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

Research output: Contribution to journalArticle

29 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 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.

Original languageEnglish
Pages (from-to)10547-10556
Number of pages10
JournalOncotarget
Volume7
Issue number9
DOIs
Publication statusPublished - 2016 Jan 1

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Mutation
Neoplasms
Head and Neck Neoplasms
Genes
TYK2 Kinase
High-Throughput Nucleotide Sequencing
Chromatin Assembly and Disassembly
Everolimus
Thyroid Neoplasms
Renal Cell Carcinoma
Sarcoma
Paraffin
Formaldehyde
Stomach Neoplasms
Exons
Nucleotides
Biomarkers
Genome
Ions
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Lim, Sun Min ; Park, Hyung Soon ; Kim, Sangwoo ; Kim, Sora ; Ali, Siraj M. ; Greenbowe, Joel R. ; Yang, In Seok ; Kwon, Nak Jung ; Lee, Jae Lyun ; Ryu, Min Hee ; Ahn, Jin Hee ; Lee, Jeeyun ; Lee, Min Goo ; Kim, Hyo Song ; Kim, Hyunki ; Kim, Hye Ryun ; Moon, Yong Wha ; Chung, Hyun Cheol ; Kim, Joo Hang ; Kang, Yoon Koo ; Cho, Byoung Chul. / Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus. In: Oncotarget. 2016 ; Vol. 7, No. 9. pp. 10547-10556.
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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 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.",
author = "Lim, {Sun Min} and Park, {Hyung Soon} and Sangwoo Kim and Sora Kim and Ali, {Siraj M.} and Greenbowe, {Joel R.} and Yang, {In Seok} and Kwon, {Nak Jung} and Lee, {Jae Lyun} and Ryu, {Min Hee} and Ahn, {Jin Hee} and Jeeyun Lee and Lee, {Min Goo} and Kim, {Hyo Song} and Hyunki Kim and Kim, {Hye Ryun} and Moon, {Yong Wha} and Chung, {Hyun Cheol} and Kim, {Joo Hang} and Kang, {Yoon Koo} and Cho, {Byoung Chul}",
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Lim, SM, Park, HS, Kim, S, Kim, S, Ali, SM, Greenbowe, JR, Yang, IS, Kwon, NJ, Lee, JL, Ryu, MH, Ahn, JH, Lee, J, Lee, MG, Kim, HS, Kim, H, Kim, HR, Moon, YW, Chung, HC, Kim, JH, Kang, YK & Cho, BC 2016, 'Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus', Oncotarget, vol. 7, no. 9, pp. 10547-10556. https://doi.org/10.18632/oncotarget.7234

Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus. / Lim, Sun Min; Park, Hyung Soon; Kim, Sangwoo; Kim, Sora; Ali, Siraj M.; Greenbowe, Joel R.; Yang, In Seok; Kwon, Nak Jung; Lee, Jae Lyun; Ryu, Min Hee; Ahn, Jin Hee; Lee, Jeeyun; Lee, Min Goo; Kim, Hyo Song; Kim, Hyunki; Kim, Hye Ryun; Moon, Yong Wha; Chung, Hyun Cheol; Kim, Joo Hang; Kang, Yoon Koo; Cho, Byoung Chul.

In: Oncotarget, Vol. 7, No. 9, 01.01.2016, p. 10547-10556.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus

AU - Lim, Sun Min

AU - Park, Hyung Soon

AU - Kim, Sangwoo

AU - Kim, Sora

AU - Ali, Siraj M.

AU - Greenbowe, Joel R.

AU - Yang, In Seok

AU - Kwon, Nak Jung

AU - Lee, Jae Lyun

AU - Ryu, Min Hee

AU - Ahn, Jin Hee

AU - Lee, Jeeyun

AU - Lee, Min Goo

AU - Kim, Hyo Song

AU - Kim, Hyunki

AU - Kim, Hye Ryun

AU - Moon, Yong Wha

AU - Chung, Hyun Cheol

AU - Kim, Joo Hang

AU - Kang, Yoon Koo

AU - Cho, Byoung Chul

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

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