The evolutionary landscape of colorectal tumorigenesis

Abstract

The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations-considered to be functionally important in the carcinogenic process-that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a 'punctuated' fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.

Proteome analysis of formalin‐fixed paraffin‐embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas

“…The CADs in our adenoma cohort derive from FAP1 patients and follow the CAD-carcinoma sequence, where loss of the tumor suppressor gene APC appears as the first most frequent genetic event at the origin of the adenoma [1,8,38]. Accordingly, we found that CADs were aberrantly activated for the Wnt/β-catenin signaling, this being supported by the numerous upregulated β-catenin targets in these adenomas (DEFA6, REG3A, REG1A, EPHB2, EPHB3, see supplementary material, Table S3) and also by the overexpression of the intestinal stem cell marker OLFM4 (supplementary material, Table S3).…”

Measuring single cell divisions in human cancers from multi-region sequencing data

“…We now proceed to in vivo per--cell mutation rates within individual human tumours. A unique sample set 21 (1) above. Simulations show that inferences are possible with as few as 6 tumour samples (SI Figure 33).…”

“…Details of the bioinformatics--analysis of the multi--region sequenced tumour samples can be found for the colon carcinomas and the adenoma in 21 , the additional three single cell whole genome sequenced colon cancers 27 the renal cell carcinomas in 29 and the lung squamous and adenocarcinoma in 28 . Details on the methodology and sequencing of single stem cells in healthy haematopoiesis can be found in 20 .…”

“…These mutational distance distributions fall into different classes based on the per--cell mutation rate and per--cell survival rate as illustrated in SI Figure21. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 0 1 2 3 4 5 6 7 Chromosome Survival probability β µ = 0.99 ⇥ 10 8 bp/division 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 0 1 2 3 4 5 6 7 Chromosome 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Panels (a) and (b) show the cohort of Cross et al 21 and panels (c) and (d) the original patients by Roerink et al 27 A Mann--Whitney--U--test was used to test between patient differences, symbols correspond to the short notation: * = < 0.01 , * * = < 0.001 and * * * = < 0.0001. (bottom).…”

“…Chromosomes with sub--clonal copy number alterations were discarded from the analysis. Original data taken from21 . Patient 04 mutational distance distribution and MCMC parameter inference per chromosome.…”