APOBEC mutagenesis is a common process in normal human small intestine

Area of Science:

• Genomics
• Cancer Biology
• Molecular Evolution

Background:

• APOBEC mutational signatures, specifically SBS2 and SBS13, are frequently observed in human cancers.
• The precise triggers, timing, and enzymes responsible for APOBEC mutagenesis remain incompletely understood.
• Understanding these signatures in normal tissues is crucial for deciphering their role in cancer development.

Purpose of the Study:

• To investigate the occurrence and characteristics of APOBEC mutational signatures (SBS2/SBS13) in normal human small intestine epithelium.
• To determine if APOBEC mutagenesis is cell-intrinsic and its pattern throughout the human lifespan.
• To elucidate the potential role of APOBEC1 in driving these mutations in the small intestine.

Main Methods:

• Whole-genome sequencing of 342 microdissected normal epithelial crypts from 39 individuals.
• Analysis of APOBEC mutational signatures (SBS2/SBS13) distribution within and between crypts.
• Quantification of APOBEC1 mRNA levels in various human tissues.

Main Results:

• APOBEC signatures SBS2/SBS13 were found in 17% of normal small intestine crypts, a higher frequency than in most other normal tissues.
• Mutations often appeared in isolated crypts, suggesting a cell-intrinsic cause.
• Mutagenesis occurred episodically across all ages, and high APOBEC1 mRNA levels in the small intestine correlated with mutation frequency.

Conclusions:

• The high prevalence of SBS2/SBS13 in the small intestine is likely a consequence of APOBEC1's normal function in APOB mRNA editing.
• APOBEC mutagenesis is cell-intrinsic and occurs throughout life, even in young individuals.
• These findings provide insights into the origin of APOBEC-driven mutations and their potential contribution to early cancer development.