Benefits for children with suspected cancer from routine whole-genome sequencing.

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care.

A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program.

Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured, the prognosis for infant-ALL remains dismal. Infant-ALL is usually caused by a single genetic hit that arises in utero: an MLL/KMT2A gene rearrangement (MLL-r). This is sufficient to induce a uniquely aggressive and treatment-refractory leukemia compared to older children. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. Using the most common MLL-r in infant-ALL, MLL-AF4, as a disease model, we show that fetal-specific gene expression programs are maintained in MLL-AF4 infant-ALL but not in MLL-AF4 childhood-ALL. We use CRISPR-Cas9 gene editing of primary human fetal liver hematopoietic cells to produce a t(4;11)/MLL-AF4 translocation, which replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data support the hypothesis that fetal-specific gene expression programs cooperate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL.

A case series of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

In this study, we report three paediatric cases of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

PAX5 alterations in genetically unclassified childhood Precursor B-cell acute lymphoblastic leukaemia.

Here, we report a high incidence of PAX5 abnormalities observed in 32/68 (47%) of patients with genetically unclassified childhood precursor B-cell acute lymphoblastic leukaemia (pre-B ALL). Various deletions, gains, mutations and rearrangements of PAX5 comprised 45%, 12%, 29% and 14%, respectively, of the abnormalities found. 28% of patients showed more than one abnormality of the gene, implying bi-allelic impairment of PAX5. Novel PAX5-RHOXF2, PAX5-ELK3 and PAX5-CBFA2T2 rearrangements, which lead to aberrant expression of PAX5, were also identified. PAX5 rearrangements demonstrated a complex mechanism of formation including concurrent duplications/deletions of PAX5 and its partner genes. Finally, the splice variant c.1013-2A>G, seen in two patients with loss of one PAX5 allele, was confirmed to be germ-line in one patient and somatic in the other. PAX5 alterations were also found to be clinically associated with a higher white blood cell count (P = 0·015). These findings contribute to the knowledge of PAX5 alterations and their role in the pathogenesis of pre-B ALL.