Great end to the Steel Symposium. Congratulations to the organizers for putting together a meeting that covered much of the pediatric oncology landscape and kept people engaged. Abstracts for next year open in the fall. #MSKDevOnc #MSKkids
Pfister - So is there a way to detect this earlier. In summary, large CNVs may initiated many pediatric tumors, before birth. Oncogenic drivers are needed for tumor progression but not initiation. The MYC clones are further selected under treatment pressure. Clonal organpoiesis! #MSKDevOnc #MSKkids
Pfister - High grade gliomas and other solid tumors. See date of origin in early common ancestor before birth. The pediatric tumors all look similar. Need some type of early trigger that convert. This looks very different from carcinomas and GBM that are all post birth. #MSKDevOnc #MSKkids
Pfister - can see tumors that at the expression level have both MYCN and MYC expression in different cells. Also looked at primary and relapse sample. At relapse the MYC clone had outgrown the MYCN and oncogene negative clones. See that in other MB tumors at relapse. #MSKDevOnc #MSKkids
Pfister - Medulloblastoma age of onset and MRCA match the average age of diagnosis of different MB subtypes. Many may begin during end of 1st trimester. Long phase of pre-malignant clone during childhood. MYC/MYCN/PRDM6 take longer consisten with older onset. #MSKDevOnc #MSKkids
Pfister - PRDM6 activation in Grp 4, can be a subclone event preceded by other CNV driven clones. They are not clonal but occur rather late. Determining most recent common ancestor (MRCA) in the tumor and an early common anceone (ECA) with normal growth rate based on NB paper. #MSKDevOnc
Pfister - Medulloblastoma 3/4 recurrent CNVs not SNVs. Early paper that tetrapolidization was an early event. 17 oncogene positive MYC/MYCN/PRDM6 subset. CNV from snATAC data - InferCNV. See sub clonal MYCN amplified preceded by CNVs. Similar for MYC amplification. #MSKDevOnc #MSKkids
Stefan Pfister - KiTZ Heidelberg Genomics of pediatric tumors. What makes childhood brain tumors different (recent publication) and new data. Pediatric hallmarks of cancer. Don’t have environmental exposure but have hijacking of normal development (maturation block) and simple genomes. #MSKDevOnc
Phillips - Looked at CBX4 dependency and appears to be specific to K27M gliomas. CBX4 seems to be repressor of CDKN2A which plays a role in response to treatment. Working towards therapeutic window by disrupting polycomb through CBX4. Manuscript in press #MSKDevOnc
Phillips - looking at EZH2 inhbitors but some of existing ones weren’t penetrant. Now focused on which genes retain their EZH2 peaks. PRC1 complex is often downstream but there is substantial complexity of PRC1 targets. Chromobox 4 was a top hit as playing role in PRC1 in midline glioma. #MSKDevOnc
Richard Phillips - UPenn - epigenetic dysregulation of midline brain tumors. Different epigenetic regulator changes with age. Where K3.1 K27M is much younger than K3.3G34R/V tumors. IDH mutant is even older adults. Vulnerable periods of plasticity may differ. #MSKDevOnc #MSKkids
Joshi - Developmental programs drive medlloblastoma tumor heterogeneity. Important timepoints between UBC progenitor and Differentiating UBC where transition to Group 3/4 or Myc-like occurs. PAX6 driven tumors with both Group 3 and Group 4 trajectories in single tumor. #MSKDevOnc
Piyush Joshi - German Cancer Research Center. Plasticity of Medulloblastoma Group 3/4. See overlapping molecular programs across subtypes. Single nucleus multi-omic experiments. Transcription factor network. #MSKDevOnc #MSKkids
Teachey - now looking at novel therapies through COG trials. Randomized to Nelarabine where T-cell ALL had a benefit not T-LL. Bortezimib, the opposite, T-cell ALL had no benefit but T-LL had a benefit. Now looking at JAK/STAT inhibitors in ETP-like ALL cases. Use genomics to predict. #MSKDevOnc
Teachey - ETP-like T-ALL do poorly. Can subdivide into 9 subgroups that differ in outcomes. One group have high levels of tumor microenvironment signals but unclear the origin. See some interaction between genomic driver and transcription clusters. Type of alteration matters for NOTCH1. #MSKDevOnc
Teachey - WGS of T-ALL see Enhancer Hijacking and Neoenhancer formation. Found 15 different genomic subtypes and mapped onto single cell RNA sequencing to see how they arise. TAL1-DP-like cells. TAL1-alphabetalike due to mapping to alphabeta T cells. #MSKDevOnc
Teachey - T-ALL stratification - not nearly as well developed as for B-ALL. COG, St. Jude study trying to analyze patients at diagnosis - WES, transcriptome, WGS germline 900 cases. Immunophenotying. Focus on talk bulk genomics. Little WGS data and excluded relapse patients. #MSKDevOnc #MSKkids
David Teachey - CHOP on pediatric ALL treatment. Most of initial treatments developed in 1950’s. Hit a threshold with standard CTX in COG trials that ended in the 90’s, Focus on T-ALL - one good shot for initial treatment. Relapse not very successful. Need to improve frontline #MSKDevOnc #MSKkids
Soulier - New condition due to ERCC6L2 syndrome with microcephaly and MDS/AML consanguineous families. Skin cancers followed by MDS/AML. Also see with XPC delTG. Stressed hematopoiesis p53 activation. See similar pathway of mutational events. Mentions new paper on ATR rescue #MSKDevOnc #MSKkids
Soulier - MDM4 appears to be key gene on 1q+. MM-EJ repair is a key event in generating the aneuploidy which activates p53. But MDM4 increase blocks this p53 activation. Made mouse duplication MDM4 of entire gene to model this and now looking at MDM2 and MDM4 inhibitors. #MSKDevOnc
Soulier - copy number abnormalities much more common than fusions. See very few TP53 mutations. Chromosomal disease. See order of chromosomal events in route to leukemias. 1q+ first. RUNX1 change is late. Dup3q EVI1 (MECOM) overexpression key event. #MSKDevOnc
Soulier - Somatic reversion - Demonstrating results from 13 FANCA patients. See loss of one mutation. 5UPD between two mutations or back mutations or crossover events. Conversely can get clonal hematopoises w/unbalanced translocation. Complex karyotypes. Small deletions (10-250kb). #MSKDevOnc
Soulier - Cells can’t resolve DNA damage and go into senescence by activation of p53/p21. Can see signs of this very early in life. Accumulate damage along life and by 6-7 years see BMF and clonal evolution. Known for years that cells can revert and repopulate. #MSKDevOnc #MSKkids
Soulier - French FA cohort published in Sebert el al Cell Stem Cell 2023 About half are not transplanted due to milder disease. Shows solid tumor go up sharply after age 20. Also see HSC attrition and clonal hemopoiesis followed by AML in patients w/o BMT. #MSKDevOnc
Jean Soulier - France Genomic Instability in MDS/Fanconi Anemia begins Day 2 of the Steel Symposium. Now up to 24 genes. See both MDS and AML with subsequent in adults get solid tumors H&N SCC. Aldehydes one cause of inter strand crosslinks. #MSKDevOnc #MSKkids
Northcott - still some cases when doing molecular anlaysis there are some briding cases of MB and pinealblastoma. Some genes are unregulated in MB, RB and Pinealblastoma. Oncogenic photoreceptor group of genes. Look along the trajectories and see active in all 3 lineages. #MSKDevOnc #MSKkids
Northcott - Pinealblastoma doing developmental pineal gland anaysis of pineal gland. See divergent cell types that originate from a central precursor that is proliferative even though there are these different pathways within pinealbloastoma. See some photoreceptors. Making RB1 model #MSKDevOnc
Northcott - used this rhombic lip development work to map MB. Group 4 correlation with glutanergic CN. Group 3 and that rhombic lip glutamtergic for human cerebellum. Extract RL and study in more details and see common hierarchy. Correlate this w/imaging Nodulus finding #MSKDevOnc
Northcott - Cross-species mapping of MB origins. What are the cerebellar correlates - also published by Taylor group in 2019. Group 4 - aligning to upper rhombic lip (glutanergic neurons). Group 3 - didn’t correlated. Others looking at cerebellar development whic aids MB work. #MSKDevOnc
Northcott - Analyzing the subtypes by transcriptome and methylation. Methylation plots initially saw interactions between Group 3 and Group 4. Single cell analysis represents hierarchies of undifferentiate to differentiated (predominant group 4) cells. Needed to know normal cerebellum. #MSKDevOnc
