IMMU-13. LARGE SCALE TUMOR MUTATIONAL BURDEN ANALYSIS OF PEDIATRIC TUMORS PROVIDES A DIAGNOSTIC TOOL FOR GERMLINE PREDISPOSITION AND REVEALS NOVEL CANDIDATES FOR IMMUNE CHECKPOINT INHIBITION

摘要

>BACKGROUND: A significant amount of childhood brain tumors emerge from cancer predisposition syndromes. Although tumor sequencing is common practice, it is currently impossible to infer germline mutations from tumor data. Glioblastoma Multiforme arising in children with Biallelic Mismatch Repair Deficiency Syndrome (bMMRD) are ultrahypermutant which is highly specific to this syndrome and confers eligibility for immune checkpoint inhibition therapy (ICI). Our objective was to quantify the frequency of hypermutant tumors in children, determine whether mutational signatures can predict germline mutations, and treat hypermutant tumors with ICIs. >METHODS: Deep panel sequencing (1000x) of 315 genes in 2984 pediatric tumors (585 brain tumors) and 79 842 adult tumors (3910 brain tumors) was performed. An algorithm was devised to determine mutation burden from 2 MB of panel sequencing data and results correlated strongly with mutation burden from exome sequencing (R² = 0.94). Mutational
signatures were analyzed to predict source of hypermutation. Patients with hypermutant brain tumors identified by panel sequencing were treated with ICI. >RESULTS: Hypermutant tumors (>10 mut/MB) comprised 5% of all pediatric tumors (n=143). These were highly enriched for replication repair mutations (p=<2x10^-16) and mutation loads correlated with hypermutant adult tumors that have shown demonstrable clinical response to ICI. Hypermutation was found in 5% of childhood and 6% of adult glioblastoma. All cases of GBM with >100 Mut/MB harbored MMR/polymerase mutations suggesting germline bMMRD (p =10^–7). Clinical data collected on 15 ultrahypermutant tumors revealed germline mutations in replication repair genes in all patients. Of the 22 patients with hypermutant cancers treated with ICI, 16 had brain tumors, and favorable sustained responses are observed. >CONCLUSION: High mutation burden is a sensitive predictor of germline bMMRD. Hypermutant tumors are more common in the pediatric setting than previously appreciated, opening novel therapeutic avenues. ICI shows promise for hypermutant pediatric cancers.