{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Pilheden M"],"funding":["European Hematology Association","NCI NIH HHS"],"pagination":["e785"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9529062"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6(10)"],"pubmed_abstract":["Infant acute lymphoblastic leukemia (ALL) with <i>KMT2A</i>-gene rearrangements (<i>KMT2A</i>-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with <i>KMT2A</i>-r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in <i>KMT2A</i>-r leukemia and included mutations in <i>KRAS</i>, <i>NRAS</i>, <i>FLT3</i>, <i>TP53</i>, <i>PIK3CA</i>, <i>PAX5</i>, <i>PIK3R1</i>, and <i>PTPN11</i>, with infants having fewer such mutations. Of identified cancer-associated mutations, 62% were below the resolution of standard NGS. Only 33 of 87 mutations exceeded 2% of cellular prevalence and most-targeted PI3K/RAS genes (31/33) and typically <i>KRAS/NRAS</i>. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with <i>FLT3</i> <sup><i>D835H</i></sup> or <i>NRAS</i> <sup><i>G13D/G12S</i></sup> mutations that comprised only 0.06% to 0.34% of diagnostic cells, expanded at relapse. Finally, in longitudinal samples, the relapse clone persisted as a minor subclone from diagnosis and through treatment before expanding during the last month of disease. Together, we demonstrate that infant and childhood <i>KMT2A</i>-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape."],"journal":["HemaSphere"],"pubmed_title":["Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood <i>KMT2A</i>-rearranged Acute Leukemia."],"pmcid":["PMC9529062"],"funding_grant_id":["TRTH75","DP2 CA239145"],"pubmed_authors":["Noren-Nystrom U","Zhang J","Barbany G","Pokrovskaja Tamm K","Hyrenius-Wittsten A","Song G","Lohi O","Hansen Marquart HV","Walsh M","Pronk CJ","Asklin J","Saal LH","Hagstrom-Andersson AK","Ahlgren L","Fogelstrand L","Gawad C","Chen Y","Ma J","Sturesson H","Pilheden M","Gonzalez-Pena V","Castor A","Lausen B"],"additional_accession":[]},"is_claimable":false,"name":"Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood <i>KMT2A</i>-rearranged Acute Leukemia.","description":"Infant acute lymphoblastic leukemia (ALL) with <i>KMT2A</i>-gene rearrangements (<i>KMT2A</i>-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with <i>KMT2A</i>-r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in <i>KMT2A</i>-r leukemia and included mutations in <i>KRAS</i>, <i>NRAS</i>, <i>FLT3</i>, <i>TP53</i>, <i>PIK3CA</i>, <i>PAX5</i>, <i>PIK3R1</i>, and <i>PTPN11</i>, with infants having fewer such mutations. Of identified cancer-associated mutations, 62% were below the resolution of standard NGS. Only 33 of 87 mutations exceeded 2% of cellular prevalence and most-targeted PI3K/RAS genes (31/33) and typically <i>KRAS/NRAS</i>. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with <i>FLT3</i> <sup><i>D835H</i></sup> or <i>NRAS</i> <sup><i>G13D/G12S</i></sup> mutations that comprised only 0.06% to 0.34% of diagnostic cells, expanded at relapse. Finally, in longitudinal samples, the relapse clone persisted as a minor subclone from diagnosis and through treatment before expanding during the last month of disease. Together, we demonstrate that infant and childhood <i>KMT2A</i>-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Oct","modification":"2025-04-19T19:42:50.627Z","creation":"2025-04-19T19:42:50.627Z"},"accession":"S-EPMC9529062","cross_references":{"pubmed":["36204688"],"doi":["10.1097/HS9.0000000000000785"]}}