Concept Vocabulary

Extracted from 7 seed papers spanning Nowell (1976) through Tarabichi et al. (2021). Concepts are organized by thematic cluster. Each entry is a planned [[wikilink]] target.

Foundational Concepts of Clonal Evolution

• clonal-evolution — The overarching theory: tumors evolve through mutation, diversification, and selection of subclones. (Nowell 1976, Greaves 2012, all papers)
• clonal-expansion — Proliferation of a cell lineage bearing a fitness-affecting mutation. (Nowell 1976, Greaves 2012)
• intratumor-heterogeneity — Genetic and phenotypic diversity within a single tumor; the substrate for clonal evolution. (McGranahan 2017, Turajlic 2019)
• subclonal-architecture — The composition and phylogenetic structure of distinct subclones within a tumor. (Nik-Zainal 2012, Gerstung 2020, Turajlic 2019)
• branching-evolution — Divergent clonal lineages arising from a common ancestor; the dominant pattern observed in solid tumors. (Greaves 2012, Turajlic 2019)
• linear-evolution — Sequential fixation of clones where only one lineage survives to sampling. (Turajlic 2019)
• neutral-evolution — Clonal diversity arising from mutation and genetic drift without differential selection. (Greaves 2012, Turajlic 2019)
• punctuated-evolution — Rapid bursts of genomic change (macroevolutionary leaps) rather than gradual accumulation. (Greaves 2012, Turajlic 2019)
• clonal-sweep — A subclone with a fitness advantage expands to dominate the population. Also called a selective sweep. (Nowell 1976, Greaves 2012, Turajlic 2019)
• clonal-interference — Competition between expanding clones that restrains each other’s growth. (Greaves 2012, Turajlic 2019)
• genetic-drift — Stochastic changes in clone frequency from random birth/death variation. (Turajlic 2019)
• hopeful-monster — A clone with a grossly altered genome (via CIN) that may be adaptive. (Turajlic 2019)

Selection and Fitness

• positive-selection — Evolutionary force increasing the frequency of a lineage in a population; drives tumor progression. (Gerstung 2020, Turajlic 2019)
• negative-selection — Removal of cells with decreased fitness from a population; also called purifying selection. (Turajlic 2019)
• driver-mutation — A mutation that confers a selective fitness advantage and drives clonal expansion. (Nowell 1976 implicitly, all subsequent papers)
• passenger-mutation — A neutral mutation with no effect on fitness; hitchhikes on clonal expansions. (Greaves 2012, Nik-Zainal 2012)
• dN-dS-ratio — Ratio of nonsynonymous to synonymous mutations normalized by expectation; used to detect selection. (Turajlic 2019)
• mutator-phenotype — Increased mutation rate in cancer cells that accelerates diversification. (Greaves 2012, Turajlic 2019)

Genomic Alterations

• genetic-instability — Acquired propensity of tumor cells for mitotic errors and genetic change; a defining property of cancer. (Nowell 1976, Greaves 2012)
• chromosomal-instability — Ongoing errors in chromosome segregation producing aneuploidy. (McGranahan 2017, Gerstung 2020, Turajlic 2019)
• aneuploidy — An unbalanced chromosome complement; can be clonal (homogeneous) or subclonal (heterogeneous with ongoing CIN). (Nowell 1976, Turajlic 2019)
• whole-genome-duplication — Doubling of the entire genome; a macroevolutionary event that precedes extensive subclonal diversification. (McGranahan 2017, Gerstung 2020, Turajlic 2019)
• copy-number-alteration — Somatic gain or loss of chromosomal segments; a major source of genetic variation in cancer. (Gerstung 2020, Turajlic 2019, Tarabichi 2021)
• chromothripsis — Catastrophic shattering of one or two chromosomes followed by error-prone repair. (Greaves 2012, Nik-Zainal 2012, Turajlic 2019)
• chromoplexy — Complex rearrangement involving multiple chromosomes. (Turajlic 2019)
• mitotic-crisis — A burst of copy number alterations driven by mitotic errors. (Gerstung 2020)

Mutational Processes and Signatures

• mutational-signature — A characteristic pattern of somatic mutations reflecting a specific DNA damage/repair process. (Nik-Zainal 2012, Gerstung 2020, McGranahan 2017)
• kataegis — Localized hypermutation; clusters of C>T/C>G mutations at TpC dinucleotides colocalizing with rearrangements. (Nik-Zainal 2012)
• APOBEC-mutagenesis — Mutational signature driven by APOBEC family cytidine deaminases; a late-acting mutational process. (McGranahan 2017, Nik-Zainal 2012)
• transcription-coupled-repair — Preferential DNA repair on the transcribed strand; reduces mutation rates in highly expressed genes. (Nik-Zainal 2012)
• molecular-clock — Use of passenger mutation counts as a measure of the time elapsed in a clone’s evolutionary history. (Greaves 2012, Gerstung 2020)

Subclonal Inference Methods

• subclonal-reconstruction — Computational inference of clonal composition from bulk DNA sequencing data. (Tarabichi 2021)
• variant-allele-fraction — The relative frequency of a variant in a tumor sample; a surrogate for clone abundance. (Tarabichi 2021, Turajlic 2019)
• cancer-cell-fraction — The fraction of cancer cells carrying a specific mutation; VAF corrected for purity and copy number. (McGranahan 2017, Tarabichi 2021)
• phylogenetic-tree — A branching diagram showing the hierarchy of clones within a tumor. (Tarabichi 2021, Turajlic 2019)
• multi-region-sequencing — Sequencing of spatially separated biopsies from the same tumor; enables phylogenetic reconstruction. (McGranahan 2017, Tarabichi 2021)
• single-cell-sequencing — Sequencing of individual cells; removes the time bias inherent to bulk sequencing. (Turajlic 2019)
• crossing-rule — In multi-sample data, if clone A has higher CCF than clone B in one region but lower in another, they are sibling clones. (Tarabichi 2021)

Clinical Implications

• therapy-resistance — Emergence of treatment-resistant clones under selective pressure of therapy. (Nowell 1976, Greaves 2012, Turajlic 2019)
• metastasis — Spread of cancer to distant sites; driven by clones with acquired invasive and migratory capacity. (Nowell 1976, Turajlic 2019)
• oligometastases — A small number of metastatic lesions confined to a single site; an intermediate state of metastatic capacity. (Turajlic 2019)
• immune-evasion — Escape of tumor cells from immune-mediated elimination; a selective advantage. (Nowell 1976, Turajlic 2019)
• neo-antigen — A peptide derived from a somatic mutation that can be recognized by the immune system. (Turajlic 2019)
• clonal-neoantigen — A neo-antigen derived from a truncal (clonal) mutation present in all tumor cells; superior immunotherapy target. (McGranahan 2017)
• cancer-stem-cell — A cell with extensive self-renewal capacity; the unit of selection in clonal evolution. (Greaves 2012)
• adaptive-therapy — Treatment strategy that controls tumor size rather than eradicating it, to avoid selecting for resistant clones. (Greaves 2012)
• cancer-early-detection — Identification of cancer at an early stage, before extensive subclonal diversification. (Gerstung 2020)

Entities

• TRACERx — TRAcking Cancer Evolution through therapy (Rx); prospective multi-region sequencing studies in NSCLC and renal cancer.
• PCAWG — Pan-Cancer Analysis of Whole Genomes Consortium; the 2,658-cancer dataset used by Gerstung et al. 2020.
• PyClone — Bayesian clustering tool for subclonal deconvolution from bulk sequencing.
• PhyloWGS — Tool for reconstructing subclonal composition and phylogenetic trees from whole-genome sequencing.
• APOBEC3 — APOBEC3A and APOBEC3B cytidine deaminases; source of a common mutational signature in cancer.