TY - JOUR
T1 - High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients
AU - Tyner, Jeffrey W.
AU - Erickson, Heidi
AU - Deininger, Michael W.N.
AU - Willis, Stephanie G.
AU - Eide, Christopher A.
AU - Levine, Ross L.
AU - Heinrich, Michael C.
AU - Gattermann, Norbert
AU - Gilliland, D. Gary
AU - Druker, Brian J.
AU - Loriaux, Marc M.
N1 - Funding Information:
Acknowledgements This work was funded by the Federal Ministry of Education and Research (BMBF), Germany within the InnoProfile Transfer research group “4DnD-Vis” (www.4dndvis.de) and the Research School on ‘Service-Oriented Systems Engineering’ of the Hasso Plattner Institute. We would like to thank virtualcitySYSTEMS for providing datasets.
PY - 2009/2/19
Y1 - 2009/2/19
N2 - Transforming mutations in NRAS and KRAS are thought to play a causative role in the development of numerous cancers, including myeloid malignancies. Although mutations at amino acids 12, 13, or 61 account for the majority of oncogenic Ras variants, we hypothesized that less frequent mutations at alternate residues may account for disease in some patients with cancer of unexplained genetic etiology. To search for additional, novel RAS mutations, we sequenced all coding exons in NRAS, KRAS, and HRAS in 329 acute myeloid leukemia (AML) patients, 32 chronic myelomonocytic leukemia (CMML) patients, and 96 healthy individuals. We detected 4 "noncanonical" point mutations in 7 patients: N-RasG60E, K-RasV14I, K-RasT74P, and K-RasA146T. All 4 Ras mutants exhibited oncogenic properties incomparison with wild-type Ras in biochemical and functional assays. The presence of transforming RAS mutations outside of positions 12, 13, and 61 reveals that alternate mechanisms of transformation by RAS may be overlooked in screens designed to detect only the most common RAS mutations. Our results suggest that RAS mutations may play a greater role in leukemogenesis than currently believed and indicate that high-throughput screening for mutant RAS alleles in cancer should include analysis of the entire RAS coding region.
AB - Transforming mutations in NRAS and KRAS are thought to play a causative role in the development of numerous cancers, including myeloid malignancies. Although mutations at amino acids 12, 13, or 61 account for the majority of oncogenic Ras variants, we hypothesized that less frequent mutations at alternate residues may account for disease in some patients with cancer of unexplained genetic etiology. To search for additional, novel RAS mutations, we sequenced all coding exons in NRAS, KRAS, and HRAS in 329 acute myeloid leukemia (AML) patients, 32 chronic myelomonocytic leukemia (CMML) patients, and 96 healthy individuals. We detected 4 "noncanonical" point mutations in 7 patients: N-RasG60E, K-RasV14I, K-RasT74P, and K-RasA146T. All 4 Ras mutants exhibited oncogenic properties incomparison with wild-type Ras in biochemical and functional assays. The presence of transforming RAS mutations outside of positions 12, 13, and 61 reveals that alternate mechanisms of transformation by RAS may be overlooked in screens designed to detect only the most common RAS mutations. Our results suggest that RAS mutations may play a greater role in leukemogenesis than currently believed and indicate that high-throughput screening for mutant RAS alleles in cancer should include analysis of the entire RAS coding region.
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U2 - 10.1182/blood-2008-04-152157
DO - 10.1182/blood-2008-04-152157
M3 - Article
C2 - 19075190
AN - SCOPUS:61849150985
SN - 0006-4971
VL - 113
SP - 1749
EP - 1755
JO - Blood
JF - Blood
IS - 8
ER -