Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure

Jack M. Shireman; Quinn White; Zijian Ni; Chitrasen Mohanty; Yujia Cai; Lei Zhao; Namita Agrawal; Nikita Gonugunta; Xiaohu Wang; Liam Mccarthy; Varshitha Kasulabada; Akshita Pattnaik; Atique U. Ahmed; James Miller; Charles Kulwin; Aaron Cohen-Gadol; Troy Payner; Chih Ta Lin; Jesse J. Savage; Brandon Lane; Kevin Shiue; Aaron Kamer; Mitesh Shah; Gopal Iyer; Gordon Watson; Christina Kendziorski; Mahua Dey

doi:10.1016/j.isci.2024.109601

Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure

Jack M. Shireman, Quinn White, Zijian Ni, Chitrasen Mohanty, Yujia Cai, Lei Zhao, Namita Agrawal, Nikita Gonugunta, Xiaohu Wang, Liam Mccarthy, Varshitha Kasulabada, Akshita Pattnaik, Atique U. Ahmed, James Miller, Charles Kulwin, Aaron Cohen-Gadol, Troy Payner, Chih Ta Lin, Jesse J. Savage, Brandon LaneKevin Shiue, Aaron Kamer, Mitesh Shah, Gopal Iyer, Gordon Watson, Christina Kendziorski, Mahua Dey^*

^*Corresponding author for this work

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

Abstract

Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

Original language	English (US)
Article number	109601
Journal	iScience
Volume	27
Issue number	4
DOIs	https://doi.org/10.1016/j.isci.2024.109601
State	Published - Apr 19 2024

Funding

Funding: This work was supported by the NIH K08NS092895 grant (MD), IU Value Research grant (MD) . JMS is partly supported by NIH/ NINDS T32 NS105602 . The authors thank the patients who participated in the trial and contributed invaluable samples for this research and whom all this work is dedicated. Funding: This work was supported by the NIH K08NS092895 grant (MD), IU Value Research grant (MD). JMS is partly supported by NIH/NINDS T32 NS105602. JMS/QW/ZN/GC/CM conducted bioinformatic analysis, LB/YZ conducted the clinical trial statistical analysis, JMS/LZ/XW/AP/LM/VK/NG conducted in vitro experiments and isolated/prepared samples for sequencing, AA/GP contributed to the article formulation and provided sequencing samples and cell lines, NA/JM/CK/ACG/TP/CL/JS/BL/KS/AK/MS/GW/MD provided clinical consultation and/or operated on patients on trial, JMS/MD/CK wrote the article, MD supervised the project and the clinical trial. The authors declare no competing interests.

Keywords

Cancer
Cancer systems biology
Genomic analysis
Genomics

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2024.109601

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Shireman, J. M., White, Q., Ni, Z., Mohanty, C., Cai, Y., Zhao, L., Agrawal, N., Gonugunta, N., Wang, X., Mccarthy, L., Kasulabada, V., Pattnaik, A., Ahmed, A. U., Miller, J., Kulwin, C., Cohen-Gadol, A., Payner, T., Lin, C. T., Savage, J. J., ... Dey, M. (2024). Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure. iScience, 27(4), Article 109601. https://doi.org/10.1016/j.isci.2024.109601

@article{62e101bc9b1b4ed2af8f777caf682b07,

title = "Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure",

abstract = "Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.",

keywords = "Cancer, Cancer systems biology, Genomic analysis, Genomics",

author = "Shireman, {Jack M.} and Quinn White and Zijian Ni and Chitrasen Mohanty and Yujia Cai and Lei Zhao and Namita Agrawal and Nikita Gonugunta and Xiaohu Wang and Liam Mccarthy and Varshitha Kasulabada and Akshita Pattnaik and Ahmed, {Atique U.} and James Miller and Charles Kulwin and Aaron Cohen-Gadol and Troy Payner and Lin, {Chih Ta} and Savage, {Jesse J.} and Brandon Lane and Kevin Shiue and Aaron Kamer and Mitesh Shah and Gopal Iyer and Gordon Watson and Christina Kendziorski and Mahua Dey",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = apr,

day = "19",

doi = "10.1016/j.isci.2024.109601",

language = "English (US)",

volume = "27",

journal = "iScience",

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Shireman, JM, White, Q, Ni, Z, Mohanty, C, Cai, Y, Zhao, L, Agrawal, N, Gonugunta, N, Wang, X, Mccarthy, L, Kasulabada, V, Pattnaik, A, Ahmed, AU, Miller, J, Kulwin, C, Cohen-Gadol, A, Payner, T, Lin, CT, Savage, JJ, Lane, B, Shiue, K, Kamer, A, Shah, M, Iyer, G, Watson, G, Kendziorski, C & Dey, M 2024, 'Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure', iScience, vol. 27, no. 4, 109601. https://doi.org/10.1016/j.isci.2024.109601

TY - JOUR

T1 - Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure

AU - Shireman, Jack M.

AU - White, Quinn

AU - Ni, Zijian

AU - Mohanty, Chitrasen

AU - Cai, Yujia

AU - Zhao, Lei

AU - Agrawal, Namita

AU - Gonugunta, Nikita

AU - Wang, Xiaohu

AU - Mccarthy, Liam

AU - Kasulabada, Varshitha

AU - Pattnaik, Akshita

AU - Ahmed, Atique U.

AU - Miller, James

AU - Kulwin, Charles

AU - Cohen-Gadol, Aaron

AU - Payner, Troy

AU - Lin, Chih Ta

AU - Savage, Jesse J.

AU - Lane, Brandon

AU - Shiue, Kevin

AU - Kamer, Aaron

AU - Shah, Mitesh

AU - Iyer, Gopal

AU - Watson, Gordon

AU - Kendziorski, Christina

AU - Dey, Mahua

PY - 2024/4/19

Y1 - 2024/4/19

N2 - Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

AB - Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

KW - Cancer

KW - Cancer systems biology

KW - Genomic analysis

KW - Genomics

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UR - http://www.scopus.com/inward/citedby.url?scp=85189638342&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2024.109601

DO - 10.1016/j.isci.2024.109601

M3 - Article

C2 - 38623341

AN - SCOPUS:85189638342

SN - 2589-0042

VL - 27

JO - iScience

JF - iScience

IS - 4

M1 - 109601

ER -

Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure

Abstract

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Keywords

ASJC Scopus subject areas

UN SDGs

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