Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge.
Jack M ShiremanQuinn WhiteNamita AgrawalZijian NiGrace ChenLei ZhaoNikita GonuguntaXiaohu WangLiam MccarthyVarshitha KasulabadaAkshita PattnaikAtique U AhmedJames MillerCharles KulwinAaron Cohen-GadolTroy PaynerChih-Ta LinJesse J SavageBrandon LaneKevin ShiueAaron KamerMitesh ShahGopal IyerGordon WatsonChristina KendziorskiMahua DeyPublished in: medRxiv : the preprint server for health sciences (2023)
Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial ( NCT03398694 ), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.
Keyphrases
- clinical trial
- dna damage
- phase ii
- oxidative stress
- open label
- white matter
- small cell lung cancer
- brain metastases
- study protocol
- machine learning
- radiation therapy
- single cell
- copy number
- gene expression
- endoplasmic reticulum stress
- resting state
- cell death
- double blind
- rna seq
- nucleic acid
- big data
- pi k akt
- genome wide