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

Mattias Pilheden, Louise Ahlgren, Axel Hyrenius-Wittsten, Veronica Gonzalez-Pena, Helena Sturesson, Hanne Vibeke Hansen Marquart, Birgitte Lausen, Anders Castor, Cornelis Jan Pronk, Gisela Barbany, Katja Pokrovskaja Tamm, Linda Fogelstrand, Olli Lohi, Ulrika Norén-Nyström, Johanna Asklin, Yilun Chen, Guangchun Song, Michael Walsh, Jing Ma, Jinghui ZhangLao H Saal, Charles Gawad, Anna K Hagström-Andersson*

*Corresponding author af dette arbejde

Abstract

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 FLT3 D835H or NRAS G13D/G12S 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 KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.

OriginalsprogEngelsk
TidsskriftHemaSphere
Vol/bind6
Udgave nummer10
Sider (fra-til)e785
ISSN2572-9241
DOI
StatusUdgivet - okt. 2022

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