Early and multiple origins of metastatic lineages within primary tumors

Abstract

Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases.tumor phylogenetics | ancestral reconstruction | cancer | chronograms | oncogenes I t has long been understood that tumorigenesis is an evolutionary process (1) associated with the accumulation of somatic mutations (2). However, many aspects of that process that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages (3, 4). Somatic mutations have revealed tumor type-specific drivers by comparison of primary tumor and normal tissues (5, 6), and studies examining the evolutionary process of cancer across multiple sites have used a handful of subjects to identify ubiquitous, shared, and private mutations (1) and to reconstruct a number of tumor phylogenies using parsimony or unweighted pair group methods with arithmetic mean (1, 7) but have lacked the power to generalize about the tumorigenic or metastatic process across cancer types (1).Tumor phylogenetics, using a larger sample with explicit evolutionary models, can be applied using molecular evolutionary models to reconstruct ancestral states of somatic mutations and infer cancer chronograms, revealing novel information about the timing of gene mutations and their contributions to tumorigenesis and metastasis and addressing three fundamental aspects of cancer biology. First, the topology of divergence of primary and metastatic lineages can differentiate between a linear model of cancer progression, in which all metastatic tumors are descended from a single original primary cell such that all metastases are more closely related to each other than they are to any tissue in the primary tumor, and a branched model, in which metastases can originate from divergent lineages within primary tumors. Second, molecular evolutionary trees and chronograms can quantify how e...

The evolution of tumour phylogenetics: principles and practice

“…After some specific methods are used in hundreds of studies, we hope that the results will be sufficiently robust and interpretable to aid in patient prognosis and treatment planning. Similarly, clinicians interpreting phylogenetic analyses should insist that different methods be tried and that results are actionable only when different methods of analysis lead to the same qualitative understanding of a patient’s tumour 68,106 .…”

“…After percolating for a decade within a specialist community of evolutionary and computational biologists, this type of analysis has exploded to become a new field known as tumour phylogenetics, which aims to reconstruct tumour evolution from genomic variations. In almost all cases, the goal of such work is to produce evolutionary trees, potentially allowing for uncertainty among the space of possible trees explaining a data set 21,67,68 .…”

“…For example, the studies that concluded that there was little selection in some tumours looked mostly at SNVs and CNVs, but perhaps there is selection in those tumours via evolutionary mechanisms that would be apparent only when looking at other marker types, such as karyotypes or methylation patterns. Few studies have tested whether the phylogenetic inferences made are robust to a change of methods, with notable exceptions 68,106 .…”

Environmental Carcinogenesis and Transgenerational Transmission of Carcinogenic Risk: From Genetics to Epigenetics

“…A complex evolutionary molecular approach (rigorously Darwinian) has been developed to study, without too much success so far, the sequential progression of mutations [45]. Surprisingly, the mutations potentially associated with metastasis do not appear late, as was expected in the context of the SMT theory [46]. On the contrary, it seems increasingly clear that the appearance of the ‘driver mutations’ is not only typical of the initial phases, but also occurs in the subsequent phases of the neoplastic process [47].…”

Circulating Tumor Cells in the Parallel Invasion Model Supporting Early Metastasis

“…[5] Genetic lineages of metastases can arise early in primary tumors, sometimes long before diagnosis of the primary tumor. [6] Circulating tumor cells (CTCs) in blood were proposed more than 100 years ago as potential founders of metastatic lesions. [7] CTCs are detectable in most malignancies, particularly at advanced and metastatic stages.…”