Abstract
BackgroundThe mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events.ResultsWe discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites. Notably, the highly mutated estrogen receptor binding sites are associated with more frequent chromatin loop contacts and the associated distal genes are expressed at higher level. To elucidate the functional significance of these non-coding mutations, we focus on two of the recurrently mutated estrogen receptor binding sites. Our bioinformatics and biochemical analysis suggest loss of DNA-protein interactions due to the recurrent mutations. Through CRISPR interference, we find that the recurrently mutated regulatory element at the LRRC3C-GSDMA locus impacts the expression of multiple distal genes. Using a CRISPR base editor, we show that the recurrent C→T conversion at the ZNF143 locus results in decreased TF binding, increased chromatin loop formation, and increased expression of multiple distal genes. This single point mutation mediates reduced response to estradiol-induced cell proliferation but increased resistance to tamoxifen-induced growth inhibition.ConclusionsOur data suggest that ER binding is associated with localized accumulation of somatic mutations, some of which affect chromatin architecture, distal gene expression, and cellular phenotypes in ER-positive breast cancer.
Highlights
Somatic mutations are the driving force for cancer cell evolution [1]
For cancers driven by external mutagens such as tobacco smoking in lung cancer and UV radiation in melanomas, differential chromatin accessibility and recruitment of nucleotide excision repair (NER) machineries have been proposed as major contributors for regional variation of mutation rate [15,16,17]
We leveraged genome-wide somatic mutations identified through whole-genome sequencing of 560 estrogen receptor (ER)+ HER2− normal-matched breast tumors (BRCA-EU) [4]
Summary
Somatic mutations are the driving force for cancer cell evolution [1]. Large-scale efforts, including The Cancer Genome Atlas (TCGA) [2] and International Cancer Genome Consortium (ICGC) [3], have mapped somatic mutations genome-wide in multiple cancer types. Yang et al Genome Biology (2018) 19:190 type-specific somatic mutation accumulation during the lifetime of cancer patients [12, 13]. Causes of mutations such as mutagen exposures, aberrant DNA editing, and replication errors are known to uniformly affect the genome [14]. We examined whole-genome somatic mutations in 560 breast cancers in order to understand the biological processes and the regulatory impacts of recurrent non-coding mutations in breast cancer. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events
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