Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus
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Sun Min Lim1,2,*, Hyung Soon Park3,*, Sangwoo Kim4, Sora Kim4, Siraj M. Ali5, Joel R. Greenbowe5, In Seok Yang4, Nak-Jung Kwon6, Jae Lyun Lee7, Min-Hee Ryu7, Jin-Hee Ahn7, Jeeyun Lee8, Min Goo Lee3, Hyo Song Kim1, Hyunki Kim9, Hye Ryun Kim1, Yong Wha Moon1,2, Hyun Cheol Chung1, Joo-Hang Kim2, Yoon-Koo Kang7 and Byoung Chul Cho1
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
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
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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