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Updated: Jun 27, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients
Jeffrey W Tyner1, Heidi Erickson, Michael W N Deininger
1Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA
Abstract:
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.
Insights
This study identified novel RAS mutations in acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) patients, revealing that cancer can develop through less common genetic alterations. These findings suggest RAS mutations are more prevalent in leukemogenesis than previously thought.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Transforming mutations in NRAS and KRAS are implicated in various cancers, including myeloid malignancies.
- Most known oncogenic RAS variants involve mutations at amino acids 12, 13, or 61.
- The role of less common RAS mutations in cancers with unknown genetic causes remains under-explored.
Purpose of the Study:
- To identify novel RAS mutations beyond the canonical sites (12, 13, 61) in patients with myeloid malignancies.
- To investigate the oncogenic potential of these newly discovered RAS mutations.
Main Methods:
- Sequencing of all coding exons in NRAS, KRAS, and HRAS.
- Analysis of samples from 329 acute myeloid leukemia (AML) patients, 32 chronic myelomonocytic leukemia (CMML) patients, and 96 healthy controls.
- Biochemical and functional assays to assess the oncogenic properties of identified Ras mutants.
Main Results:
- Four noncanonical point mutations (N-Ras(G60E), K-Ras(V14I), K-Ras(T74P), K-Ras(A146T)) were detected in 7 patients.
- All four identified Ras mutants demonstrated oncogenic properties in vitro compared to wild-type Ras.
- These findings highlight that transforming RAS mutations can occur at residues other than the common hotspots.
Conclusions:
- RAS mutations may contribute to leukemogenesis through mechanisms beyond the well-characterized canonical mutations.
- Current screening methods might overlook a significant number of oncogenic RAS variants.
- Comprehensive screening of the entire RAS coding region is recommended for a thorough understanding of RAS mutations in cancer.
