What is cancer genesis?

Cancer Genesis: A Multistep Molecular Process

Cancer genesis (carcinogenesis) is a multistep evolutionary process in which normal cells progressively transform into malignant tumors through the sequential acquisition of genetic mutations in critical genes that control cell growth, death, and genomic stability.

Fundamental Mechanisms of Transformation

The Multistep Mutation Model

• Cancer develops through accumulation of multiple genetic "hits" rather than a single mutation 1, 2
• Typically 5-10 critical mutations (termed "gatekeeper" mutations) are required to transform a normal cell into a clinically detectable malignant cancer 1
• These mutations must occur in specific gene categories: oncogenes (which promote growth), tumor suppressor genes (which normally inhibit growth), and DNA repair genes 1, 2, 3

Three Distinct Stages of Carcinogenesis

The process unfolds through sequential stages 3:

1. Initiation: Irreversible genetic alterations (mutations, transversions, transitions, or small DNA deletions) occur in critical genes 3
2. Promotion: Reversible changes in gene expression occur without structural DNA changes, mediated through promoter-receptor interactions 3
3. Progression: Irreversible stage characterized by chromosomal instability, karyotypic changes, and malignant growth with alterations in both alleles of tumor suppressor genes 3

Critical Molecular Targets

Gatekeeper vs. Caretaker Mutations

Gatekeeper mutations directly affect biochemical pathways controlling cell cycle progression and are directly responsible for malignant transformation 1:

• Each gatekeeper alteration affects a specific "gate" in signaling networks
• Examples include mutations in TP53, RB (retinoblastoma), EGFR, K-ras, and MYC 1

Caretaker mutations accelerate cancer development by reducing DNA replication fidelity 1:

• These mutations increase the baseline probability of acquiring additional gatekeeper mutations
• They cause chromosomal instability, fragmentation, and copy number alterations
• Caretaker mutations act as a "time-scale compression" mechanism in cancer evolution 1

The G1-S Cell Cycle Checkpoint

• The G0-G1-S cell cycle phase transition is a critical decision point where cells commit irreversibly to DNA replication 1
• Driver/gatekeeper mutations are particularly abundant in signaling networks controlling this checkpoint 1
• Phosphorylation of RB family proteins by cyclin-dependent kinases (CyclinD:Cdk4, CyclinE:Cdk2) releases transcription factors (E2F1-3) that activate S-phase entry 1

Sources of Genetic Damage

Endogenous and Exogenous Causes

DNA damage leading to carcinogenic mutations arises from 2:

• Endogenous sources: DNA replication errors, chemical instability of DNA bases, free radical attack during metabolism
• Exogenous sources: Ionizing radiation, UV radiation, chemical carcinogens (e.g., tobacco smoke components)

Viral Integration Mechanisms

In virus-associated cancers like hepatitis B virus (HBV)-induced hepatocellular carcinoma 1:

• HBV DNA integration occurs within days of infection, creating pro-oncogenic genetic lesions early 1
• Viral integrations cause chromosomal structural rearrangements and copy number alterations (CNAs) 1
• Common CNA patterns include: large deletions of chromosome 17p (including TP53), gains at chromosome 8q (including MYC), and focal gains of TERT at 5p 1
• The number of viral integrations correlates directly with viral load 1

Clonal Evolution and Expansion

The Darwinian Selection Process

• Cancer evolution follows Darwinian principles where cells with selective growth advantages undergo clonal expansion 1, 2
• A single pro-oncogenic change is insufficient for cancer; accumulation of multiple changes through clonal expansion is necessary 1
• Each clonally expanded population increases the probability that additional mutations will occur in descendant cells 1

Role of Chronic Inflammation

Chronic inflammation accelerates carcinogenesis through two mechanisms 1:

1. Promoting pro-oncogenic cell growth via cell cycle activation
2. Allowing cells to escape immune-mediated clearance

• Inflammation increases hepatocyte turnover, accelerating clonal expansion of cells with heritable selective advantages 1
• This creates an environment conducive to accumulation of precancerous cell populations 1

Hereditary Cancer Syndromes

Germline Predisposition

Between 5-15% of cancers develop from underlying genetic predisposition caused by inherited germline mutations 1:

• Most hereditary syndromes follow autosomal dominant inheritance (50% transmission risk to offspring) 1
• Germline mutations cause cancer at much earlier ages than sporadic cases 1

Major Hereditary Syndromes

Familial Adenomatous Polyposis (FAP) 4:

• Lifetime colorectal cancer risk approaches 90% without colectomy
• Associated with duodenal, thyroid, brain tumors, and desmoid tumors

Lynch Syndrome (HNPCC) 1, 4:

• Caused by DNA mismatch-repair gene defects that accelerate malignant transformation of adenomas 1
• Lifetime colorectal cancer risk approximately 80%, plus elevated risks for endometrial, ovarian, gastric, and other cancers 4

Li-Fraumeni Syndrome 1:

• Germline p53 mutations (70-75% of cases) predispose to breast cancer, osteosarcoma, soft-tissue sarcoma, brain tumors, adrenocortical carcinoma, and leukemia 1
• Affected individuals develop metachronous tumors at high frequencies throughout life 1

Additional Molecular Mechanisms

Epigenetic Alterations

Beyond DNA sequence mutations, somatically inheritable epigenetic changes contribute to carcinogenesis 1:

• CpG methylation in promoter regions of driver/gatekeeper genes
• Chromatin alterations affecting transcription of large gene sets
• MicroRNAs and noncoding RNAs affecting specific gene expression levels

Copy Number Alterations

Chromosomal instability results in copy number changes that affect cancer gene dosage 1:

• Decreases in tumor suppressor gene copy numbers
• Increases in dominant oncogene copy numbers
• Formation of chimeric oncogenes through chromosomal rearrangements

Clinical Implications

The "Passenger vs. Driver" Distinction

• Genomes contain thousands of somatic "passenger" mutations, but only a few "driver" mutations actually transform cells 1
• Identifying true driver mutations is essential for targeted therapy development 1

Timing and Prevention

• Pro-oncogenic genetic lesions can occur very early in disease course (e.g., within days of HBV infection) 1
• This underscores the importance of early intervention to prevent mutation accumulation 1
• Antiviral treatment reduces transcriptionally active viral integrations and subsequent translocations 1