Panel-based NGS identifies prognostic and actionable genes in childhood acute lymphoblastic leukemia and suits for clinical sequence

Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Whereas the cure rate has been much improved, considerable number of patients suffered from leukemia relapse. The cure rates of relapsed ALL patients remained poor as low as 40%, thus ALL is leading cause of cancer death during childhood. To improve the cure rates of these patients, precise re-stratification and newer targeted therapy are needed. For those reasons, detecting genes that had prognostic value and that are potentially actionable for in a short time is desired in clinical settings. Methods: We perform next generation sequence of matched diagnosis, remission, and relapse samples of eighteen relapsed ALL patients. We use the desktop sequencer MiSeq (Illumina, Inc., San Diego, CA, USA) and HaloPlex custom panels (Agilent Technologies, Santa Clara, CA, USA). These HaloPlex custom panels include more than 150 cancer-related genes. In the same sequencing run, we checked single nucleotide variations (SNV), insertion/deletion, and copy number variations (CNV) simultaneously. We also compare the genetic alterations between diagnosis and relapse samples, and presume the type of clonal evolutions. Results: We identified total 16 SNV and insertion/deletion and 19 CNV at diagnosis, and 28 SNV and insertion/deletion and 22 CNV at relapse. With these gene alterations, we could re-stratify many patients otherwise without any high-risk features (4/8 B-cell precursor ALL patients, 50%). We could also detect potentially actionable gene variants in most patients (13/17 of all patients, 76.5%). Among them, one patient harbored widely reported germline TP53 R248Q mutation, thus regarded as Li-Fraumeni syndrome. Most relapse samples (9/13 analyzed cases, 69.2%) acquire new lesions and lost some lesions present at diagnosis, suggesting their clonal evolution from ancestral clones. Remaining four cases (4/13 cases, 30.7 %) showed clonal evolution direct from diagnosis clones. Conclusion: This inexpensive, rapid, sequential next generation sequence method will immediately apply as clinical sequence, and lead to better management of these patients and potential improvement in survival rate in childhood ALL. Citation Format: Hisashi Ishida, Akihiro Iguchi, Michinori Aoe, Takehiro Matsubara, Hirokazu Tsukahara, Akira Shimada. Panel-based NGS identifies prognostic and actionable genes in childhood acute lymphoblastic leukemia and suits for clinical sequence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-139.