors: In Seok
authors: IS
authors: Yang
authors: MacroGen Inc., Seoul, Korea.
authors: Nak-Jung
authors: NJ
authors: Kwon
authors: Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Jae Lyun
authors: JL
authors: Lee
authors: Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Min-Hee
authors: MH
authors: Ryu
authors: Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Jin-Hee
authors: JH
authors: Ahn
authors: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Jeeyun
authors: J
authors: Lee
authors: Department of Pharmacology and Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors: Min Goo
authors: MG
authors: Lee
authors: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Hyo Song
authors: HS
authors: Kim
authors: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors: Hyunki
authors: H
authors: Kim
authors: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Hye Ryun
authors: HR
authors: Kim
authors: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.|Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
authors: Yong Wha
authors: YW
authors: Moon
authors: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Hyun Cheol
authors: HC
authors: Chung
authors: Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea.
authors: Joo-Hang
authors: JH
authors: Kim
authors: Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors: Yoon-Koo
authors: YK
authors: Kang
authors: Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors: Byoung Chul
authors: BC
authors: Cho
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D007765:Lacrimal Apparatus / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012509:Sarcoma / Q000188:drug therapy; D013274:Stomach Neoplasms / Q000188:drug therapy; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000188:drug therapy; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000068338:Everolimus; D025542:Neurofibromin 1; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C495901:TP53 protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C546760:PIK3CG protein, human
keywords: NF1; TSC1; everolimus; mTOR; next-generation sequencing