Genomic and Functional Approaches to Understanding Cancer Aneuploidy

TLDR

Aneuploidy, a near‑universal imbalance of whole chromosomes or arms, is a hallmark of human cancers and shows cancer‑specific patterns such as frequent loss of chromosome arm 3p in squamous tumors. The study aims to define genomic and phenotypic correlates of cancer aneuploidy and to provide an experimental approach for investigating chromosome arm aneuploidy. The authors used genome engineering to delete chromosome arm 3p in lung cells, observing reduced proliferation that was partially rescued by duplicating chromosome 3. Analysis of 10,522 TCGA cancer genomes revealed that aneuploidy correlates with TP53 mutations, higher somatic mutation rates, and proliferation‑gene expression, while inversely correlating with immune‑signaling gene expression due to reduced leukocyte infiltration.

Abstract

Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy.