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Sensitive detection of somatic mutations in GC-rich cancer gene promoters

Meifang Qi1,2,3, Preshita Sanjay Dave1,2,3, Nicole Francis3,4

  • 1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129 Boston, MA, United States.

NAR Cancer
|May 6, 2026
PubMed

Insights

Researchers developed a new assay to deeply sequence GC-rich gene promoters, uncovering novel noncoding mutations in cancer. This method aids in identifying potential cancer driver genes, advancing our understanding of tumor development.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Somatic mutations in coding and noncoding regions drive cancer.
  • Identifying noncoding driver mutations, especially in GC-rich promoters, is challenging due to sequencing limitations.
  • Known noncoding drivers include mutations in TERT, FOXA1, and TP53 promoters.

Purpose of the Study:

  • To develop and validate a hybrid capture assay for deep sequencing of cancer gene promoters.
  • To identify novel somatic noncoding driver mutations in GC-rich promoter regions.
  • To nominate candidate driver mutations for further functional investigation.

Main Methods:

  • A hybrid capture assay was designed to target over 3000 cancer gene promoters.
  • The assay was optimized for deep sequencing of GC-rich regions.
  • The method was applied to cell line models and archival formalin-fixed, paraffin-embedded (FFPE) tissue samples.

Main Results:

  • The assay successfully enabled deep sequencing of challenging GC-rich promoter regions.
  • It allowed for the discovery of point mutations, short insertions/deletions, copy number variants, and mutational signatures.
  • Candidate noncoding driver mutations in CDK4, SMAD3, and GATA3 promoters were identified in breast cancer.

Conclusions:

  • The developed hybrid capture assay is effective for discovering somatic noncoding mutations in cancer gene promoters.
  • This advancement addresses a critical gap in identifying cancer drivers within promoter regions.
  • The nominated mutations in CDK4, SMAD3, and GATA3 warrant further functional studies to confirm their role in breast cancer.

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