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 language | English |
|---|---|
| Pages (from-to) | 10547-10556 |
| Number of pages | 10 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2016 Jan 1 |
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All Science Journal Classification (ASJC) codes
- Oncology
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=84961589557&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961589557&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.7234
DO - 10.18632/oncotarget.7234
M3 - Article
C2 - 26859683
AN - SCOPUS:84961589557
VL - 7
SP - 10547
EP - 10556
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 9
ER -