Whole Exome Sequencing-identified Germline Variants Underlie High Familial Risk and Early-onset Colorectal Cancer in...

Area of Science:

• Genetics
• Oncology
• Genomic Medicine

Background:

• Germline genetic factors significantly influence colorectal cancer (CRC) clinical features.
• These factors are underexplored in the Taiwanese population.
• Understanding these variants is crucial for familial risk and early-onset CRC assessment.

Purpose of the Study:

• To evaluate the pathogenicity of germline variants in Taiwanese CRC patients.
• To investigate associations between germline variants, familial risk, and early-onset CRC.
• To identify novel candidate genes and pathogenic variants contributing to CRC.

Main Methods:

• Whole exome sequencing of 600 Taiwanese CRC patients.
• Variant pathogenicity assessment using American College of Medical Genetics and Genomics (ACMG) guidelines.
• Comparative analysis with 1492 controls and correlation of clinical features with genetic variants.

Main Results:

• Identified novel candidate genes (e.g., CCDC18, CEP135) and 24 pathogenic variants in hereditary cancer genes (5.2% of patients).
• Early-onset CRC cases showed the highest prevalence of pathogenic variants (8.2%).
• A novel POLD1 stop-gain variant (p.Y594X) was found in a young patient; ATM and MUTYH variants were also highlighted. 41 candidate pathogenic variants were linked to familial and early-onset CRC.

Conclusions:

• Findings enhance understanding of germline genetics in Taiwanese CRC.
• Results support improved screening and management strategies for CRC.
• Emphasizes the need for expanded Asian variant databases for better risk assessment and patient care.