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Oncogene

An oncogene is a mutated or altered form of a normal cellular gene, known as a proto-oncogene, that drives uncontrolled cell proliferation and contributes to the development of cancer by promoting malignant transformation.^[1] Proto-oncogenes typically encode proteins involved in essential cellular processes such as growth signaling, cell cycle progression, and differentiation, but when activated abnormally, they function like a "stuck accelerator" in the cell's regulatory machinery.^[2] This activation often results from genetic changes including point mutations, chromosomal translocations, gene amplifications, or insertions, leading to overexpression or constitutive activity of the encoded protein.^[3] The concept of oncogenes emerged from studies of tumor-causing viruses in the 1970s, with key discoveries revealing that viral oncogenes like src in Rous sarcoma virus originated from captured cellular proto-oncogenes.^[1] Pioneering work by researchers such as Harold Varmus and J. Michael Bishop demonstrated that these proto-oncogenes exist in normal cells and can be converted to oncogenes through mutations, earning them the 1989 Nobel Prize in Physiology or Medicine.^[1] In human cancers, oncogenes play a central role in tumorigenesis by disrupting signaling pathways—such as the RAS/MAPK pathway—that regulate cell division, survival, and apoptosis inhibition.^[3] Unlike tumor suppressor genes, which act as "brakes" on cell growth and require loss-of-function mutations to contribute to cancer, oncogenes exhibit gain-of-function alterations that actively promote tumor initiation, progression, and metastasis.^[2] Notable examples include the RAS family of oncogenes, which harbor point mutations in approximately 20-30% of human cancers, particularly in pancreatic, colorectal, and lung malignancies, leading to persistent activation of downstream growth signals.^[1] The MYC oncogene, often amplified or translocated as in Burkitt's lymphoma, regulates transcription to accelerate cell cycle entry and inhibit differentiation.^[3] Similarly, amplification of HER2 (also known as ERBB2) occurs in about 20% of breast cancers, enhancing receptor tyrosine kinase signaling for tumor growth.^[3] The BCR-ABL fusion oncogene, resulting from the Philadelphia chromosome translocation, drives chronic myeloid leukemia by constitutively activating tyrosine kinase activity.^[2] Oncogenes frequently cooperate with inactivated tumor suppressors like p53 or RB1 to fully unleash carcinogenic potential, underscoring their role in the multi-hit model of cancer development.^[3]

Fundamentals

Definition

An oncogene is a mutated or overexpressed form of a proto-oncogene (a normal gene that regulates cell growth and division), resulting in uncontrolled cell proliferation and tumor formation.^[4] These genes arise from alterations in normal cellular genes known as proto-oncogenes, which typically regulate cell growth and division; when mutated, oncogenes drive uncontrolled cellular activity that disrupts normal tissue homeostasis.^[5] At the cellular level, oncogenes act in a dominant manner, meaning that alteration of only one allele is sufficient to promote oncogenic effects, in contrast to tumor suppressor genes, which require inactivation of both alleles to lose their protective function.^[6] This dominant behavior stems from the enhanced or hyperactive protein products they encode, which override normal regulatory signals to stimulate proliferation even in the presence of a wild-type allele.^[7] Well-known examples include the RAS oncogene, which encodes a GTPase involved in signal transduction pathways, and the MYC oncogene, a transcription factor that regulates cell cycle progression and metabolism; both are frequently mutated or amplified across various cancers.^[8] Oncogenes were first identified as viral oncogenes (v-onc) in retroviruses capable of inducing tumors in animals, such as the src gene in Rous sarcoma virus.^[9]

Relation to Proto-oncogenes

Proto-oncogenes, often denoted as c-onc genes, are normal cellular genes that encode proteins essential for regulating cell growth, proliferation, division, and differentiation in eukaryotic cells. These genes are ubiquitous across species and function as positive regulators of cellular processes under physiological conditions. When altered—typically through gain-of-function mutations, amplification, or dysregulation—they convert into oncogenes, which promote uncontrolled cell proliferation and contribute to tumorigenesis.^[3] In their unmutated form, proto-oncogenes are integral to key cellular pathways, including signal transduction, where they relay extracellular signals to intracellular responses; transcriptional regulation, influencing gene expression that drives cell cycle progression; and apoptosis control, balancing cell survival and death to maintain tissue homeostasis. For instance, the proto-oncogene EGFR encodes the epidermal growth factor receptor, a transmembrane tyrosine kinase that, upon ligand binding, activates downstream cascades like the RAS-MAPK pathway to stimulate cell division and survival in response to growth factors. Similarly, c-MYC regulates transcription of genes involved in proliferation and metabolism, while BCL2 modulates apoptosis to prevent unnecessary cell loss during development or stress. These roles ensure coordinated cellular responses to environmental cues, preventing aberrant growth in healthy tissues.^[10]^[3] Proto-oncogenes are highly conserved across diverse species, from invertebrates to mammals, reflecting their essential roles in eukaryotic cell regulation over hundreds of millions of years. Their viral counterparts (v-onc) originated from ancient retroviral capture and transduction of these cellular genes into viral genomes, a process that occurred millions of years ago and facilitated the discovery of proto-oncogenes through studies of tumor-inducing viruses. The high degree of sequence and functional conservation, as seen in homologs like c-src in vertebrates derived from viral v-src, highlights their indispensable contributions to multicellular organism development and homeostasis.^[11]^[12] The transformation of a proto-oncogene into an oncogene requires only a single genetic alteration—the "single-hit" model—due to the gain-of-function nature of these mutations, which can dominantly override normal regulatory controls. This contrasts with tumor suppressor genes, as even heterozygous mutations in proto-oncogenes can lead to haploinsufficiency or hyperactivity, providing a selective advantage for clonal expansion in early carcinogenesis. For example, a point mutation in KRAS can lock the protein in an active GTP-bound state, sufficient to drive pancreatic tumorigenesis without needing a second hit.^[3]^[10]

Historical Development

Early Discoveries

The discovery of oncogenes began with the pioneering work of Peyton Rous in 1911, when he identified a filterable agent capable of transmitting sarcomas in chickens, later named the Rous sarcoma virus (RSV). This finding provided the first evidence that viruses could cause cancer, challenging prevailing views that tumors arose solely from cellular mutations or environmental factors. Rous's experiments demonstrated that cell-free extracts from the tumors could induce malignancy in healthy birds, establishing the concept of viral oncogenesis. For this breakthrough, Rous was awarded the Nobel Prize in Physiology or Medicine in 1966.^[13] In the 1970s, research on RSV led to the identification of the src gene as the first recognized oncogene, marking a pivotal advancement in understanding cancer's genetic basis. J. Michael Bishop and Harold E. Varmus demonstrated that the viral src (v-src) gene was responsible for RSV's transforming ability and originated from a normal cellular gene in the host genome. Their work revealed that acute transforming retroviruses, such as RSV, acquire oncogenes (v-onc genes) through transduction from host cellular sequences during viral replication, enabling rapid tumor induction. This discovery earned Bishop and Varmus the Nobel Prize in Physiology or Medicine in 1989.^[14] The realization that v-onc genes derived from cellular counterparts, termed proto-oncogenes or c-onc genes, shifted the paradigm from purely viral causation to the role of endogenous genes in oncogenesis. Studies showed that these normal cellular genes, present in all multicellular organisms, regulate growth and development but can become oncogenic when altered, as seen in viral transduction. This insight laid the groundwork for molecular oncology by highlighting how viruses exploit host genetics to drive cancer.^[6]^[15]

Key Experiments

In the late 1970s, building briefly on earlier insights from viral oncogene research, key experiments shifted focus to non-viral contexts by demonstrating that DNA from transformed mammalian cells could transfer oncogenic properties to normal cells via transfection. A seminal study in 1979 by Robert Weinberg and colleagues used calcium phosphate-mediated DNA transfection to introduce genomic DNA from chemically transformed mouse and rat cells into NIH 3T3 mouse fibroblasts, resulting in the formation of transformed foci—piles of multilayered, anchorage-independent cells indicative of oncogenic activity.^[16] This assay confirmed that transforming sequences were present in the DNA of non-virally transformed cells and could be propagated through multiple rounds of transfection, establishing a functional test for oncogenes without relying on viral vectors.^[16] This transfection approach was rapidly extended to human tumor DNA in the early 1980s, providing direct evidence of human oncogenes. In 1981, Weinberg's group transfected DNA from the human bladder carcinoma cell line EJ into NIH 3T3 cells, observing focus formation and tumorigenicity in nude mice, which indicated the presence of an activated transforming gene distinct from known viral oncogenes. Similar results were reported independently by groups led by Michael Wigler and Mariano Barbacid using DNA from various human carcinomas, including lung and bladder tumors, further validating the method's sensitivity in detecting rare transforming sequences (occurring at frequencies of about 10^{-5} to 10^{-6}). These experiments not only isolated the first human oncogene—a mutated RAS homolog—but also highlighted the assay's utility in pinpointing dominant, gain-of-function genetic alterations driving cellular transformation. Throughout the 1980s, focus-forming assays in rodent fibroblasts became central to identifying and characterizing specific oncogenes, particularly the RAS family. Transfection of tumor DNA into NIH 3T3 or Rat-1 fibroblasts produced quantifiable foci of transformed cells, allowing researchers to map transforming activity to specific genomic fragments; for instance, Barbacid's group used this to clone the activated HRAS oncogene from human tumors, demonstrating its homology to rodent sarcoma virus genes while confirming its role in morphological transformation and soft agar growth. These assays revealed that RAS activation conferred a growth advantage in low-serum conditions, with transformed foci exhibiting significantly enhanced proliferation compared to untransfected controls, underscoring RAS's potent oncogenic potential in mammalian systems. Hybridization studies using Southern blotting provided complementary evidence for the existence of cellular oncogene (c-onc) homologs in normal human genomes, bridging viral and cellular discoveries. In the early 1980s, probes derived from viral oncogenes (e.g., v-ras or v-myc) were hybridized to restriction-digested human DNA, revealing conserved sequences in non-tumorigenic cells; for example, Southern blots showed single-copy c-ras loci on human chromosomes, with tumor samples displaying altered restriction patterns indicative of mutations or amplifications. This technique, applied to diverse tissues, confirmed that proto-oncogenes were ubiquitous in the human genome, present at one or two copies per haploid genome, and laid the groundwork for detecting structural changes in cancer. Key milestones from these efforts included the 1982 cloning of the human c-myc proto-oncogene from Burkitt lymphoma cells, where Southern blotting and library screening identified its translocation to the immunoglobulin heavy chain locus on chromosome 14, juxtaposing it with enhancer elements to drive overexpression. Concurrently, evidence emerged for point mutations as a mechanism of oncogene activation; sequencing of the HRAS gene from the EJ bladder carcinoma revealed a G-to-A transition at codon 12, substituting glycine with valine and locking the protein in its GTP-bound, active state, which was sufficient to transform NIH 3T3 cells at efficiencies comparable to viral RAS. These findings solidified point mutations as a common activation route for proto-oncogenes in sporadic human cancers.

Activation Mechanisms

Genetic Mutations

Genetic mutations in oncogenes primarily involve point mutations, which are single nucleotide alterations in the DNA sequence of proto-oncogenes that result in their conversion to constitutively active oncogenes. These mutations often occur at critical codons, leading to proteins that promote uncontrolled cell proliferation by disrupting normal regulatory mechanisms.^[17] A common type is the missense mutation, where a single amino acid substitution alters the protein's function, frequently locking enzymes in an active state. For instance, the G12V mutation in the KRAS proto-oncogene replaces glycine with valine at codon 12, impairing the GTPase activity required for signal termination and causing persistent activation of downstream pathways like MAPK/ERK. This exemplifies how such mutations in GTPases lead to constitutive signaling, a hallmark of oncogenic transformation.^[18]^[19] Similarly, in the BRAF proto-oncogene, the V600E missense mutation substitutes valine with glutamic acid at codon 600, resulting in kinase domain activation independent of upstream signals and driving melanomagenesis through hyperactive RAF-MEK-ERK signaling. This mutation is particularly prevalent in melanoma, underscoring its role in tissue-specific oncogenesis.^[20]^[21] Mutations in the RAS family (KRAS, NRAS, HRAS) are found in approximately 19% of all human cancers, with higher frequencies in solid tumors such as pancreatic (over 90% KRAS), colorectal (about 40% KRAS), and lung adenocarcinomas (around 30% KRAS). These alterations typically impair GTP hydrolysis, maintaining the protein in its GTP-bound active form and facilitating tumor initiation and progression.^[22] Detection of these point mutations relies on next-generation sequencing (NGS) techniques, which enable high-throughput identification of single nucleotide variants in tumor DNA, often through targeted panels focusing on hotspot regions in known oncogenes. This approach has become standard for precise diagnosis and guiding targeted therapies, such as inhibitors for specific mutants like BRAF V600E.^[23]^[24]

Amplification and Rearrangement

Gene amplification represents a key mechanism for oncogene activation, wherein multiple tandem copies of a proto-oncogene are generated within the genome, leading to elevated expression levels of the encoded protein and heightened signaling activity without any alteration to the gene's coding sequence. This process increases the effective gene dosage, often resulting in aggressive tumor phenotypes. A well-characterized instance is the amplification of the HER2 (ERBB2) gene in breast cancer, which occurs in 20–30% of cases and drives overexpression of the HER2 receptor tyrosine kinase, promoting cell proliferation and invasion while correlating with poorer prognosis and shorter relapse-free survival.^[25]^[26] Another critical example involves the MYCN oncogene in neuroblastoma, where amplification is detected in approximately 20–25% of tumors, particularly those classified as high-risk, and serves as an independent predictor of adverse outcomes by enhancing MYCN-mediated transcription of genes involved in cell growth and survival.^[27]^[28] This amplification fosters rapid tumor progression and resistance to therapy, underscoring its role as a driver of aggressive pediatric malignancies. Chromosomal rearrangements, including translocations, activate oncogenes by juxtaposing proto-oncogene sequences with potent regulatory elements or by generating chimeric proteins with deregulated function. The paradigmatic case is the t(9;22) translocation, known as the Philadelphia chromosome, which fuses the BCR and ABL1 genes to produce the BCR-ABL oncoprotein in over 95% of chronic myeloid leukemia (CML) patients. This fusion imparts constitutive kinase activity to ABL1, disrupting normal cellular signaling, inhibiting apoptosis, and enabling uncontrolled myeloid proliferation, thereby initiating and sustaining the leukemic state.^[29]^[30] Insertional mutagenesis provides another route for oncogene activation, particularly through viral integration, where the viral genome inserts adjacent to a proto-oncogene, co-opting viral long terminal repeat (LTR) promoters or enhancers to drive ectopic expression. Retroviruses exemplify this mechanism; for instance, avian leukosis virus integration near the c-myc proto-oncogene in chickens leads to its overexpression, transforming B-lymphocytes and inducing lymphomas by amplifying MYC-dependent proliferative signals.^[31]^[32] Such events highlight how structural genomic disruptions can enhance oncogene signaling independently of sequence mutations, contributing to oncogenesis across diverse contexts.

Regulatory Changes

Regulatory changes in oncogene activation encompass epigenetic and transcriptional mechanisms that dysregulate gene expression without altering the underlying DNA sequence, thereby promoting overexpression or aberrant activity in cancer cells. These alterations often involve modifications to chromatin structure, enhancer-promoter interactions, and post-transcriptional processing, which can silence repressive elements or enhance activating signals to drive tumorigenesis.^[33] Promoter hypomethylation represents a key epigenetic mechanism where reduced DNA methylation at CpG islands in oncogene promoters leads to their transcriptional derepression and overexpression. For instance, hypomethylation of BCL2 in B-cell chronic lymphocytic leukemia (CLL) results in elevated BCL2 levels, contributing to apoptotic resistance and disease progression.^[34] Hypermethylation in specific regulatory regions can also activate oncogenes by relieving repression. For instance, hypermethylation of the telomerase reverse transcriptase (TERT) promoter in the telomerase hypermethylated oncological region (THOR) activates TERT expression, contributing to replicative immortality observed in approximately 90% of human cancers overall, including those of the thyroid, lung, and prostate.^[34] Enhancer hijacking occurs when chromosomal translocations reposition oncogenes adjacent to potent enhancers, thereby placing them under the control of constitutively active regulatory elements and causing their inappropriate overexpression. A prominent example is the t(8;14) translocation in Burkitt lymphoma, which juxtaposes the MYC oncogene with immunoglobulin heavy chain (IGH) enhancers, leading to MYC deregulation and lymphomagenesis through enhanced transcriptional activation.^[35] This mechanism exemplifies how structural rearrangements can exploit distant regulatory landscapes to fuel oncogene activation in hematopoietic malignancies.^[36] MicroRNA (miRNA) dysregulation contributes to oncogene activation by downregulating miRNAs that normally repress target oncogenes at the post-transcriptional level, resulting in unchecked protein expression. In CLL, deletion or downregulation of the miR-15/16 cluster, located at 13q14, relieves inhibition of BCL2 translation, leading to BCL2 overexpression and impaired apoptosis, which is a hallmark of the disease.^[37] This miRNA-oncogene axis highlights the role of non-coding RNAs in fine-tuning oncogene activity during cancer initiation.^[38] Post-transcriptional changes, particularly altered mRNA splicing, generate oncogenic isoforms that promote tumor progression by evading normal regulatory controls. For example, in various cancers including breast and colon, alternative splicing of the PKM gene favors the PKM2 isoform over PKM1, enhancing aerobic glycolysis (the Warburg effect) and supporting rapid proliferation through regulation by splicing factors like hnRNPA1 and PTBP1.^[33] Likewise, splicing of BCL2L1 to produce the anti-apoptotic Bcl-xL isoform predominates in many tumors, inhibiting cell death and driven by elevated PTBP1 expression.^[33] These isoform switches underscore the splicing machinery's vulnerability in oncogenic transformation.^[33]

Classification

By Protein Function

Oncogenes are classified by the biochemical functions of their encoded proteins, which typically correspond to key steps in cellular growth and proliferation pathways. This functional categorization highlights how dysregulated proteins drive oncogenesis by mimicking or amplifying normal signaling. Common groups include growth factors, growth factor receptors, intracellular signal transducers, nuclear transcription factors, and cell cycle regulators, with additional roles in anti-apoptotic processes.^[39] Growth factor oncogenes encode proteins that stimulate cell proliferation by binding to and activating their cognate receptors. A representative example is PDGFB, which encodes platelet-derived growth factor beta and promotes autocrine signaling in gliomas, leading to uncontrolled glial cell growth.^[40] Activation of such oncogenes often occurs through gene amplification or overexpression, enabling persistent mitogenic stimulation independent of external cues. Growth factor receptor oncogenes primarily involve receptor tyrosine kinases (RTKs) that transduce extracellular signals into intracellular responses. EGFR (epidermal growth factor receptor), for instance, is frequently activated in various carcinomas through mutations or amplifications, resulting in ligand-independent dimerization and downstream signaling that enhances cell survival and motility.^[41] Similarly, ERBB2 (also known as HER2) functions as an RTK that amplifies signaling from other ErbB family members; its overexpression, often due to gene amplification, potently drives proliferation in breast and ovarian cancers by forming constitutive heterodimers.^[42] Intracellular signaling oncogenes mediate the relay of signals from receptors to downstream effectors, often through kinase cascades or lipid second messengers. Non-receptor tyrosine kinases like SRC propagate signals by phosphorylating multiple substrates, thereby integrating growth factor inputs with cytoskeletal reorganization and metabolic changes; SRC activation, typically via dephosphorylation or mutation, contributes to invasive phenotypes.^[43] G-proteins such as RAS exemplify GTPase oncogenes that lock in an active state due to point mutations, constitutively activating pathways like MAPK and sustaining proliferation signals.^[44] The PI3K/AKT pathway represents another critical transducer group, where oncogenic PIK3CA mutations hyperactivate lipid kinase activity, leading to AKT-mediated promotion of survival and nutrient uptake.^[45] Transcription factor oncogenes directly regulate gene expression to enforce proliferative programs. MYC, a basic helix-loop-helix leucine zipper protein, drives the transcription of genes involved in biomass accumulation and cell cycle entry; its deregulation through translocation or amplification broadly reprograms cellular metabolism toward growth.^[46] JUN, part of the AP-1 complex, similarly activates promoters for proliferation and angiogenesis genes; oncogenic forms, often from amplification, enhance survival under stress by modulating immediate early response elements.^[47] Cell cycle regulator oncogenes, such as CYCLIN D1 (CCND1), facilitate progression through G1/S checkpoints by activating cyclin-dependent kinases (CDKs). Overexpression of CCND1 sequesters CDK inhibitors, promoting hyperphosphorylation of Rb and E2F release, which commits cells to DNA replication; this is commonly seen in endocrine-responsive tumors via chromosomal rearrangements.^[48] Anti-apoptotic oncogenes counteract programmed cell death, allowing survival of damaged cells. The BCL2 family, particularly BCL2 itself, inhibits mitochondrial outer membrane permeabilization by sequestering pro-apoptotic members like BAX and BAK; translocation-induced overexpression, as in follicular lymphoma, confers resistance to apoptosis and clonal expansion.^[49] Other family members, such as BCL-XL, similarly tilt the balance toward survival in response to oncogenic stress.^[50]

By Cellular Location

Oncogenes can be classified based on the subcellular location where their protein products primarily function, as this localization influences their role in oncogenic signaling and cellular transformation. This spatial organization determines how oncogenes interact with cellular components, such as membranes for receptor-mediated signaling or the nucleus for transcriptional regulation, often overlapping with functional categories like receptors or transcription factors.^[51] Membrane-bound oncogenes typically encode receptor tyrosine kinases or membrane-associated proteins that initiate signaling cascades upon ligand binding or mutation, driving uncontrolled cell proliferation. For instance, the MET proto-oncogene product is a transmembrane receptor tyrosine kinase overexpressed in papillary renal cell carcinoma, where it promotes invasive growth through hepatocyte growth factor stimulation.^[52] Other examples include RAS family members like H-RAS and K-RAS, which are anchored to the inner plasma membrane and act as GTPases in signal transduction.^[53] Cytoplasmic oncogenes often produce signaling proteins that relay messages from the membrane to downstream effectors, amplifying mitogenic signals within the cell. RAF kinases, such as BRAF, are serine/threonine kinases located in the cytoplasm that activate the MAPK/ERK pathway in response to RAS activation, with mutations frequently observed in melanomas and other cancers.^[51] Additional cytoplasmic examples include SRC and ABL tyrosine kinases, which phosphorylate targets to enhance cell motility and survival.^[53] Nuclear oncogenes encode transcription factors that directly regulate gene expression, leading to the promotion of cell cycle progression and inhibition of differentiation. The FOS proto-oncogene product forms part of the AP-1 transcription factor complex in the nucleus, where it heterodimerizes with JUN to activate genes involved in proliferation, as seen in osteosarcomas induced by v-fos.^[54] MYC and MYB are other nuclear examples, binding DNA to drive oncogenic transcription programs.^[53] Mitochondrial oncogenes are less common but play critical roles in modulating apoptosis and cellular metabolism at the organelle's membranes. BCL2, an anti-apoptotic proto-oncogene, localizes to the mitochondrial outer membrane, where it prevents cytochrome c release and inhibits programmed cell death, contributing to follicular lymphoma survival.^[55] Variants or related proteins like AKT can also localize mitochondrially to suppress apoptosis through calcium regulation.^[56] Secreted oncogenes produce growth factors that act in an autocrine or paracrine manner to stimulate nearby cells, fostering tumor microenvironment support. FGF3, a member of the fibroblast growth factor family, is secreted and binds FGFRs to promote angiogenesis and proliferation, with amplification observed in breast cancers.^[57] The v-sis product, homologous to PDGF-B, exemplifies this by enabling ligand-independent receptor activation.^[53]

Role in Cancer

Oncogenic Pathways

Oncogenic pathways represent critical signaling cascades that, when dysregulated by oncogenes, drive uncontrolled cell proliferation, survival, and other hallmarks of tumorigenesis. These pathways often originate from developmental or growth factor signaling networks that become aberrantly activated through genetic alterations in oncogenes such as mutated RAS or amplified receptor tyrosine kinases. Central to this process is the RAS-RAF-MEK-ERK pathway, a mitogen-activated protein kinase (MAPK) cascade that transduces signals from extracellular stimuli to the nucleus, promoting cell cycle progression and proliferation. Upon activation by oncogenic RAS mutations, which occur in approximately 30% of human cancers but lead to pathway hyperactivity in up to 50% through various mechanisms including upstream receptor amplification, RAF kinases phosphorylate and activate MEK1/2, which in turn phosphorylate ERK1/2; this culminates in the transcription of genes like c-MYC and cyclin D1 that sustain tumor growth.^[58]^[59] Another major oncogenic pathway is the PI3K-AKT-mTOR axis, which regulates cell survival, metabolism, and protein synthesis, often hijacked by oncogenes like PIK3CA mutations or loss of the tumor suppressor PTEN. Activation begins with PI3K phosphorylating PIP2 to PIP3, recruiting and activating AKT, which then inhibits pro-apoptotic proteins like FOXO and BAD while stimulating mTOR to enhance anabolic processes; PTEN loss, observed in 40-60% of endometrial cancers and 15-25% of prostate cancers, removes negative regulation, leading to persistent signaling that confers resistance to apoptosis and metabolic reprogramming favoring tumor expansion.^[60]^[61]^[62] The Wnt/β-catenin pathway further contributes to oncogenesis by maintaining stemness and promoting invasion, particularly through stabilizing β-catenin via loss-of-function mutations in the tumor suppressor APC or gain-of-function mutations in CTNNB1 (β-catenin). In the canonical pathway, Wnt ligand binding inhibits the destruction complex (including APC and GSK3β), allowing β-catenin to accumulate, translocate to the nucleus, and activate transcription factors like TCF/LEF that upregulate genes such as AXIN2 and LEF1, fostering cancer stem cell properties and epithelial-mesenchymal transition (EMT) for metastatic potential.^[63]^[64] Developmental pathways like Notch and Hedgehog are also frequently co-opted by oncogenes in cancer, amplifying proliferative and differentiative signals. The Notch pathway, activated by ligands such as Jagged or Delta-like, leads to proteolytic cleavage and release of the Notch intracellular domain (NICD), which translocates to the nucleus to co-activate transcription factors like RBPJ, promoting genes involved in cell fate decisions; oncogenic Notch mutations or amplifications, as seen in T-ALL, hijack this for sustained proliferation and inhibition of differentiation. Similarly, the Hedgehog (Hh) pathway, driven by ligands like Sonic Hedgehog binding to Patched, relieves inhibition of Smoothened, activating GLI transcription factors that induce targets like PTCH1 and CYCLIN D; aberrant activation via PTCH1 loss or SMO mutations in basal cell carcinoma exemplifies how this developmental cascade supports tumor initiation and maintenance.^[65]^[66] These pathways do not operate in isolation; extensive cross-talk amplifies oncogenic effects, such as RAS signaling enhancing Notch activity or PI3K-AKT intersecting with Wnt to boost β-catenin stability, creating robust networks that sustain tumorigenesis across diverse cancer types.^[67]

Multi-step Carcinogenesis

The development of cancer follows a multi-step process involving the sequential accumulation of genetic alterations, in which oncogenes contribute gain-of-function mutations that drive tumor initiation and progression. This framework adapts Knudson's two-hit hypothesis, originally proposed for tumor suppressor genes requiring biallelic inactivation, to incorporate oncogenes as dominant, single-hit events that provide initiating "gain" alterations complemented by suppressor losses.^[68]^[69] In this extended model, a single activating mutation in an oncogene can confer proliferative advantages, but full tumorigenesis demands cooperation with additional hits, such as suppressor gene disruptions, to bypass cellular checkpoints.^[70] A seminal illustration of this sequential cooperation is the Vogelstein model of colorectal carcinogenesis, which delineates the orderly progression from normal colonic epithelium to adenoma and then to carcinoma through specific genetic events. Inactivation of the APC tumor suppressor gene represents an early hit that initiates small adenomas; this is followed by activating mutations in the KRAS oncogene, which enlarge adenomas and confer growth autonomy; subsequent loss of TP53 function then propels the transition to malignant carcinoma by impairing DNA damage responses.^[71] Here, the KRAS oncogene exemplifies how a gain-of-function alteration integrates with suppressor losses to advance multistage tumor evolution, with mutations accumulating in a temporal sequence that correlates with histopathological progression.^[72] Within this multi-hit paradigm, clonal evolution further amplifies oncogene roles by enabling Darwinian selection of aggressive tumor subpopulations. Tumors arise from a single progenitor cell and progress through rounds of genetic diversification and subclonal expansion, where oncogene activations—such as those enhancing proliferation or survival—impart selective advantages, favoring the dominance of fitter clones in the tumor microenvironment.^[73] This process, driven by oncogene-induced genetic instability, generates intratumor heterogeneity and promotes the emergence of variants with heightened malignancy, underscoring how oncogenes shape adaptive landscapes during carcinogenesis.^[74] Achieving full malignant transformation often involves threshold effects, wherein multiple oncogene activations must accumulate alongside other genetic hits to surpass critical barriers to tumorigenesis. Computational analyses of somatic mutations reveal that cancer typically requires 2–8 hits, with oncogenic combinations synergistically enabling malignancy by overwhelming regulatory networks; for example, single oncogene mutations alone rarely suffice, but paired with complementary alterations, they achieve high penetrance toward tumor formation.^[75] These thresholds highlight the cooperative necessity of diverse oncogene engagements in sustaining the multistep trajectory to cancer.^[76]

Clinical Relevance

Detection and Diagnosis

Detection and diagnosis of oncogene alterations involve a range of molecular and histopathological techniques applied to patient tumor samples or circulating biomarkers to identify activating mutations, amplifications, fusions, or overexpression that drive cancer progression. These methods enable precise identification of oncogenic drivers, facilitating cancer subtyping and personalized management. Common approaches include genomic sequencing for point mutations and structural variants, cytogenetic assays for gene copy number changes, and protein-based assays for expression levels, often integrated into clinical workflows for solid tumors like lung, breast, and colorectal cancers. According to the National Comprehensive Cancer Network (NCCN) guidelines as of 2025, comprehensive genomic profiling is recommended for advanced non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer to detect actionable oncogene alterations.^[77]^[78] Next-generation sequencing (NGS) has become a cornerstone for detecting oncogene mutations, offering high-throughput analysis of tumor DNA to identify somatic alterations such as point mutations, insertions, deletions, and fusions. In non-small cell lung cancer (NSCLC), NGS panels routinely screen for EGFR mutations, including exon 19 deletions, which occur in approximately 10-15% of cases in Western populations (higher in Asian cohorts) and are actionable targets; for instance, targeted NGS achieves over 95% sensitivity and specificity compared to single-gene assays like PCR. Studies validate NGS for comprehensive profiling, detecting not only EGFR but also co-occurring variants in genes like KRAS and BRAF, guiding subtype classification in advanced NSCLC.^[79] Fluorescence in situ hybridization (FISH) is widely used to detect oncogene amplifications by visualizing gene copy number gains directly on chromosomes, particularly for genes like HER2 in breast cancer, where amplification is present in 15-20% of cases and correlates with aggressive disease. Immunohistochemistry (IHC) complements FISH by assessing protein overexpression, scoring HER2 on a 0-3+ scale; scores of 3+ indicate high expression, though concordance with FISH is about 90%, with discrepancies resolved by reflex testing. In breast cancer diagnostics, IHC serves as an initial screen due to its accessibility, while FISH confirms equivocal (2+) results, ensuring accurate identification of amplified oncogenes.^[80]^[81]^[82] Liquid biopsies, analyzing circulating tumor DNA (ctDNA) from blood plasma, provide a non-invasive alternative for oncogene detection, capturing mutations, amplifications, and fusions shed from tumors with sensitivities exceeding 80% in advanced stages. Techniques like targeted NGS on ctDNA identify EGFR mutations in NSCLC with comparable accuracy to tissue biopsies, enabling serial monitoring without invasive procedures. ctDNA assays detect fusions such as EML4-ALK in NSCLC, present in 3-7% of cases, supporting real-time subtyping in metastatic settings. As of 2025, NCCN guidelines endorse liquid biopsies for initial diagnosis and monitoring in eligible patients with advanced NSCLC.^[83]^[84]^[77]^[78] The status of oncogenes holds significant prognostic value by informing cancer subtyping and risk stratification; for example, ALK fusions in NSCLC define a distinct subtype with unique clinical behavior, often associated with younger patients and never-smokers, influencing therapeutic decisions despite variable survival impacts across studies. Detection of such alterations via integrated diagnostics refines prognosis, as ALK-positive cases may exhibit better responses to specific inhibitors compared to wild-type tumors. Overall, oncogene profiling enhances diagnostic precision, with guidelines recommending upfront testing in eligible cancers to subtype and prognosticate effectively.^[85]^[86]^[87]

Targeted Therapies

Targeted therapies for oncogene-driven cancers focus on inhibiting the activity of oncogenic proteins or disrupting the signaling pathways they activate, offering precision-based interventions that improve outcomes compared to traditional chemotherapy. These approaches exploit oncogene addiction, where cancer cells become dependent on the continued activity of the mutated oncogene for survival, allowing selective targeting with minimal impact on normal cells. Tyrosine kinase inhibitors (TKIs) represent a cornerstone of this strategy, particularly for receptor and non-receptor tyrosine kinases frequently altered in cancers.^[30] Imatinib, a seminal TKI, specifically targets the BCR-ABL fusion oncoprotein in chronic myeloid leukemia (CML), binding to its ATP-binding site and inhibiting constitutive kinase activity. In the phase III IRIS trial, imatinib achieved a complete cytogenetic response in 74% of newly diagnosed chronic-phase CML patients at 18 months, establishing it as first-line therapy and dramatically improving survival rates. However, acquired resistance often arises through secondary point mutations in the BCR-ABL kinase domain, such as T315I, which alter the drug-binding conformation and reduce efficacy in up to 20-30% of patients progressing on therapy.^[88] Monoclonal antibodies provide another key modality by blocking extracellular domains of oncogene products. Trastuzumab, a humanized antibody targeting the HER2 oncogene (amplified in ~15-20% of breast cancers), inhibits HER2 dimerization and downstream signaling while also eliciting antibody-dependent cellular cytotoxicity. In the pivotal HERA trial, adjuvant trastuzumab added to chemotherapy reduced the risk of recurrence by 46% and mortality by 33% in HER2-positive early breast cancer patients, with benefits persisting beyond 10 years of follow-up.^[89] Small-molecule inhibitors targeting intracellular oncogenes have also transformed treatment landscapes. Vemurafenib, approved for BRAF V600E-mutant melanoma (present in ~50% of cases), selectively inhibits the mutant BRAF kinase, leading to tumor regression. In the phase III BRIM-3 trial, vemurafenib extended median progression-free survival to 5.3 months versus 1.6 months with dacarbazine in unresectable or metastatic BRAF V600E melanoma. To counter rapid resistance via MAPK pathway reactivation, combination with MEK inhibitors like cobimetinib has become standard; the coBRIM trial demonstrated that vemurafenib plus cobimetinib improved progression-free survival to 9.9 months compared to 6.2 months with vemurafenib alone, delaying resistance through dual blockade of the RAF-MEK-ERK cascade.^[90]^[91] For RAS oncogenes, which are mutated in 20-30% of human cancers, targeted therapies have emerged more recently. KRAS G12C inhibitors, such as sotorasib (approved by the FDA in 2021 for NSCLC) and adagrasib (approved in 2022), covalently bind the mutant KRAS protein, locking it in an inactive state. In the CodeBreaK 100 trial, sotorasib achieved an objective response rate of 37.1% and median progression-free survival of 6.8 months in previously treated KRAS G12C-mutant NSCLC patients. As of 2025, combinations with immunotherapy or other agents are under investigation to overcome resistance and expand applicability to other RAS mutations.^[92]^[93] Despite these advances, acquired resistance remains a major challenge, often driven by secondary mutations or pathway bypass. For instance, the EGFR T790M mutation emerges in ~50-60% of non-small cell lung cancer patients progressing on first-generation EGFR TKIs like gefitinib, sterically hindering inhibitor binding while enhancing kinase activity. Third-generation TKIs such as osimertinib overcome T790M but face their own resistance mechanisms, underscoring the need for sequential or combinatorial strategies. Synthetic lethality approaches offer promising alternatives by exploiting vulnerabilities in oncogene-addicted cells; for example, PARP inhibitors like olaparib induce lethal DNA damage in cancers with BRCA1/2 alterations (which can co-occur with oncogenic drivers), achieving objective response rates of ~40-50% in platinum-sensitive ovarian cancers through selective toxicity to homologous recombination-deficient cells.^[94]^[95] Oncogene-driven tumors generally exhibit higher response rates to targeted therapies than non-oncogene-addicted cancers, highlighting the clinical value of molecular profiling. In ROS1 fusion-positive non-small cell lung cancer (~1-2% of cases), TKIs like crizotinib yield objective response rates of approximately 70%, with median progression-free survival exceeding 18 months, far surpassing historical chemotherapy benchmarks.^[96]

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