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Duplex Sequencing U...
Duplex Sequencing Uncovers Recurrent Low-frequency Cancer-associated Mutations in Infant and Childhood KMT2A-rearranged Acute Leukemia
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2022-10
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Ovid Technologies (Wolters Kluwer Health),2022
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LIBRIS-ID:oai:gup.ub.gu.se/321701
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https://gup.ub.gu.se/publication/321701URI
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https://doi.org/10.1097/hs9.0000000000000785DOI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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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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Ahlgren, L.
(author)
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Hyrenius-Wittsten, A.
(author)
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Gonzalez-Pena, V.
(author)
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Sturesson, H.
(author)
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Marquart, H. V. H.
(author)
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Lausen, B.
(author)
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Castor, A.
(author)
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Pronk, C. J.
(author)
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Barbany, G.
(author)
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Tamm, K. P.
(author)
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Fogelstrand, Linda,1974Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine(Swepub:gu)xsvlin
(author)
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Lohi, O.
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Noren-Nystrom, U.
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Asklin, J.
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Chen, Y. L.
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Song, G. C.
(author)
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Walsh, M.
(author)
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Ma, J.
(author)
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Zhang, J. H.
(author)
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Saal, L. H.
(author)
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Gawad, C.
(author)
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Hagstrom-Andersson, A. K.
(author)
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Göteborgs universitetInstitutionen för biomedicin, avdelningen för laboratoriemedicin
(creator_code:org_t)
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In:Hemasphere: Ovid Technologies (Wolters Kluwer Health)6:102572-9241
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Pilheden, M.
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Ahlgren, L.
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Hyrenius-Wittste ...
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Gonzalez-Pena, V ...
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Sturesson, H.
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Marquart, H. V. ...
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Lausen, B.
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Castor, A.
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Pronk, C. J.
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Barbany, G.
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Tamm, K. P.
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Fogelstrand, Lin ...
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Lohi, O.
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Noren-Nystrom, U ...
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Asklin, J.
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Chen, Y. L.
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Song, G. C.
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Walsh, M.
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Ma, J.
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Zhang, J. H.
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Saal, L. H.
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Gawad, C.
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Hagstrom-Anderss ...
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- MEDICAL AND HEALTH SCIENCES
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and Hematology
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Hemasphere
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University of Gothenburg