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

iScience. 2024 Mar 27;27(4):109601. doi: 10.1016/j.isci.2024.109601. eCollection 2024 Apr 19.

Authors

Jack M Shireman¹, Quinn White², Zijian Ni², Chitrasen Mohanty², Yujia Cai², Lei Zhao¹, Namita Agrawal³, Nikita Gonugunta¹, Xiaohu Wang¹, Liam Mccarthy¹, Varshitha Kasulabada¹, Akshita Pattnaik¹, Atique U Ahmed⁴, James Miller⁵, Charles Kulwin⁶, Aaron Cohen-Gadol⁵, Troy Payner⁶, Chih-Ta Lin⁵, Jesse J Savage⁵, Brandon Lane⁵, Kevin Shiue³, Aaron Kamer⁷, Mitesh Shah⁵, Gopal Iyer⁸, Gordon Watson³, Christina Kendziorski², Mahua Dey¹

Affiliations

¹ Department of Neurosurgery, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA.
² Department of Biostatistics and Medical Informatics, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA.
³ Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Department of Neurological Surgery, Northwestern University, Chicago, IL, USA.
⁵ Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Goodman Campbell Brain and Spine Neurological Surgery, Indianapolis, IN, USA.
⁷ Department of Clinical Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
⁸ Department of Human Oncology, University of Wisconsin Madison School of Medicine and Public Health, Madison, WI, USA.

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.

Abstract

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