Long-telomeropathy is associated with tumor predisposition syndrome

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Telomeres protect chromosome ends, and telomere length (TL) is influenced by genetic and environmental factors.
• Short telomeres are associated with rare telomeropathies, but the role of long telomeres in disease is less understood.

Purpose of the Study:

• To investigate the hypothesis that a
• long-telomeropathy
• syndrome predisposes individuals to cancer.
• To identify genetic factors contributing to long telomere length and associated cancer risk.

Main Methods:

• Developed a trans-ancestry polygenic risk score for TL (PRS_TL) using genomic and health data from over 113,000 individuals.
• Conducted a phenome-wide association study (PheWAS) to link PRS_TL with tumor traits.
• Developed and validated a trans-ancestry phenotype risk score for long TL (PheRS_LTL) and performed rare variant analyses.

Main Results:

• Identified 65 tumor traits associated with elevated PRS_TL.
• Discovered 13 novel genes linked to PheRS_LTL through rare variant analysis.
• Confirmed that carriers of rare variants in these genes exhibit a predisposition for long TL, supporting the study's hypothesis.

Conclusions:

• This research identifies a novel tumor-predisposing syndrome associated with long telomere length.
• The findings highlight the role of both common and rare genetic variants in this syndrome.
• The study expands the definition of telomeropathies to include conditions predisposing to long telomeres.