Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors

Clinical targeted exome-based sequencing in combination with genome-wide copy number profiling: precision medicine analysis of 203 pediatric brain tumors
Sub-type specific mutations have been identified in many pediatric brain tumors, and are critical to developing and initiating targeted therapy. This report from Boston describes their experience in pediatric neuro-oncology with targeted exome sequencing and genome-wide copy number analysis of the tumour using a CLIA approved test.
Clinical data was extracted from the chart and histology was reviewed. OncoPanel was used for targeted exome sequencing (surveys 300 cancer genes) and classified into 4 tiers (Tier 1 is a well described mutation with evidence confirming clinical utility). Clinical array comparative genomic hybridization (aCGH) was used to identify copy number alterations, known as OncoCopy. Whole genome sequencing was also done. Medulloblastomas underwent further DNA-based molecular analysis to determine subgroup.
OncoPanel was requested on 142 tumors and clinical data was available on 120 of these patients. OncoCopy was requested with results available on 146 patients during time of study. Sixty patients had both tests performed. Clustering of copy number variations was shown to predict histology (i.e. HGG clustered together with embryonal tumors, LGG clustered together in a separate group, etc.). OncoPanel identified relevant alterations in 56% of patients with 38% having tier 1-3 mutations and an additional 17% having an actionable target. Eight out of 37 patients with an actionable target were treated with a small molecule inhibitor. Rearrangements (fusions) were identified in 25/115 samples, most commonly BRAF:KIAA1549 in LGGs. Novel fusions were found and verified using whole exome sequencing. There is further description regarding medulloblastoma, HGG and LGG methods and specific findings.
Germline DNA was not assessed and therefore germline variants couldn't be evaluated which would be needed to be sure about the identified variants in the tumor being somatic (arising in the tumor rather than associated with cancer predispositions). While the authors mention how many patients received targeted therapy (a small minority), they do not discuss the response of these patients to this treatment. Most of this information was not used to influence patient treatment, rather for better understanding. They do not discuss the outcomes of patients with particular alterations (i.e. BRAF V600E mutation) to learn more about how these molecular events influence response to treatment.
Targeted exome sequencing and copy number alterations can be used to identify previously-known and novel mutations and fusions. This testing is already underway and offered at other institutions. This may influence if a patient may be eligible/benefit from certain phase 1 studies, but generally is not being using to guide treatment.

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