Researchers at the Wellcome Sanger Institute have found that the enzyme APOBEC1 may cause the mutations SBS2 and SBS13 – 2 mutational signatures of human cancers. The paper, recently published in Nature, is the first ever comprehensive study of somatic mutations in the human small intestine.
APOBEC1 is an enzyme that performs a critical role in normal cell function, allowing for nutrient absorption to occur in the small intestine. It belongs to the APOBEC family of enzymes, which can edit DNA or RNA. The physiological function of APOBEC1 in editing APOB mRNA is well established – but the researchers wanted to explore whether APOBEC1 could have other functions that are mediated by DNA or RNA editing. They also wondered whether there could be “collateral damage” as a result of the high levels of APOBEC1 present that result in mutations, including SBS2 and SBS13. Previous studies have focussed on APOBEC3A and APOBEC3B as the primary generators of mutational signatures associated with cancer, but Mike Stratton and his team are the first to investigate APOBEC1.
Comprehensive sequencing the small intestine
The small intestine is the longest segment of the gastrointestinal (GI) tract, and its epithelium is thought to be one of the most frequently self-renewing tissues in adult mammals. Despite this, small intestine tumours constitute only around 4% of all GI tumours. Researchers have previously analysed sections of the small intestine, but this study is the first to extensively sequence the small intestine epithelium.
To do this, the researchers used laser capture microdissection microscopy (LCM) and performed whole-genome sequencing of 342 individual small intestine crypts from 39 individuals aged between 4 and 82 years. They found that the total somatic mutation rates of small intestine stem cells are similar to those of the colorectum. This suggests that the lower cancer incidence in the small bowel compared to the large bowel is not due to lower mutational burdens in adult cells. They also investigated APOBEC mutagenesis in the small intestine epithelium and found that it occurs more frequently compared to the large intestine epithelium and most other cell types.
These findings suggest that the stimulus triggering APOBEC mutagenesis is controlled by cell-intrinsic factors, is episodic, and can initiate APOBEC mutagenesis during the whole human lifespan. They also compared APOBEC1 mRNA expression levels and SBS2/SBS13 frequency in small and large intestine epithelia, finding that APOBEC1 is likely responsible for the high SBS2/SBS13 mutation levels found in the normal small intestine.
Heading for human organoids?
Further research is needed to examine the role APOBEC1 plays in SBS2 and SBS13 mutations in human cells, and how APOBEC1 performs both RNA editing and DNA editing in the normal small intestine. Knockout experiments in human organoids derived from the normal small intestine epithelium could be one approach for studying this – but if SBS2 and SBS13 mutation episodes are as infrequent in vitro as they are in vivo, this could pose some problems.
