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

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 KangByoung Chul Cho

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31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)10547-10556
Number of pages10
JournalOncotarget
Volume7
Issue number9
DOIs
Publication statusPublished - 2016

All Science Journal Classification (ASJC) codes

  • Oncology

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    Lim, S. M., Park, H. S., Kim, S., Kim, S., Ali, S. M., Greenbowe, J. R., Yang, I. S., Kwon, N. J., Lee, J. L., Ryu, M. H., Ahn, J. H., Lee, J., Lee, M. G., Kim, H. S., Kim, H., Kim, H. R., Moon, Y. W., Chung, H. C., Kim, J. H., ... Cho, B. C. (2016). Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus. Oncotarget, 7(9), 10547-10556. https://doi.org/10.18632/oncotarget.7234