Inferring modes of evolution from colorectal cancer with residual polyp of origin.

Minsoo Kim,Taejeong Bae,Nicholas Chia,Nikolaos Vasmatzis,Brooke R Druliner,Alexej Abyzov,Lisa A Boardman

doi:10.18632/oncotarget.23687

Minsoo Kim, Taejeong Bae + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.23687

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Journal: Oncotarget	Publication Date: Dec 26, 2017
Citations: 3	License type: cc-by

Affiliation: University of Minnesota, Mayo Clinic

Abstract

Besides the classical evolutionary model of colorectal cancer (CRC) defined by the stepwise accumulation of mutations in which normal epithelium transforms through an intermediary polyp stage to cancer, a few studies have proposed alternative modes of evolution (MOE): early eruptive subclonal expansion, branching of the subclones in parallel evolution, and neutral evolution. However, frequencies of MOEs and their connection to mutational characteristics of cancer remain elusive. In this study, we analyzed patterns of somatic single nucleotide variations (SNVs) and copy number aberrations (CNAs) in CRC with residual polyp of origin from 13 patients in order to determine this relationship. For each MOE we defined an expected pattern with characteristic features of allele frequency distributions for SNVs in cancers and their matching adenomas. From these distinct patterns, we then assigned an MOE to each CRC case and found that stepwise progression was the most common (70% of cases). We found that CRC with the same MOE may exhibit different mutational spectra, suggesting that different mutational mechanisms can result in the same MOE. Inversely, cancers with different MOEs can have the same mutational spectrum, suggesting that the same mutational mechanism can lead to different MOEs. The types of somatic substitutions, distribution of CNAs across genome, and mutated pathways did not correlate with MOEs. As this could be due to small sample size, these relations warrant further investigation. Our study paves the way to connect MOE with clinical and mutational characteristics not only in CRC but also to neoplastic transformation in other cancers.

Highlights

The foundation for the studies of genetic evolution in many cancer types was built upon the finding first presented in the seminal work by Fearon and Vogelstein that the accumulation of genetic alterations led to neoplastic transformation in the colon to colorectal cancer (CRC) [1]
We found that CRC with the same modes of evolution (MOE) may exhibit different mutational spectra, suggesting that different mutational mechanisms can result in the same MOE
We derived an expected pattern of Allele Frequency (AF) distributions in CRC and its corresponding polyp for each MOE based on its key characteristics (Figure 1B)

Summary

Introduction

The foundation for the studies of genetic evolution in many cancer types was built upon the finding first presented in the seminal work by Fearon and Vogelstein that the accumulation of genetic alterations led to neoplastic transformation in the colon to colorectal cancer (CRC) [1] This widely accepted and dominant paradigm that CRC arises in a linear model of accumulated genetic mutation and large-scale genomic disruptions of chromosomal instability continues to be the infrastructure upon which extensive research on carcinogenesis is based [2]. One recent study on the distribution of somatic mutations in CRC proposed an extension of the linear model into a quick eruptive accumulation of mutations in the polyp followed by subclonal competition and a plateau of extensive mutation accumulation in the resulting cancer [3] This phenomenon results from a lack of selection pressure in combination with high rate of mutation accumulation. One noteworthy aspect of this model, known as the ‘Big Bang,’ is that it describes how early mutations shape the high intratumoral heterogeneity (ITH) observed in the late stage of CRC and may be associated with a more aggressive clinical behavior and decreased rates of survival [4]

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