Precision Medicine Bioinformatics of Childhood Cancer in Denmark

This PhD started under the umbrella of iCOPE (Interregional Childhood Oncology Precision Medicine Explora5on) project, which aims to improve life of children with cancer in Denmark implementing a personalized medicine approach. This thesis contributed by establishing a set of Next Generation  Sequencing (NGS) workflows in a High Performance Computer (HPC) environment that allowed to detect, annotate and store efficiently germline and somatic short variants (SNV) as well as structural variants (SV) from Danish children with cancer. With the developed tools, four manuscripts have been produced and included in this thesis: Manuscript 1 where germline short variants identified by our first WGS variant calling pipeline were used to investigate how frequently children with cancer were likely to have a cancer predisposition syndrome (CPS); similarly, in the Manuscript 4 our latest whole genome sequencing (WGS) short variant detection pipeline was used to report the genetic variation and investigate the genetic predisposition in children with molecularly classified ependymoma in Denmark over the past 20 years; for Manuscript 2, a cohort of 566 WGS samples from Danish children with cancer was analyzed and Variants of Uncertain Significance (VUS) from interested genes were evaluated using RoseKaDDG framework for structure-based calculations of the free energy changes upon amino acid substitution (ΔΔGs). Finally, in Manuscript 3 we performed germline WGS in siblings and parents as well as RNAseq and WGS of DNA from the tumours to identify short nucleotide variants (SNVs) as well as structural variants (SVs) and described mechanisms possibly underlying a previously unseen co-occurrence of Philadelphia + Acute Lymphoblastic Leukaemia (Ph+ ALL) in siblings from a Danish family.