Uncovering variable neoplasms between ATM protein-truncating and common missense variants using 394 694 UK Biobank...

Area of Science:

• Genetics
• Oncology
• Genomic Medicine

Background:

• The ataxia-telangiectasia mutated (ATM) gene is a critical DNA damage regulator in cancer.
• While ATM's role in oncology is established, the distinct impacts of its missense variants versus protein-truncating variants (PTVs) on neoplasms require further investigation.

Purpose of the Study:

• To investigate the independent associations of ATM missense variants and protein-truncating variants (PTVs) with various neoplasms.
• To determine if ATM missense variant effects on neoplasms are independent of ATM PTV carrier status.

Main Methods:

• Utilized whole-exome sequencing data and clinical health records from 394,694 UK Biobank European participants.
• Performed gene-level and variant-level phenome-wide association studies (PheWAS).
• Conducted variant-level conditional association analysis to assess independence of missense variant effects from PTVs.

Main Results:

• Gene-level analysis confirmed significant associations between ATM PTVs and 31 malignant neoplasm phenotypes (p < 2 × 10⁻⁹).
• Three individual ATM missense variants showed significant associations with nine distinct tumor-related phenotypes (p < 2 × 10⁻⁹).
• Crucially, these nine missense-associated phenotypes did not overlap with malignancies linked to ATM PTVs, and conditional analysis confirmed their independence.

Conclusions:

• ATM PTVs are strongly associated with a broad spectrum of malignancies, consistent with existing literature.
• Specific ATM missense variants are independently associated with distinct sets of neoplasms, suggesting unique biological roles beyond PTVs.
• This highlights the importance of distinguishing between different variant types within the ATM gene for a comprehensive understanding of cancer risk.