The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers

Area of Science:

• Genomics
• Cancer Biology
• Molecular Genetics

Background:

• Phylogenetically ultraconserved elements (UCEs), particularly noncoding UCEs (ncUCEs), are crucial genomic regions.
• Their specific roles and mutation patterns in various cancers are not well understood.

Purpose of the Study:

• To systematically analyze the mutational landscape of UCEs in cancer.
• To investigate the functional significance of ncUCE alterations in cancer development and progression.

Main Methods:

• Whole-genome and targeted sequencing of 13,736 UCEs from over 3000 cancer patients.
• CRISPR knockout screens in colorectal cancer cells.
• In vitro and in vivo functional assays.

Main Results:

• Somatic alterations in ncUCEs are frequently observed across multiple cancer types.
• Loss of specific ncUCEs significantly impacts cancer cell proliferation.
• Identified ncUCEs function as enhancers for tumor suppressors (e.g., ARID1B) and silencers for oncogenes (e.g., RPS13).
• Recurrent mutations in ncUCE-located microRNAs (miRNAs), including miR-142, affect miRNA processing and expression.

Conclusions:

• ncUCEs play significant and diverse regulatory roles in cancer.
• Altered ncUCEs contribute to tumorigenesis through various mechanisms, including affecting gene expression and miRNA maturation.