High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients.
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-Ras(G60E), K-Ras(V14I), K-Ras(T74P), and K-Ras(A146T). All 4 Ras mutants exhibited oncogenic properties in comparison 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.
Tyner
Jeffrey W
JW
Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA
Erickson
Heidi
H
Deininger
Michael W N
MW
Willis
Stephanie G
SG
Eide
Christopher A
CA
Levine
Ross L
RL
Heinrich
Michael C
MC
Gattermann
Norbert
N
Gilliland
D Gary
DG
Druker
Brian J
BJ
Loriaux
Marc M
MM
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D017354:Point Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D016283:Proto-Oncogene Proteins p21(ras)