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

Pilheden, Mattias LU ; Ahlgren, Louise LU ; Hyrenius-Wittsten, Axel LU ; Gonzalez-Pena, Veronica ; Sturesson, Helena LU ; Hansen Marquart, Hanne Vibeke ; Lausen, Birgitte ; Castor, Anders LU orcid ; Pronk, Cornelis Jan and Barbany, Gisela , et al. (2022) In HemaSphere 6(10). p.1-8
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
HemaSphere
volume
6
issue
10
article number
e785
pages
1 - 8
publisher
Wolters Kluwer
external identifiers
  • pmid:36204688
  • scopus:85144861303
ISSN
2572-9241
DOI
10.1097/HS9.0000000000000785
language
English
LU publication?
yes
additional info
Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.
id
56b0b16a-0876-4464-afa4-6fa193efcdc1
date added to LUP
2023-04-14 12:07:08
date last changed
2024-10-05 13:51:17
@article{56b0b16a-0876-4464-afa4-6fa193efcdc1,
  abstract     = {{<p>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.</p>}},
  author       = {{Pilheden, Mattias and Ahlgren, Louise and Hyrenius-Wittsten, Axel and Gonzalez-Pena, Veronica and Sturesson, Helena and Hansen Marquart, Hanne Vibeke and Lausen, Birgitte and Castor, Anders and Pronk, Cornelis Jan and Barbany, Gisela and Pokrovskaja Tamm, Katja and Fogelstrand, Linda and Lohi, Olli and Norén-Nyström, Ulrika and Asklin, Johanna and Chen, Yilun and Song, Guangchun and Walsh, Michael and Ma, Jing and Zhang, Jinghui and Saal, Lao H and Gawad, Charles and Hagström-Andersson, Anna K}},
  issn         = {{2572-9241}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{1--8}},
  publisher    = {{Wolters Kluwer}},
  series       = {{HemaSphere}},
  title        = {{Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood KMT2A-rearranged Acute Leukemia}},
  url          = {{http://dx.doi.org/10.1097/HS9.0000000000000785}},
  doi          = {{10.1097/HS9.0000000000000785}},
  volume       = {{6}},
  year         = {{2022}},
}