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

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.

Ahlgren, L. (author)
Hyrenius-Wittsten, A. (author)
Gonzalez-Pena, V. (author)
Sturesson, H. (author)
Marquart, H. V. H. (author)
Lausen, B. (author)
Castor, A. (author)
Pronk, C. J. (author)
Barbany, G. (author)
Tamm, K. P. (author)
Fogelstrand, Linda,1974Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine(Swepub:gu)xsvlin (author)
Lohi, O. (author)
Noren-Nystrom, U. (author)
Asklin, J. (author)
Chen, Y. L. (author)
Song, G. C. (author)
Walsh, M. (author)
Ma, J. (author)
Zhang, J. H. (author)
Saal, L. H. (author)
Gawad, C. (author)
Hagstrom-Andersson, A. K. (author)
Göteborgs universitetInstitutionen för biomedicin, avdelningen för laboratoriemedicin (creator_code:org_t)

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Hematology

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