Which of the following is the most common proto-oncogene activated in human cancers?

Question

Accepted Answer

C. RAS. ## Proto-oncogenes and Activation Frequency

**Key Point:** RAS proto-oncogene is activated in approximately 30% of all human cancers, making it the single most frequently mutated oncogene across all malignancies.

### RAS Gene Characteristics

**High-Yield:** RAS (HRAS, KRAS, NRAS) encodes a small GTPase protein involved in signal transduction. Mutations typically occur at codons 12, 13, or 61, resulting in constitutive activation and loss of GTPase activity.

### Tissue-Specific Activation Patterns

| Cancer Type | RAS Mutation Frequency | Common Isoform |
| --- | --- | --- |
| Pancreatic adenocarcinoma | 90% | KRAS |
| Colorectal cancer | 40–50% | KRAS |
| Lung cancer (non-small cell) | 30% | KRAS |
| Melanoma | 25–30% | NRAS |
| Acute myeloid leukemia | 20–30% | NRAS, KRAS |

**Clinical Pearl:** KRAS mutations in pancreatic cancer are nearly universal and represent an early event in carcinogenesis, making them a potential biomarker for early detection.

### Mechanism of Oncogenic Transformation

1. Wild-type RAS cycles between inactive (GDP-bound) and active (GTP-bound) states
2. Mutant RAS remains locked in GTP-bound active state
3. Continuous downstream signaling through RAF-MEK-ERK pathway
4. Uncontrolled cell proliferation independent of growth factor signals

**Mnemonic:** **RAS = Rapid Abnormal Signaling** — constitutively active due to loss of intrinsic GTPase activity.

### Why RAS is Most Common

- Single point mutations are sufficient for activation (unlike multi-hit tumor suppressors)
- Affects multiple signaling pathways simultaneously (MAPK, PI3K)
- Present in diverse cancer types and tissues
- Early event in multi-step carcinogenesis

[cite:Robbins 10e Ch 7]

Answer

A. MYC

Answer

B. TP53

Answer

D. BRCA1

Which of the following is the most common proto-oncogene activated in human cancers?

Explanation

Proto-oncogenes and Activation Frequency

RAS Gene Characteristics

Tissue-Specific Activation Patterns

Mechanism of Oncogenic Transformation

Why RAS is Most Common

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Cancer Type	RAS Mutation Frequency	Common Isoform
Pancreatic adenocarcinoma	90%	KRAS
Colorectal cancer	40–50%	KRAS
Lung cancer (non-small cell)	30%	KRAS
Melanoma	25–30%	NRAS
Acute myeloid leukemia	20–30%	NRAS, KRAS