Journal
NUCLEIC ACIDS RESEARCH
Volume 49, Issue 15, Pages 8714-8731Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab685
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Funding
- NIH [R35GM127006, R01CA232425]
- University of Iowa Carver College of Medicine
- NIGMS [R35GM127006]
- NIH [NCI] [P30CA086862]
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There are substantial differences in frequency and complexity of MMB-TI events between normal and cancer cells, with MMB-TIs readily accumulating in several cancer types, particularly in breast and lung cancers. In normal human fibroblast cells, MMB-TIs only appear as germline variants and do not accumulate as de novo somatic mutations.
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.
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