biostudies-literatureDas ACIHR125-135https://www.ebi.ac.uk/biostudies/studies/S-EPMC8799468biostudies-literatureUnknown28(1)Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden Nature medicineGenomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.PMC8799468PJT-156006Sumerauer DMaris JMShroff MBowers DCVillani AZatzman MYen LYOhashi PSZiegler DSConstantini SSarosiek TKulkarni AVAlsafwani NBianchi VYalon-Oren MSudhaman SVan Damme ANichols KEMorgenstern DCampino GAMagimairajan VTaylor MDHansford JRLuna-Fineman SBouffet ENabbi AScheers IBendel AFrojd CDe Mola RLHawkins CEdwards MZapotocky MChen DReddy AZimmermann SLarouche VMassimino MTomboc PLossos AXu WBlumenthal DTHoffman LMLadany HCabric VGetz GGeorge BDirks PGass DLaetsch TWKnipstein JMason GOpocher EOsborn MDurno CErcan ABMordechai OKarsaneh OAACole KMcGee RBLiu ZAPugh TJTsang DSMaruvka YEChiaravalli SNobre LMalkin DTabori UChung JBronsema AShlien ACoblentz AStone SCCaspi SHijiya NDvir RSabel MAronson MSoleimani SDas ASambira Nahum LCLindhorst SSamuel DfalseGenomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden 2022-01-01T00:00:00Z2022 Jan2026-05-30T15:13:42.993Z2024-11-20T14:11:07.018ZS-EPMC87994683499226310.1038/s41591-021-01581-6