Negative selection maintains transcription factor binding motifs in human cancer

Area of Science:

• Genomics
• Cancer Biology
• Molecular Biology

Background:

• Somatic mutations in cancer cells can disrupt gene regulation by altering transcription factor binding sites.
• While positive selection of some mutations is observed, the role of negative selection in non-coding regions is debated.
• Promoter mutations are linked to increased cancer risk, highlighting the importance of regulatory elements.

Purpose of the Study:

• To analyze transcription factor binding motifs co-localized with non-coding variants in cancer.
• To investigate the impact of negative selection on these binding sites, accounting for cancer-specific mutation signatures.
• To understand the stability of regulatory elements in cancer genomes.

Main Methods:

• Analysis of transcription factor binding motifs and non-coding variants.
• Accounting for cancer-specific mutation signatures to avoid statistical bias.
• Examination of binding motif stability in DNase accessible regions.

Main Results:

• Human cancers exhibit fewer mutations than expected in transcription factor binding sites, indicating negative selection.
• This stabilizing effect is particularly pronounced for binding motifs in DNase accessible regions.
• Multiple transcription factor families, including FOX, HOX, and NR, show conserved binding motifs.

Conclusions:

• Negative selection actively protects cancer cells by preventing alterations in critical transcription factor binding sites.
• This selection pressure safeguards against the rewiring of cellular regulatory circuits.
• Identifying transcription factors with conserved binding motifs may reveal key pathways for cancer survival and therapeutic targeting.