proto-oncogene

**Definition:** Proto-oncogenes are normal genes that encode proteins controlling the cell cycle, growth signaling, and apoptosis inhibition. When they are abnormally activated ("gain of function"), they become oncogenes (often written c-onc for cellular, v-onc for viral).

**Mechanisms of activation (proto-oncogene → oncogene):** 1. **Point mutation:** e.g., RAS (G-protein locked in the GTP-bound active state); BRAF V600E in melanoma, hairy cell leukemia, and papillary thyroid cancer; RET in MEN2 and medullary thyroid cancer. 2. **Gene amplification:** HER2/neu (ERBB2) in breast and gastric cancer; N-myc in neuroblastoma. 3. **Chromosomal translocation:** - t(9;22) BCR-ABL (Philadelphia chromosome) in CML → constitutive tyrosine kinase - t(8;14) c-myc with the IgH locus in Burkitt lymphoma - t(14;18) BCL-2 with the IgH locus in follicular lymphoma → inhibition of apoptosis - t(15;17) PML-RARα in APL 4. **Overexpression:** via insertional mutagenesis by retroviruses or loss of regulation. 5. **Viral transduction:** retroviruses can capture proto-oncogenes (e.g., v-src, v-onc).

**Functional classes (high-yield examples):** - **Growth factors:** PDGF (sis; astrocytoma), FGF - **Growth factor receptors (receptor tyrosine kinases):** HER2/neu, EGFR (ERBB1; lung adenocarcinoma), RET, KIT (GIST), PDGFR - **Non-receptor tyrosine kinases:** ABL, SRC - **Signal transducers (GTPases/kinases):** RAS (KRAS in colon, lung, pancreatic cancer; HRAS; NRAS), BRAF - **Transcription factors:** MYC (Burkitt), N-myc, L-myc (small cell lung cancer), MYB - **Cell cycle regulators:** Cyclin D1 (CCND1; mantle cell lymphoma, t(11;14)), CDK4 - **Anti-apoptotic proteins:** BCL-2

**Key principle:** Oncogenes act in a **dominant** fashion at the cellular level (one mutated allele is sufficient), whereas tumor suppressor genes (p53, Rb, APC, BRCA1/2, NF1, WT1) are typically **recessive** (the "two-hit hypothesis": both alleles must be inactivated). Proto-oncogene activation is usually somatic, though germline activation occurs in some syndromes (e.g., RET in MEN2A/2B).

**Clinical significance:** - **Diagnosis/prognosis:** HER2 amplification, N-myc amplification (poor prognosis in neuroblastoma), BCR-ABL PCR/FISH for monitoring CML. - **Targeted therapies:** - Imatinib (BCR-ABL, KIT, PDGFR) → CML, GIST - Trastuzumab (HER2) → breast cancer - Vemurafenib/dabrafenib (BRAF V600E) → melanoma - Erlotinib/gefitinib/osimertinib (EGFR) → lung adenocarcinoma - Venetoclax (BCL-2) → CLL - Cetuximab/panitumumab (EGFR) are ineffective with KRAS mutations (downstream activation) - Selpercatinib (RET) - Alectinib/crizotinib (ALK; EML4-ALK fusion in lung adenocarcinoma)

**Pearls:** Cancer arises from multiple accumulated hits (oncogene activation plus loss of tumor suppressors, e.g., the adenoma-carcinoma sequence: APC → KRAS → p53). Proto-oncogenes are essential for normal development and tissue repair, so they are tightly regulated.