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Cancer cells are highly susceptible to accumulation of templated insertions linked to MMBIR

Beth Osia1, Thamer Alsulaiman2, Tyler Jackson1

  • 1Department of Biology, University of Iowa, Iowa City, IA 52245, USA.

Nucleic Acids Research
|August 11, 2021
PubMed

Insights

Microhomology-mediated break-induced replication (MMBIR) templated insertions (MMB-TIs) accumulate in cancer genomes but not normal cells. This DNA repair process drives genomic instability and tumor evolution.

Area of Science:

  • Genomics
  • DNA repair mechanisms
  • Cancer biology

Background:

  • Microhomology-mediated break-induced replication (MMBIR) is a DNA repair pathway.
  • MMBIR can cause templated insertions, leading to chromosomal rearrangements and cancer.
  • Identifying MMBIR-associated templated insertions (MMB-TIs) in genomes is challenging with standard whole genome sequencing (WGS).

Purpose of the Study:

  • To develop a method for directly detecting MMB-TIs in human genomes.
  • To investigate the frequency and complexity of MMB-TIs in normal versus cancer cells.
  • To understand the role of MMB-TIs in cancer development and genomic instability.

Main Methods:

  • Development and application of the MMBSearch software for MMB-TI detection.
  • Analysis of 71 cancer genomes from The Cancer Genome Atlas (TCGA).
  • Whole genome sequencing (WGS) of normal human fibroblast cells and a lung adenocarcinoma patient.

Main Results:

  • MMBSearch successfully detected MMB-TIs in human genomes.
  • MMB-TIs accumulate de novo in various cancer types, notably breast and lung cancers.
  • MMB-TIs were found as germline variants in normal cells but not as de novo somatic mutations.
  • MMB-TI-initiated chromosome fusions were confirmed in a lung cancer case, disrupting tumor suppressors and causing chromothripsis-like rearrangements.

Conclusions:

  • MMB-TIs accumulate significantly in cancer genomes, unlike in normal cells.
  • MMBIR-templated insertions are a source of genomic instability and a driver of tumor evolution.
  • MMB-TIs may act as a trigger for complex genomic rearrangements in cancer.

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