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

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

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  • Media type: E-Article
  • Title: Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood KMT2A-rearranged Acute Leukemia
  • Contributor: Pilheden, Mattias; Ahlgren, Louise; Hyrenius-Wittsten, Axel; Gonzalez-Pena, Veronica; Sturesson, Helena; Hansen Marquart, Hanne Vibeke; Lausen, Birgitte; Castor, Anders; Pronk, Cornelis Jan; Barbany, Gisela; Pokrovskaja Tamm, Katja; Fogelstrand, Linda; Lohi, Olli; Norén-Nyström, Ulrika; Asklin, Johanna; Chen, Yilun; Song, Guangchun; Walsh, Michael; Ma, Jing; Zhang, Jinghui; Saal, Lao H.; Gawad, Charles; Hagström-Andersson, Anna K.
  • Published: Wiley, 2022
  • Published in: HemaSphere, 6 (2022) 10, Seite e785
  • Language: English
  • DOI: 10.1097/hs9.0000000000000785
  • ISSN: 2572-9241
  • Keywords: Hematology
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access