What is a proto-oncogene?

What is a Proto-Oncogene?

A proto-oncogene is a normal cellular gene that regulates cell growth, proliferation, and differentiation, but can be converted into an oncogene (cancer-causing gene) through mutations, chromosomal rearrangements, gene amplification, or overexpression, thereby contributing to cancer development. 1

Normal Function of Proto-Oncogenes

Proto-oncogenes serve essential physiological roles in healthy cells:

• They encode proteins that regulate normal cell growth and proliferation, functioning as critical components of cellular signaling pathways 1, 2
• They act as growth factors, growth factor receptors, or intracellular signal transduction molecules that transmit proliferative signals 3, 2
• They regulate the balance between cell proliferation and differentiation, maintaining normal tissue homeostasis 3
• Examples include RET (receptor tyrosine kinase), MET, ROS1, KRAS, NRAS, and BRAF, all of which are proto-oncogenes that can become oncogenic when altered 4

Mechanisms of Proto-Oncogene Activation

Proto-oncogenes become oncogenes through several distinct molecular mechanisms:

Point Mutations

• Single nucleotide changes in critical codons can activate proto-oncogenes, converting them from growth-regulating genes to cancer-driving genes 5
• KRAS mutations at specific codons (particularly codon 12) are common in lung and colon cancers, occurring in 8-10% of Chinese NSCLC patients 4
• RET proto-oncogene mutations at specific codons (883,918,922,634) cause hereditary medullary thyroid carcinoma in MEN2 syndromes 4, 6

Chromosomal Rearrangements and Translocations

• Gene fusions through chromosomal rearrangements can create constitutively active oncoproteins, particularly common in hematologic malignancies 5
• ALK gene rearrangements occur in 2.4-5.5% of NSCLC cases, creating fusion proteins with oncogenic activity 4
• ROS1 fusions are found in 0.8% of lung adenocarcinomas, representing targetable oncogenic drivers 4

Gene Amplification

• Increased copy number of proto-oncogenes leads to overexpression of growth-promoting proteins 5
• HER2 amplification occurs in 2.4-4.3% of lung adenocarcinomas and is associated with tumor progression 4
• MYC amplification at chromosome 8q is frequently associated with HBV integration sites in hepatocellular carcinoma 4

Overexpression Without Amplification

• Proto-oncogenes can be aberrantly expressed through promoter alterations or loss of regulatory control 5
• TERT promoter mutations create focal gains at chromosome 5p, driving telomerase expression in multiple cancer types 4

Clinical Significance

Diagnostic Implications

• Identifying specific proto-oncogene alterations is essential for cancer diagnosis and classification, as certain mutations are highly specific for particular cancer types 4
• EGFR mutations occur in 39-57.7% of Chinese NSCLC patients, making it the most common oncogenic driver in this population 4
• Genetic testing for RET proto-oncogene mutations should be performed in all medullary thyroid carcinoma patients, as approximately 6% of apparently sporadic cases carry germline mutations 4, 6

Therapeutic Implications

• Proto-oncogene alterations serve as targets for precision cancer therapy, with multiple FDA-approved targeted agents available 4
• Tyrosine kinase inhibitors targeting mutant EGFR, ALK, ROS1, and RET have dramatically improved survival in patients with these specific oncogenic drivers 4
• The specific RET codon mutation dictates timing of prophylactic thyroidectomy in MEN2, with highest-risk mutations (codons 883,918,922) requiring surgery within the first year of life 6

Prognostic Implications

• Certain proto-oncogene mutations correlate with clinical outcomes, such as RET codon 918 mutations being associated with poorer prognosis in medullary thyroid carcinoma 4
• The presence of oncogenic drivers influences treatment response and survival, with targeted therapy significantly prolonging progression-free survival in mutation-positive patients 4

Common Pitfalls and Caveats

• Not all proto-oncogene alterations are oncogenic—some variants are benign polymorphisms or variants of uncertain significance, requiring systematic classification using established criteria 4
• Context matters—the same proto-oncogene can function as an oncogene in one tissue type but have minimal impact in another 4
• Multiple hits are usually required—a single proto-oncogene alteration is typically insufficient for malignant transformation, requiring accumulation of additional genetic changes 4, 2
• Clonal expansion is necessary—cells with pro-oncogenic changes must undergo clonal expansion and acquire additional mutations to develop into cancer 4