Flagship Guide · 15 min read

Gene Function Explained: A Complete Guide to Cancer Biology

This guide explains how genes control the fundamental decisions of a cell — to divide, to die, to repair — and what happens when those controls fail. From the basics of cell cycle regulation to the molecular mechanisms of targeted therapy, this is the foundation of modern cancer biology.

TP53 BRCA1 EGFR KRAS BRAF PTEN RB1 CDKN2A MYC ATM

What Are Genes and What Do They Do?

Genes are discrete segments of DNA that encode functional molecules — predominantly proteins, but also regulatory RNAs. The human genome contains approximately 20,000 protein-coding genes, each regulated by an intricate system of promoters, enhancers, transcription factors, and epigenetic marks that determine when and where each gene is expressed. Cells in the liver, neurons, and skin cells each contain identical genomic DNA, but gene expression patterns differ dramatically between them — and it is this differential expression that creates cell identity.

In the context of cancer biology, the most important genes are those that control the core decisions of cell fate: should this cell divide? should it die? should it repair its DNA first? Disruption of these decision-making circuits — through mutation, amplification, deletion, or epigenetic silencing — is the molecular basis of cancer. Understanding which genes control which decisions, and how, is the foundation of targeted therapy.

The Cell Cycle: The Decision to Divide

Cell division is not a default state — it requires active signalling and multiple molecular checkpoints to proceed. The cell cycle consists of four phases: G1 (growth, preparation), S (DNA replication), G2 (further growth, quality control), and M (mitosis, cell division). Each phase transition is controlled by cyclin-dependent kinases (CDKs), whose activity is regulated by cyclins and CDK inhibitors.

The G1/S restriction point — enforced by the retinoblastoma protein (pRb, encoded by RB1) — is the most critical checkpoint. When cells receive mitogenic signals (e.g. through EGFR), they increase cyclin D expression, which activates CDK4 and CDK6. These kinases phosphorylate pRb, releasing the E2F transcription factors that activate S-phase entry genes. This pRb phosphorylation step is irreversible — once E2F is released, the cell is committed to division. Virtually every cancer disrupts this checkpoint by one mechanism or another.

Cyclin D-CDK4/6 activity is opposed by the CDK inhibitor p16INK4a, encoded by CDKN2A. p16 competitively inhibits CDK4 and CDK6, keeping pRb active and maintaining G1 arrest. The CDKN2A locus is the most frequently deleted locus in human cancer — not coincidentally, since deleting it simultaneously removes p16 (disabling the RB pathway) and p14ARF (disabling the p53 pathway through MDM2 de-repression).

Oncogenes: The Accelerators

Oncogenes are genes that, when mutated or overexpressed, actively drive tumour development. They are the accelerators of cell proliferation, and unlike tumour suppressors, they typically require only a single activating mutation in one allele to exert their effect — a dominant gain-of-function. The first human oncogene to be identified was KRAS, discovered in the 1980s through DNA transfection assays in NIH3T3 cells.

KRAS encodes a small GTPase that relays signals from receptor tyrosine kinases like EGFR to downstream effectors including RAF, MEK, ERK, PI3K, and AKT. In normal cells, KRAS activity is tightly controlled by its intrinsic GTPase activity, which hydrolyses GTP to GDP, terminating the signal within seconds. Oncogenic KRAS mutations at codons 12 and 13 impair this GTPase activity, locking KRAS in the active GTP-bound state and providing constitutive mitogenic signalling regardless of upstream receptor input.

The transcription factor MYC represents a different class of oncogene — one that amplifies rather than initiates signalling. MYC does not have its own enzymatic activity; instead, it is a transcription factor that drives expression of thousands of target genes involved in ribosome biogenesis, metabolism, and cell cycle progression. When overexpressed or amplified, MYC creates a state of forced proliferation that also paradoxically sensitises cells to apoptosis — a phenomenon called oncogene-induced apoptosis that requires co-mutations in anti-apoptotic genes like BCL2 for survival.

Tumor Suppressor Genes: The Brakes

Tumour suppressor genes encode proteins that restrain cell proliferation, promote DNA repair, or induce apoptosis when cellular stress exceeds safe thresholds. Unlike oncogenes, tumour suppressors typically require biallelic inactivation — both copies must be lost — for their protective function to be eliminated. This principle, the two-hit hypothesis, was proposed by Alfred Knudson in 1971 to explain why children with hereditary retinoblastoma develop tumours at a younger age and in both eyes, while sporadic retinoblastoma is typically unilateral and later-onset.

TP53 is the quintessential tumour suppressor — mutated in over 50% of all human cancers and the most frequently altered gene across cancer types. The p53 protein acts as a transcription factor that integrates signals from DNA damage (through ATM and ATR kinases), oncogene activation (through ARF, encoded by the CDKN2A locus), and metabolic stress to decide the cell's fate. p53 activation leads to transcriptional upregulation of p21 (CDKN1A) for G1 arrest, GADD45 for G2/M arrest, and BAX and PUMA for apoptosis. This flexibility — arrest or death depending on damage severity — makes p53 a highly context-sensitive safeguard.

BRCA1 and BRCA2 represent a specialised class of tumour suppressors: DNA repair genes. BRCA1 coordinates homologous recombination (HR), the highest-fidelity repair pathway for DNA double-strand breaks. HR uses the intact sister chromatid as a template for accurate repair, preserving the original sequence. When BRCA1 is lost, cells are forced to use error-prone repair mechanisms that introduce deletions and translocations, progressively destabilising the genome. This HR deficiency creates the synthetic lethality that PARP inhibitors exploit — blocking the only remaining repair pathway available to BRCA1-deficient cells.

Key Signalling Pathways in Cancer

Three signalling axes are disrupted in the vast majority of cancers, and understanding their normal functions reveals why their dysregulation is so consequential.

The RAS/MAPK pathway is a linear cascade from receptor tyrosine kinase → RAS → RAF → MEK → ERK that controls cell proliferation and differentiation. Mutations at virtually every level are found in cancer: EGFR mutations and amplifications activate the pathway at the receptor level; KRAS and NRAS mutations lock RAS in the active state; BRAF V600E constitutively activates the kinase cascade without RAS input; MEK mutations are rarer but occur in melanoma and haematological malignancies.

The PI3K/AKT/mTOR pathway is activated in parallel with RAS/MAPK downstream of receptor tyrosine kinases, primarily controlling cell survival, metabolic activity, and protein synthesis. PIK3CA hotspot mutations constitutively generate PIP3; PTEN loss removes the PIP3 phosphatase; AKT1 E17K promotes constitutive membrane association. At the pathway node, MTOR integrates nutrient and growth-factor signals to control ribosome biogenesis and anabolic metabolism through mTORC1.

The p53 pathway connects diverse stress signals to cell fate decisions. p53 is regulated primarily by MDM2, which ubiquitinates p53 for proteasomal degradation in unstressed cells. DNA damage → ATM → p53 Ser15 phosphorylation disrupts MDM2 binding and stabilises p53. Oncogene activation → ARF → MDM2 sequestration similarly stabilises p53. MDM2 amplification in liposarcomas functionally inactivates p53 without TP53 mutation — an alternative mechanism that maintains wild-type p53 as a therapeutic target for MDM2 inhibitors.

From Mutation to Targeted Therapy

The central insight of precision oncology is that specific molecular alterations create specific therapeutic vulnerabilities. BRAF V600E in melanoma predicts response to vemurafenib. EGFR activating mutations predict osimertinib sensitivity. KRAS G12C creates a unique covalent drug target for sotorasib. BCR-ABL fusion drives CML and is precisely targeted by imatinib — the drug that transformed CML from a lethal diagnosis to a manageable chronic condition.

The matching of driver mutations to targeted agents is now codified in comprehensive genomic profiling, where tumour DNA is sequenced across hundreds of cancer-relevant genes, identifying actionable alterations and excluding ineffective therapies. This approach has displaced histology-first empirical chemotherapy as the primary treatment selection paradigm in oncology.

Resistance remains the central challenge. Initial responses to targeted therapy are often dramatic, but resistance mechanisms — secondary mutations, alternative pathway activation, lineage switching — emerge in most patients within months to years. Understanding the mechanisms of resistance, and designing combination strategies to preempt them, is the dominant focus of current translational cancer research.

Common Questions About Gene Function

What is the difference between a mutation and a variant?

A mutation is any change in DNA sequence. A variant is a broader term encompassing all sequence changes including benign polymorphisms. In clinical genetics, the term 'pathogenic variant' is preferred over 'mutation' to describe disease-causing alterations, reserving precision in a field where false positives can have profound consequences.

Can a cell have too many tumor suppressors?

Experimentally, overexpression of some tumour suppressors (notably p53) can cause premature senescence, but this is not a clinically significant problem. Tumour suppressor activity is tightly regulated by post-translational mechanisms (MDM2-p53, CDK-pRb) that prevent inappropriate activation in normal cells.

Why do different cancers have different driver mutations?

Different tissues have distinct cell types, proliferation rates, mutagenic exposures, and developmental origins. UV exposure predominantly causes C→T transitions at dipyrimidines in melanoma; tobacco carcinogens cause G→T transversions in lung cancer. The tissue microenvironment also determines which oncogenes provide growth advantage — KRAS is essential in pancreatic epithelium but less potent in lymphocytes.

What is synthetic lethality?

Synthetic lethality describes a relationship between two genes where loss of either alone is compatible with cell survival, but simultaneous loss of both is lethal. BRCA1 loss + PARP inhibition is the most clinically validated example: either alone allows survival, but together they create irreparable DNA damage. Synthetic lethality is a powerful drug target strategy in cancer.

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