Clonal Evolution

Index

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Research Wiki Index

Topic map — quick navigation. For comprehensive search, read the full index below.

Conceptual spine

How the core concepts connect — from mutational source through measurement to clinical outcome:

flowchart LR
    subgraph Source["Mutational Source"]
        MP["[[mutator-phenotype]]<br>Elevated mutation rate<br>(Loeb 1991)"]
    end

    subgraph Variation["Variation Generated"]
        PM["[[passenger-mutation]]<br>Neutral hitchhikers<br>(Bozic 2016)"]
        DM["[[driver-mutation]]<br>Fitness advantage<br>~0.4% (Greaves 2012)"]
    end

    subgraph Dynamics["Evolutionary Dynamics"]
        CI["[[clonal-interference]]<br>Competing clones<br>prevent sweeps"]
        CS["[[clonal-sweep]]<br>Selective fixation<br>(Nowell 1976)"]
    end

    subgraph Genomic["Genomic Alterations"]
        CNA["[[copy-number-alteration]]<br>Gains, losses, cnLOH<br>(Turajlic 2019)"]
        AN["[[aneuploidy]]<br>Abnormal chromosome<br>number"]
    end

    subgraph Measurement["Measurement Pipeline"]
        VAF["[[variant-allele-fraction]]<br>Observed read proportion"]
        CCF["[[cancer-cell-fraction]]<br>VAF corrected for purity<br>and copy number"]
    end

    subgraph Inference["Phylogenetic Inference"]
        PT["[[phylogenetic-tree]]<br>Ancestral relationships<br>among subclones"]
        CR["[[crossing-rule]]<br>CCF crossing → siblings<br>not ancestor-descendant"]
    end

    subgraph Immune["Immune Interface"]
        NA["[[neo-antigen]]<br>Tumor-specific<br>peptide antigens"]
        IE["[[immune-evasion]]<br>HLA LOH, neoantigen<br>depletion, escape"]
    end

    MP -->|"generates"| PM
    MP -->|"accelerates"| DM
    PM -->|"hitchhike on"| DM
    DM -->|"when τ_k > sweep_time"| CS
    DM -->|"when τ_k ≤ sweep_time"| CI
    CI -->|"produces"| CNA
    CS -->|"can generate"| CNA
    CNA -->|"defines"| AN
    CNA -->|"confounds"| VAF
    VAF -->|"corrected via"| CCF
    CCF -->|"constrains"| PT
    CR -->|"resolves topology of"| PT
    CI -->|"shapes"| PT
    CNA -->|"generates<br>frameshift peptides"| NA
    NA -->|"marks clones for"| IE
    IE -->|"edits"| CI

    MP -.->|"CIN as<br>chromosomal mutator"| CNA
    CCF -.->|"N_T, m depend on"| CNA
    AN -.->|"fitness paradox<br>just-right CIN"| CI

Conceptual spine of the wiki’s core concepts. Solid arrows: direct mechanistic relationships. Dashed arrows: important cross-connections. Synthesized from the 47 concept pages as of 2026-07-11. The spine traces the flow from mutational source (mutator-phenotype) through variation (passenger/driver), evolutionary dynamics (sweeps vs. interference), genomic alterations (CNA, aneuploidy), measurement (VAF → CCF), phylogenetic inference (tree + crossing rule), and immune interface (neoantigens → evasion).

Sources (72)

Concepts (53)

Foundational

  • clonal-evolution — The overarching Darwinian theory of tumor development.
  • population-bottleneck — Consequences of population bottlenecks for adaptive strategy; the bottleneck paradox; cross-domain synthesis (cancer + ecology).
  • compression-progress-evolution — The compression-evolution isomorphism: natural selection as compression, fitness as compressibility, cancer as decompression.
  • compression-progress-olog — Category-theoretic ontology log for the compression progress domain: 24 objects, 16 arrows, 8 commutativity conditions.
  • cancer-evolution-olog — Formal ontology log for cancer evolution: 37 objects, 51 arrows, 12 commutativity conditions, 14 proarrows. Foundation for all cross-domain functorial mappings. Updated 2026-07-16 with APOBEC mutagenesis, kataegis, convergent phenotype, and spatial mutation distribution from Gerlinger 2012 + Burns et al. 2013 papers.
  • ecology-invasion-olog — Formal ontology log for ecological invasion (Geng et al. 2016): 18 objects, 19 arrows, 5 commutativity conditions.
  • cross-domain-functors — Functor construction and commutativity verification across all three domain ologs. F: Ecology→Cancer (profunctor), G: Compression→Cancer (functor on subcategory), H: Ecology→Compression (composite). Four testable predictions.
  • dual-regime-evolution — The genetic/epigenetic dual-regime model: Darwinian at the sequence level, non-Darwinian at the chromatin level.
  • branching-process-model — Mathematical scaffolding unifying the Bozic-Nowak trilogy; δ = d/b, μ reconciliation, survival probability.
  • productive-error — The principle that replication errors fuel evolutionary innovation; cancer as productive error escaping suppression.
  • hopeful-monster — Large-effect mutation producing a radically altered clone; Goldschmidt’s concept revived for cancer.
  • clonal-expansion — Proliferation of a cell lineage bearing a fitness-affecting mutation.
  • intratumor-heterogeneity — Genetic and phenotypic diversity within a single tumor; both product of past evolution and substrate for future adaptation. Components: SNV, CNA, SV, epigenetic, transcriptional, phenotypic, microenvironmental. Measurement: VAF → CCF → SMF pipeline. Compression-entrenchment hypothesis predicts U-shaped ITH-outcome relationship.
  • subclonal-architecture — Composition and phylogenetic structure of tumor subclones.
  • branching-evolution — Divergent clonal lineages from a common ancestor.
  • neutral-evolution — Clonal diversity from mutation and drift without selection.
  • punctuated-evolution — Rapid bursts of genomic change rather than gradual accumulation.
  • clonal-sweep — A fitter subclone expanding to dominate the population.
  • intermediate-clones — Transient low-frequency subclones bridging pre- and post-sweep states; why they’re invisible and why they matter.
  • clonal-interference — Competition between expanding clones with different drivers preventing any single sweep; dominant dynamic in established tumors.
  • linear-evolution — Sequential clonal succession with complete replacement; Nowell’s original model. Dominant in early tumors (small N); transitions to branching as N grows.

Selection and Fitness

  • positive-selection — The evolutionary process by which advantageous mutations (drivers) increase in frequency; s ≈ 0.4% per driver.
  • negative-selection — Purifying selection against deleterious variants; immune-mediated elimination of neoantigen-bearing clones.
  • genetic-drift — Random frequency fluctuations from stochastic sampling in finite populations; mechanism underlying neutral evolution. P(survival) ≈ 2s.
  • driver-mutation — A mutation conferring selective fitness advantage.
  • passenger-mutation — A neutral mutation with no fitness effect; hitchhikes on expansions.
  • neo-antigen — Tumor-specific peptide antigens from somatic mutations; link between genetic ITH and immune-mediated selection. CIN-driven neoantigen generation vs. CNA-mediated neoantigen depletion.

Growth Kinetics

  • gompertzian-growth — Decelerating tumor growth model; constrains clone detectability and neutrality inference.

Genomic Alterations

  • genetic-instability — Acquired propensity for elevated mutation and mitotic error.
  • chromosomal-instability — Ongoing chromosome segregation errors producing aneuploidy; dual adaptive/deleterious role.
  • copy-number-alteration — Somatic gains and losses of chromosomal segments; logR/BAF measurement, subclonal CNA detection, CNA/SNV interdependence via CCF correction, just-right CIN burden.
  • aneuploidy — Abnormal chromosome number; clonal vs. subclonal aneuploidy, fitness paradox, metastasis association.
  • chromothripsis — Catastrophic shattering of chromosomes in a single event; early clonal, 22.3% pan-cancer.
  • whole-genome-duplication — Tetraploidization event enabling subsequent diversification.
  • metastasis — Spread of cancer to distant sites; an evolutionary process.

Mutational Processes

  • mutational-signature — Characteristic mutation pattern reflecting a specific DNA damage/repair process.
  • APOBEC-mutagenesis — C>T and C>G at TpC dinucleotides from AID/APOBEC cytidine deaminase activity.
  • kataegis — Localized hypermutation colocalizing with rearrangement breakpoints.
  • mutator-phenotype — Heritably elevated mutation rate accelerating driver generation; genetic (MMR, POLE), enzymatic (APOBEC3B), and chromosomal (CIN) mechanisms. Loeb’s 1991 hypothesis.
  • molecular-clock — Passenger mutation accumulation as a temporal record of tumor evolutionary history; enables relative timing of branching, drivers, CNAs, and mutational process shifts.

Imprinting and Epigenetics

  • genomic-imprinting — Parent-of-origin-specific gene silencing; functional haploidy at imprinted loci and its consequences for clonal evolution.
  • loss-of-imprinting — LOI as an epigenetic driver mechanism; biallelic activation of growth promoters without sequence change.

Methods

  • subclonal-reconstruction — Computational inference of clonal composition from sequencing data.
  • variant-allele-fraction — Proportion of reads carrying a variant; surrogate for clone abundance.
  • cancer-cell-fraction — Proportion of cancer cells carrying a mutation after purity and CNA correction; fundamental metric for clone abundance.
  • phylogenetic-tree — Ancestral relationships among tumor subclones inferred from mutation profiles; trunk/branch/private mutation classification.
  • crossing-rule — Phylogenetic constraint: if clone A has higher CCF than B in one region but lower in another, they are siblings, not ancestor-descendant.
  • ffpe-pre-analytical-variables — The five-stage pre-analytical pipeline from tissue excision to sequencing; three-confounder problem (true subclonal + CNA miscalibration + FFPE artifact); oxidative damage > deamination; DNA > RNA >> protein analyte hierarchy.
  • sequencing-library-artifacts — Index swapping, cross-contamination, and chimeric molecules from library amplification; 7–58% contamination under unoptimized conditions; corner library detection method; PCR conditions not indexing strategy dominate contamination risk.

Clinical

  • therapy-resistance — Emergence of resistant clones under therapeutic selective pressure.
  • immune-evasion — Somatic evolution of immune escape through HLA LOH, neoantigen depletion, and immunosuppressive signaling; CIN’s dual role in visibility and escape.

Entities (27)

  • TRACERx — Prospective multi-region sequencing study tracking cancer evolution through therapy.
  • PCAWG — Pan-Cancer Analysis of Whole Genomes; 2,658 cancers across 38 types.
  • apobec3b — APOBEC3B cytidine deaminase; nuclear, 5’RTCA preference.
  • apobec3a — APOBEC3A cytidine deaminase; main somatic mutator per Petljak 2022.
  • tp53 — p53 tumor suppressor; most frequently mutated gene in cancer.
  • egfr — Epidermal growth factor receptor; NSCLC driver.
  • kras — KRAS GTPase; pancreatic, colorectal, lung adenocarcinoma driver.
  • cdk4 — Cyclin-dependent kinase 4; CDK4/6 inhibitor target.
  • igf2 — Insulin-like growth factor 2; imprinted gene, LOI in cancer.
  • rb1 — Retinoblastoma protein; tumor suppressor, CDK4/6 inhibitor resistance.
  • cxcr4 — Chemokine receptor; WHIM syndrome hopeful monster.
  • esr1 — Estrogen receptor alpha; endocrine therapy resistance.
  • ar — Androgen receptor; prostate cancer driver.
  • aid — AID/AICDA cytidine deaminase; somatic hypermutation.
  • bladder-cancer — Bladder/urothelial carcinoma; extreme C/G mutation bias from APOBEC3B mutagenesis.
  • cervical-cancer — Cervical carcinoma; APOBEC3B signature, HPV-driven.
  • head-and-neck-cancer — HNSCC; kataegis-characterized, strong APOBEC3B upregulation.
  • ctdna — Circulating tumor DNA; non-invasive tumor monitoring.
  • cfdna — Cell-free DNA; hematopoietic and tumor-derived.
  • breast-cancer — Breast cancer; APOBEC mutagenesis, CDK4/6 inhibitor resistance.
  • prostate-cancer — Prostate cancer; AR-dependent, transcriptional plasticity.
  • lung-cancer — NSCLC and SCLC; TRACERx, EGFR-driven.
  • colorectal-cancer — CRC; adenoma-carcinoma sequence, therapy-driven evolution.
  • hodgkin-lymphoma — Hodgkin lymphoma; ctDNA genotyping, clonal evolution during therapy.
  • cisplatin — Platinum-based DNA crosslinking chemotherapy.
  • imatinib — BCR-ABL TKI; CML targeted therapy paradigm.
  • lenalidomide — IMiD immunomodulatory drug; multiple myeloma.

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