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

Beth Osia; Thamer Alsulaiman; Tyler Jackson; Juraj Kramara; Suely Oliveira; Anna Malkova

doi:10.1093/nar/gkab685

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

Journal article

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

Beth Osia, Thamer Alsulaiman, Tyler Jackson, Juraj Kramara, Suely Oliveira and Anna Malkova

Nucleic acids research, Vol.49(15), pp.8714-8731

09/07/2021

DOI: 10.1093/nar/gkab685

PMCID: PMC8421209

PMID: 34379776

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Abstract

Microhomology-mediated break-induced replication (MMBIR) is a DNA repair pathway initiated by polymerase template switching at microhomology, which can produce templated insertions that initiate chromosomal rearrangements leading to neurological and metabolic diseases, and promote complex genomic rearrangements (CGRs) found in cancer. Yet, how often templated insertions accumulate from processes like MMBIR in genomes is poorly understood due to difficulty in directly identifying these events by whole genome sequencing (WGS). Here, by using our newly developed MMBSearch software, we directly detect such templated insertions (MMB-TIs) in human genomes and report substantial differences in frequency and complexity of MMB-TI events between normal and cancer cells. Through analysis of 71 cancer genomes from The Cancer Genome Atlas (TCGA), we observed that MMB-TIs readily accumulate de novo across several cancer types, with particularly high accumulation in some breast and lung cancers. By contrast, MMB-TIs appear only as germline variants in normal human fibroblast cells, and do not accumulate as de novo somatic mutations. Finally, we performed WGS on a lung adenocarcinoma patient case and confirmed MMB-TI-initiated chromosome fusions that disrupted potential tumor suppressors and induced chromothripsis-like CGRs. Based on our findings we propose that MMB-TIs represent a trigger for widespread genomic instability and tumor evolution.

Adenocarcinoma of Lung - genetics

DNA Repair

Fibroblasts

Genes, Tumor Suppressor

Genome, Human

Genomic Instability

Humans

Lung Neoplasms - genetics

Mutagenesis, Insertional

Neoplasms - genetics

Skin - cytology

Software

Details

Title: Subtitle: Cancer cells are highly susceptible to accumulation of templated insertions linked to MMBIR
Creators: Beth Osia - Department of Biology, University of Iowa, Iowa City, IA 52245, USA
Thamer Alsulaiman - Department of Computer Science, University of Iowa, Iowa City, IA 52245, USA
Tyler Jackson - Department of Biology, University of Iowa, Iowa City, IA 52245, USA
Juraj Kramara - Department of Biology, University of Iowa, Iowa City, IA 52245, USA
Suely Oliveira - Department of Computer Science, University of Iowa, Iowa City, IA 52245, USA
Anna Malkova - Department of Biology, University of Iowa, Iowa City, IA 52245, USA
Resource Type: Journal article
Publication Details: Nucleic acids research, Vol.49(15), pp.8714-8731
DOI: 10.1093/nar/gkab685
PMID: 34379776
PMCID: PMC8421209
NLM abbreviation: Nucleic Acids Res
ISSN: 0305-1048
eISSN: 1362-4962
Grant note: R35 GM127006 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 09/07/2021
Academic Unit: Stead Family Department of Pediatrics; Biology; Computer Science; Mathematics; Infectious Disease (Pediatrics)
Record Identifier: 9984217531802771

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