Somatic evolution and global expansion of an ancient transmissible cancer lineage

Abstract

The canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by "metastasizing" between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage's worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer's evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.

Fig. 1. Phylogeny and geographical expansion of CTVT.

(A) Time-resolved phylogenetic tree inferred from clock-like exonic somatic variation in CTVT. Each tip is a tumour and sampling locations are labelled. Numbers refer to phylogenetic groups displayed on maps in B–D. Sublineages 1 and 2, referred to in C and D respectively, are marked. Three groups of ancestral somatic variation (A1, A2, A3) and their respective numbers of single nucleotide variants (SNVs) are indicated. The estimated age of the CTVT founder tumour and the earliest detected node are indicated in years before present (BP), with grey error bars depicting Bayesian 95% HPDI. (B to D) Maps presenting likely routes of early (prior to ~500 years BP) and late (from ~500 years BP) expansion of CTVT. Numbered circles indicate the geographical locations of phylogenetic groups labelled in A; arrows represent inferred geographical movements. Circle and arrow colours indicate different sets of geographical movements, as labelled in A. Thin arrows indicate expansion routes for which there is limited phylogenetic evidence; dots without numbers denote tumours that are not represented in the tree. C.V., Cape Verde; Gr., Greece; Guat., Guatemala; Hond., Honduras; Ken., Kenya; Rom., Romania; Tan., Tanzania; Tur., Turkey.

Fig. 2. Mutational processes in CTVT.

(A) Trinucleotide-context mutational spectrum of somatic SNVs in a single CTVT tumour. Horizontal axis presents 96 mutation types displayed in pyrimidine context. Relevant trinucleotide mutation contexts are indicated. (B) Trinucleotide-context mutational spectra of extracted mutational signatures 1, 5, 2*, A and 7, with relevant trinucleotide mutation contexts indicated. (C) Pentanucleotide-context mutational spectra of signature A (top) and signature 7 (bottom). Horizontal axis presents 256 C>T mutation types with relevant mutation contexts indicated. The inset tree shows the phylogenetic branches with exposure to signature A. (D) Bayesian logarithmic regression and Spearman’s correlation between absolute mean latitude and normalised CC>TT mutations in phylogenetic groups shown in Fig. 1A. Normalised CC>TT mutations represent the ratio between group-unique CC>TT mutations and group-unique C>T changes at CpG dinucleotides. The black line and shadowed area indicate the regression curve and associated 95% HPDI. The orange dot and bars represent predicted absolute mean latitude and associated 90% prediction interval for the basal trunk ancestral variation (group A1). Posterior median and 95% HPDI of the correlation coefficient are shown. (E) Map showing the latitude range corresponding to the 90% prediction interval for group A1, presented in D, in the northern hemisphere. (F) Trinucleotide-context mutational spectra of a phylogenetic tumour group showing evidence of signature 5 hyperactivity (top) and a closely related group without signature 5 hyperactivity (bottom). (G) Diagram indicating the phylogenetic situation of the tumour groups displaying signature 5 hyperactivity.

Fig. 3. Selection in CTVT.

(A) Somatic SNV prevalence across six human cancer types and CTVT. Dots represent individual tumours; red lines indicate median SNV prevalence. ALL, acute lymphoblastic leukaemia. (B) Bars showing the percentage of protein-coding genes in the CTVT genome harbouring ≥1 non-synonymous somatic mutation (SNV or indel; 14,412 genes) and ≥1 somatic protein-truncating somatic mutation (5,704 genes). (C) Diagram presenting the putative driver events found in the set of basal trunk ancestral variants (group A1, Fig. 1A). A description of each somatic alteration is shown next to the corresponding gene symbol. (D) Exome-wide dN/dS ratios estimated for somatic SNVs in all protein-coding genes (left) and in sets of genes defined according to gene essentiality, copy number state and expression level. Estimates of dN/dS are presented for missense (blue) and nonsense (orange) mutations in each gene group. The dashed line indicates dN/dS = 1 (neutrality); error bars indicate 95% confidence intervals.