Systematic analysis of noncoding somatic mutations and gene expression alterations across 14 tumor types

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• Somatic mutations in noncoding DNA are largely uncharacterized in cancer.
• Activating mutations in TERT regulatory DNA represent a known exception.
• The hypothesis of widespread oncogene activation via promoter mutations remains largely untested.

Purpose of the Study:

• To map somatic mutations across 14 cancer types and investigate their association with RNA expression changes.
• To systematically screen for recurrent mutations in regulatory regions and their impact on gene expression.
• To provide a pan-cancer analysis of TERT transcriptional activation and explore potential oncogenic promoter mutations.

Main Methods:

• Genome-wide mapping of somatic mutations in 505 tumor genomes.
• Systematic screening for associations between regulatory region mutations and RNA expression levels.
• Detailed analysis of TERT expression across various cancer types, considering copy number stability.

Main Results:

• Recurrent promoter mutations were identified in several genes, but TERT mutations showed a unique, strong association with increased expression.
• The association between TERT mutations and expression varied significantly across cancer types, being strongest in copy number-stable cancers like thyroid carcinoma.
• Evidence suggests TERT promoter mutations may also regulate the expression of the adjacent CLPTM1L gene.

Conclusions:

• TERT promoter mutations are a significant driver of TERT transcriptional activation across multiple cancers.
• While TERT mutations are exceptional, the study found no clear evidence for frequent oncogenic promoter mutations in other genes.
• The findings highlight TERT promoter mutations as a key mechanism in cancer development and suggest a regulatory role in CLPTM1L expression.