High-order chromatin architecture determines the landscape of chromosomal alterations in cancer

TL;DR

This study investigates how high-order chromatin structure influences the distribution of chromosomal alterations in cancer, revealing that 3D genome architecture and natural selection shape mutational landscapes.

Contribution

It introduces a maximum likelihood framework to link 3D genome organization with somatic copy-number alterations in cancer, highlighting the roles of spatial structure and selection.

Findings

Chromosomal alterations are spatially related to 3D genome architecture.

Purifying and positive selection influence the landscape of SCNAs.

The fractal-globule model explains the distribution of alterations.

Abstract

The rapid growth of cancer genome structural information provides an opportunity for a better understanding of the mutational mechanisms of genomic alterations in cancer and the forces of selection that act upon them. Here we test the evidence for two major forces, spatial chromosome structure and purifying (or negative) selection, that shape the landscape of somatic copy-number alterations (SCNAs) in cancer1. Using a maximum likelihood framework we compare SCNA maps and three-dimensional genome architecture as determined by genome-wide chromosome conformation capture (HiC) and described by the proposed fractal-globule (FG) model2. This analysis provides evidence that the distribution of chromosomal alterations in cancer is spatially related to three-dimensional genomic architecture and additionally suggests that purifying selection as well as positive selection shapes the landscape of SCNAs during somatic evolution of cancer cells.