Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer

Abstract

BackgroundPatients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging.Patients and methodsHere, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo ‘stopwatch’. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively ‘carbon date’ the malignant progression.ResultsThe primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity.ConclusionOur data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.

Rapid evolution and biogeographic spread in a colorectal cancer

“…Importantly, early metastases, such as the one described here, have already been proposed in mCRC 8,9,15 . Although Leung et al 20 recently inferred a late-dissemination model in mCRC, they failed to provide quantitative measurements, and their timing of metastatic dissemination was simply determined by visual inspection of mutational trees, making their results difficult to interpret and compare with.…”

“…Collectively, our analyses provide a detailed picture of the evolutionary history of this tumor. While we are not the first ones applying Bayesian phylogenetics for cancer dating 8,9,15 , previous attempts used sample trees and absence/presence mutational profiles instead of clonal phylogenies and clonal sequences, and therefore are subject to potential biases 16,17 . Besides, the evolutionary framework presented here has several advantages over previous approaches.…”

Inferring parsimonious migration histories for metastatic cancers

“…In other words, the migration history follows directly from the topology and branch lengths of a phylogenetic tree constructed from mutations. The mutation-migration concordance assumption underlies many recent analyses of metastatic cancers 9 , 23 – 25 , 27 – 29 , 34 – 36 , 38 , as well as a recent method, Treeomics 51 , for reconstructing clone trees given sequencing data of metastatic tumors 52 , 53 . However, there are two problems with the mutation-migration concordance assumption.…”

Metastasis and the evolution of dispersal

“…R. Soc. B 286: 20192186 cancer cell dissemination may start as early as 1 year after initiation [68][69][70][71], and up to 80% of metastases result from early dissemination [69]. Metastasis thus coexists with other strategies that can lead cancer cells to thrive in the primary tumour micro-environment.…”