Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours By: Anh Pham

Overview of pan-cancer analysis Pan cancer analysis finds similarities and differences in important biological process that are dysregulated in cancer cells. Most pan cancer analysis has been on adult and not a lot has been made pediatric Goal is to find similarities, differences, and causation of diverse tumors to learn more about cancer This research is one of the first where they did a Pan-cancer analysis of pediatric

What is this research on? Research on 1699 pediatric leukemias and solid tumors. All patients are 20 years of younger 689 B-lineage acute lymphoblastic leukaemias (B-ALL) 267 T-lineage ALLs (T-ALL) 210 acute myeloid leukaemias (AML) 316 neuroblastomas (NBL) 128 Wilms tumours 89 osteosarcomas  Used whole genome sequencing, whole exome sequencing, and transcriptome data. Looked at somatic alterations such as nucleotide variants, small insertions, deletions, structural variation, gene fusion, copy number changes, and tandem duplication. This is to help build a accurate pediatric cancer data and improve cancer research in pediatric cancer Exome-focus on protein coding sequencing , and rna sequencing Tall-Acute lymphoblastic leukemia affect white blood cell counts acute myeloid leukaemias –excess immature white blood cell Wilms' tumor is a rare kidney cancer that primarily affects children. Also known as nephroblastoma, it's the most common cancer of the kidneys in children. Osteosarcoma is a type of cancer that produces immature bone. Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue

Background B-all-B linage acute lymphoblastic leukemia affect white blood cell counts Affect B cells (T-all)-T linage Acute lymphoblastic leukemia affect white blood cell counts Affect T cell (ALL) Acute myeloid leukemias –excess immature white blood cell Wilms' tumor is a rare kidney cancer that primarily affects children. Also known as nephroblastoma. A common kidney cancer in children Osteosarcoma is a type of cancer that produces immature bone. Neuroblastoma (NB) is a type of cancer that forms in certain types of immature nerve tissue Common area is the adrenal gland

What was found Using WGS and WES they found 142 cancer driver genes 45 percent were similar to adult pan cancer studies 11 genome wide mutation signatures Mutant alleles Median somatic mutation ranges from .17 in AML (Adult acute myeloid leukemia ) and WT (Wilms' tumor is a rare kidney cancer that primarily affects children). Muttion rate for OS(Osteosarcoma is a type of cancer that produces immature bone). In adult is 1-10 per Mb mutation rate Driver genes promote cancer Whole exome sequencing

Mutant signatures

driver genes role in leukemia and tumors The found 142 driver genes (genes that promote cancer growth) Changes in CDKN2A (mostly deletions) affected 207 of 267 (78%) T- ALLs, 91 of 218 (42%) B-ALLs and 2 of 19 (11%) osteosarcomas CDKN2A are types of genes that help with proteins production. Examples are p16 and p14 which are tumor suppressors. So changes in CDKN2A causes tumor suppressors not to work correctly. Most of the drivers genes are specific to one cancer. Driver genes that affect both leukemia and tumors only accounted for 17 percent

142 driver

C-drivers that affect leakemia D-drivers that affect tumors C- drivers that effect both

Driver genes that affect both tumors and leukemia STAG2 (driver gene) plays a role in both adult AML (Acute myeloid leukemia) and Ewing sarcoma. This gene changes by single nucleotide variant (SNVs), deletion, insertions, number alteration, and duplication. 9 of these STAG2 variations are known to cause cancer and 78 of the 142 driver are not found in adult pan genomic 43 driver genes are not found in the Cancer Gene Census and 29 are not found in both Cancer gene census and adult pan genomic New knowledge Knowing these driver genes can benefit both adult and pediatric cancer

ITD-internal tandem duplications

Low frequency drivers Low frequency drivers are very difficult to detect. In order to find these driver subnetwork analyses and pathogenicity classification Somatic variant pathogenicity analysis By is done by looking at single nucleotide variants and indel of cancer gene Use the database Clinvar Searches for mutations in suppressor genes, fusions, focal deletions, truncations, and amplifications that affect important pathway of cancer

Advantages of finding driver genes Since driver genes promote tumor growth by target it we can slow down tumor growth For example TAL1 is specific to T-Acute lymphoblastic leukemia and ALK for neuroblastoma by targeting these we can hinder tumor growth. Targeting STAG2 can alleviate tumor growth and leukemia Some of these driver disrupt the regular biological pathway so by finding these and fixing it we can alleviate the problem. JAK–STAT is a signaling pathway that is involve in cell death, cell division, immunity, and tumor growth. When driver genes disrupt this it causes tumor growth.

Pan-genomic study of Mutant alleles By studying more about mutant alleles make it possible to find potential epigenetic regulation that disrupt the alleles process and function. Using WGS and RNA sequencing they looked at 6,959 coding mutations. Found that 34 percent were mutants alleles. Usually DNA MAF (oncogene) Looked at the allele specific expression of the 486 patient and found that 279 had no mutant alleles was in detectable while 207 had ASE mutant alleles 87 percent of these mutant alleles shows elevated expression Allele-specific expression (ASE) is to the differential abundance of the allelic copies of a transcript.

Benefits of Pan genomic studies Since this is one of the first pan genomic studies of pediatric it can inspire other people to add on in the future The current data can be view on National Cancer Institute TARGET Data Matrix This will help improve future studies of pediatric cancer and tumors Help doctor develop new clinical technique for pediatric cancer

Reference Ma, Xiaotu, et al. “Pan-Cancer Genome and Transcriptome Analyses of 1,699 Paediatric Leukaemias and Solid Tumours.” Nature News, Nature Publishing Group, 28 Feb. 2018, www.nature.com/articles/nature25795.