TY - JOUR

T1 - Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood KMT2A -rearranged Acute Leukemia

AU - Pilheden, Mattias

AU - Ahlgren, Louise

AU - Hyrenius-Wittsten, Axel

AU - Gonzalez-Pena, Veronica

AU - Sturesson, Helena

AU - Hansen Marquart, Hanne Vibeke

AU - Lausen, Birgitte

AU - Castor, Anders

AU - Pronk, Cornelis Jan

AU - Barbany, Gisela

AU - Pokrovskaja Tamm, Katja

AU - Fogelstrand, Linda

AU - Lohi, Olli

AU - Norén-Nyström, Ulrika

AU - Asklin, Johanna

AU - Chen, Yilun

AU - Song, Guangchun

AU - Walsh, Michael

AU - Ma, Jing

AU - Zhang, Jinghui

AU - Saal, Lao H.

AU - Gawad, Charles

AU - Hagström-Andersson, Anna K.

N1 - Publisher Copyright: © 2022 Wolters Kluwer Health. All rights reserved.

PY - 2022

Y1 - 2022

N2 - Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-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 KMT2A-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 KMT2A-r leukemia and included mutations in KRAS, NRAS, FLT3, TP53, PIK3CA, PAX5, PIK3R1, and PTPN11, 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 KRAS/NRAS. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with FLT3D835Hor NRASG13D/G12Smutations 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 KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.

AB - Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-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 KMT2A-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 KMT2A-r leukemia and included mutations in KRAS, NRAS, FLT3, TP53, PIK3CA, PAX5, PIK3R1, and PTPN11, 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 KRAS/NRAS. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with FLT3D835Hor NRASG13D/G12Smutations 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 KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.

UR - http://www.scopus.com/inward/record.url?scp=85144861303&partnerID=8YFLogxK

U2 - 10.1097/HS9.0000000000000785

DO - 10.1097/HS9.0000000000000785

M3 - Journal article

C2 - 36204688

AN - SCOPUS:85144861303

VL - 6

JO - HemaSphere

JF - HemaSphere

SN - 2572-9241

IS - 10

M1 - E785

ER -