Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA.
Changcun PanBill H DiplasXin ChenYuliang WuXiong XiaoLiping JiangYibo GengCheng XuYu SunPeng ZhangWenhao WuYu WangZhen WuJunting ZhangYuchen JiaoHai YanLiwei ZhangPublished in: Acta neuropathologica (2018)
Brainstem gliomas are molecularly heterogeneous diseases, many of which are difficult to safely surgically resect and have limited treatment options due to their eloquent location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular-peritoneal shunt (3.5%, 2/57), or by lumbar puncture (5.3%, 3/57), all prior to surgical manipulation of the tumor. Deep sequencing of glioma-associated genes was performed on CSF-derived ctDNA and, where available, matched blood and tumor DNA from 57 patients, including nine medullary and 23 diffuse intrinsic pontine gliomas (DIPG). At least one tumor-specific mutation was detected in over 82.5% of CSF ctDNA samples (47/57). In cases with primary tumors harboring at least one mutation, alterations were identified in the CSF ctDNA of 97.3% of cases (36/37). In over 83% (31/37) of cases, all primary tumor alterations were detected in the CSF, and in 91.9% (34/37) of cases, at least half of the alterations were identified. Among ten patients found to have primary tumors negative for mutations, 30% (3/10) had detectable somatic alterations in the CSF. Finally, mutation detection using plasma ctDNA was less sensitive than sequencing the CSF ctDNA (38% vs. 100%, respectively). Our study indicates that deep sequencing of CSF ctDNA is a reliable technique for detecting tumor-specific alterations in brainstem tumors. This approach may offer an alternative approach to stereotactic biopsy for molecular profiling of brainstem tumors.
Keyphrases
- circulating tumor
- end stage renal disease
- cell free
- circulating tumor cells
- cerebrospinal fluid
- single cell
- ejection fraction
- newly diagnosed
- chronic kidney disease
- prognostic factors
- heart failure
- minimally invasive
- small cell lung cancer
- risk assessment
- left ventricular
- dna methylation
- genome wide
- pulmonary hypertension
- high grade
- atrial fibrillation