All of the following statements regarding the RAS oncogene are true EXCEPT:
A. RAS protein functions as a GTPase that cycles between active GTP-bound and inactive GDP-bound states
B. RAS mutations typically occur at codons 12, 13, and 61, which abolish GTPase activity and lock the protein in the active GTP-bound state
C. RAS mutations are most frequently associated with hematologic malignancies and rarely occur in solid tumors
D. RAS mutations are the most common oncogenic mutations found in human cancers, occurring in approximately 30% of malignancies
Explanation
RAS Oncogene: Mechanism and Clinical Significance
Key Point
RAS is the most frequently mutated oncogene in human cancers (~30% of malignancies), and mutations occur across BOTH hematologic AND solid tumors — not exclusively in hematologic cancers.
RAS Structure and Function
RAS is a small GTPase that acts as a molecular switch:
Active state (GTP-bound): Recruits and activates downstream effectors (RAF, PI3K)
Inactive state (GDP-bound): Dissociated from effectors
GTPase activity: Intrinsic GTPase converts GTP → GDP, returning RAS to inactive state
Mechanism of RAS Mutations
Table
Codon
Frequency
Effect
12
~40% of RAS mutations
Impairs GTPase activity
13
~20% of RAS mutations
Impairs GTPase activity
61
~30% of RAS mutations
Impairs GTPase activity
High-YieldNEET PG
Mutations at codons 12, 13, and 61 abolish GTPase activity, locking RAS in the constitutively active GTP-bound state. This leads to continuous downstream signaling (MAPK/ERK pathway activation) without requiring growth factor stimulation.
RAS Mutations Across Cancer Types
Solid Tumors (HIGH frequency):
Pancreatic cancer: ~90%
Colorectal cancer: ~40–50%
Lung cancer (especially KRAS): ~30%
Thyroid cancer: ~25–30%
Hematologic Malignancies (LOWER frequency):
Acute myeloid leukemia: ~20–30%
Chronic myelomonocytic leukemia: ~30–40%
Lymphomas: ~10–15%
Clinical Pearl
KRAS mutations in pancreatic cancer are so common that they are considered a hallmark of the disease and are used in diagnostic panels. RAS mutations are a hallmark of solid tumors, NOT a rarity.
