Neotelomeres and telomere-spanning chromosomal arm fusions in cancer genomes revealed by long-read sequencing

Summary

Alterations in the structure and location of telomeres are pivotal in cancer genome evolution. Here, we applied both long-read and short-read genome sequencing to assess telomere repeat-containing structures in cancers and cancer cell lines. Using long-read genome sequences that span telomeric repeats, we defined four types of telomere repeat variations in cancer cells: neotelomeres where telomere addition heals chromosome breaks, chromosomal arm fusions spanning telomere repeats, fusions of neotelomeres, and peri-centromeric fusions with adjoined telomere and centromere repeats. These results provide a framework for the systematic study of telomeric repeats in cancer genomes, which could serve as a model for understanding the somatic evolution of other repetitive genomic elements.

Graphical abstract

Highlights

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  Long-read cancer DNA sequences define structure of neotelomeres and telomere fusions

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  Neotelomeres have similar telomere length as normal chromosomal arms

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  Short telomeric repeats are found at sites of chromosomal arm fusions

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  Frequency of neotelomere and arm fusion events varies across 40 cancer types

Abstract

Long-read genome sequencing describes the existence and structures of neotelomeres and telomere-spanning chromosome arm fusions in cancer samples. Short-read sequences of 3,651 cancer samples were used to infer the frequency of these telomeric alterations across 40 cancer types.