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Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus

Authors
 Sun Min Lim  ;  Hyung Soon Park  ;  Sangwoo Kim  ;  Sora Kim  ;  Siraj M. Ali  ;  Joel R. Greenbowe  ;  In Seok Yang  ;  Nak-Jung Kwon  ;  Jae Lyun Lee  ;  Min-Hee Ryu  ;  Jin-Hee Ahn  ;  Jeeyun Lee  ;  Min Goo Lee  ;  Hyo Song Kim  ;  Hyunki Kim  ;  Hye Ryun Kim  ;  Yong Wha Moon  ;  Hyun Cheol Chung  ;  Joo-Hang Kim  ;  Yoon-Koo Kang  ;  Byoung Chul Cho 
Citation
 Oncotarget, Vol.7(9) : 10547-10556, 2016 
Journal Title
 Oncotarget 
Issue Date
2016
MeSH
Adenocarcinoma/drug therapy* ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use* ; Carcinoma, Renal Cell/drug therapy ; Class I Phosphatidylinositol 3-Kinases ; Class Ib Phosphatidylinositol 3-Kinase/genetics ; Drug Resistance, Neoplasm/genetics* ; Everolimus/therapeutic use* ; Female ; Head and Neck Neoplasms/drug therapy ; High-Throughput Nucleotide Sequencing ; Humans ; Kidney Neoplasms/drug therapy ; Lacrimal Apparatus/pathology* ; Male ; Middle Aged ; Mutation/genetics ; Neurofibromin 1/genetics* ; Phosphatidylinositol 3-Kinases/genetics ; Polymorphism, Single Nucleotide/genetics ; Sarcoma/drug therapy ; Stomach Neoplasms/drug therapy ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/genetics* ; Thyroid Neoplasms/drug therapy ; Tumor Suppressor Protein p53/genetics* ; Tumor Suppressor Proteins/genetics ; Young Adult
Keywords
NF1 ; TSC1 ; everolimus ; mTOR ; next-generation sequencing
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.
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DOI
10.18632/oncotarget.7234
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
Kim, So Ra(김소라)
Kim, Hyunki(김현기) ORCID logo https://orcid.org/0000-0003-2292-5584
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Kim, Hyo Song(김효송) ORCID logo https://orcid.org/0000-0002-0625-9828
Park, Hyung Soon(박형순)
Yang, In Seok(양인석) ORCID logo https://orcid.org/0000-0001-5224-2587
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Lim, Sun Min(임선민)
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/152318
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