A213: Chromosomal catastrophes and punctuated evolution in colorectal carcinogenesis

William Cross1,Ville Mustonen3,Michal Kovac2,Simon Leedham2,Trevor Graham1,Ian Tomlinson2

1Barts Cancer Institute, London, UK,2Wellcome Trust Centre for Human Genetics, Oxford, UK,3Wellcome Trust Sanger Institute, Cambridge, UK

Presenting date: Monday 2 November
Presenting time: 13.10-14.00



How colorectal cancers (CRCs) evolve over time remains undetermined. Recent studies have shown the progression of esophageal carcinogenesis through contrast of pre-malignant and malignant tissue(1). Here we have sought to resolve the clonal evolutionary dynamics underpinning the transition of pre-malignant colon to cancer along the adenoma-carcinoma pathway.



We performed multi-region whole genome or whole exome sequencing of 11 CRCs, 6 adenomas and 6 carcinoma in-situ (Haggitt) polyps. Using a phylogenetic approach, we evaluated the evolution of mutational signatures, temporally ordered copy-number alterations (CNAs), and quantified the spatial clonal structure of the tumour, to build a comprehensive picture of CRC progression.



In CRCs, most of the well-described driver single nucleotide mutations were truncal indicating that they were acquired and selected ancestrally, as described previously in lung cancer(2). By contrast adenomas showed sub-clonal driver mutations and proportionally greater intra-tumoural heterogeneity, revealing a primordial carcinogenic state. Timing of CNA events in CRCs revealed a historical “chromosomal catastrophe” whereby many CNAs were accrued concurrently. Phylogenetic analysis revealed that these chromosomal catastrophes are linked with trunk branching, implicating them as initiators of clonal expansions and therefore responsible for transition of adenoma to cancer.



Our data indicate that CRC growth is sometimes initiated by concurrent chromosomal alterations, an event that we term a “chromosomal catastrophe”. This implies a punctuated evolutionary process, whereby one pre-cancerous cell transitions to a distant peak within the fitness space and thereby produces the first dominant cancer clone. Multiple different catastrophic events were observed, implying a complex fitness landscape with many fitness peaks. Implicating chromosomal catastrophes as initiators of carcinogenesis has potential ramifications to oncogene addition and therefore targeted therapy. Further investigation will be required to determine how prevalent this phenomenon is in CRC and other solid malignancies.