Multiregional genomic sequencing of pediatric cancer patients from Qatar, solid tumor heterogeneity and clinical impact.

Sidra Medicine is the primary pediatric cancer care facility in Qatar since opening the oncology clinic in 2018. The overall incidence rates of childhood cancer vary between 50 and 200 per million children across the world (Steliarova-Foucher et al. 2017), which puts Qatar with 126 per million children in 2019 right in the middle of that bracket. Cancer patients presenting at Sidra consist of mainly Arab and Asian ancestry, representing 70 and 25 percent of our patients, respectively. 39 percent of these patients are diagnosed with Leukemia, 14 percent have a diagnosis of a Central Nervous System malignancy, other common diagnosis in descending order of incidence are Lymphoma, Germ cell tumors, Neuroblastoma and Sarcomas. Which is, with the exception of germ-cell tumors, in line with what is observed in the Surveillance, Epidemiology, and End Results (SEER) Program from NCI/NIH, USA (“Surveillance, Epidemiology, and End Results Program” n.d.). In order to let pediatric patients with solid tumors that are included in our cohort take advantage of the revolution in the treatment of cancer brought on by the application of targeted and immunotherapy, a deeper understanding of the immune phenotype in these patients’ tumors is required. So far, limited presence of neo-antigens due less unstable cancer genomes and thus lower mutational load and sparse infiltration of T-cells has prevented the application of early immunotherapeutic strategies. However, the emerging approaches to manipulate the tumors microenvironment towards a more immunogenic state potentiates this population for immunologic eradication of their tumor burden. Understanding the genetic determinants of the immune phenotypes in these cancer types, including, the variation in mutational load between patients, the intra-tumoral heterogeneity of both the somatic mutations and copy number alterations, and the characterization of the immune infiltrate, will provide us with insight in the potential for targeted and immunotherapy adaptation to these pediatric patients. Preliminary study of the public data available in the TARGET database and comparison with the TCGA pan-cancer work we did over the last few years indicates a great similarity between prognostic value of the transcriptomically determined immune infiltrate between the cancer types evaluated. So far, a positive prognosis is associated with immune infiltration is observed in Osteosarcoma while the opposite is seen in Wilms renal tumors. Neuroblastoma seems display a neutral effect of the immune infiltrate. These observations seem to reflect what is observed in for example melanoma, kidney cancer and CNS tumors in adults (Roelands et al. 2020) The recent establishment of the Sidra Pediatric Cancer Biorepository at Sidra Medicine and our expertise obtained during the last decade in the study of cancer immunogenetics combined with the expertise provided by the Sidra genomics core puts us in an excellent position to tackle this challenge. In close collaboration with the Sidra Medicine Oncology and Pathology department we aim to provide research grade multi-regional and multi-omics tumor sequencing to all our pediatric solid tumor patients. Next to this cohort-wide bulk sequencing effort we will apply a single cell approach to several sub cohorts of solid pediatric cancer. Studying cancer at the single cell level will allow us to achieve mechanistic insight in the crosstalk between tumor, stromal and immune cell signaling. It will allow us to correlate somatic mutations with changes in the transcriptomic profile of each population of the tumor microenvironment. This mechanistic understanding of the immune suppressive environment, often present in these tumors, will ultimately be key in developing and testing strategies to activate the anti-tumor immune response and providing a curative therapy to all who are currently still lost to this disease. This treasure of data will enable us to, on the short term, advice clinical grade diagnostician of rare targetable somatic mutation and facilitate patient enrollment in worldwide clinical trials. On the median term it will help us highlight new molecular targets in specific subgroups of patients, leading to the development of new biomarkers or therapeutic modalities. On the longer term this project will pave the way for personalized precision medicine for each pediatric cancer patient in Qatar.

Sidra Medicine