Researchers and clinicians from National Taiwan University (NTU) and NTU Hospital have compiled the first large-scale genetic database for colorectal cancer (CRC) in Taiwan. This initiative identified inherited genetic abnormalities specifically linked to familial and early-onset cases within the local population.
CRC isn't always random. Genetic factors play a significant role, with 10%–30% of patients reporting a family history and 5%–10% carrying pathogenic variants passed down through generations, a condition known as hereditary CRC (HCRC). One prominent example is Lynch syndrome, which stems from malfunctioning DNA mismatch repair genes and often manifests as early-onset cancer (before the age of 50).
Early identification of pathogenic variants
Familial Adenomatous Polyposis (FAP) is caused by variants in the APC gene, which normally functions to suppress overactive cell growth. Patients with FAP often develop hundreds to thousands of polyps during adolescence; without medical intervention, these growths almost inevitably progress to cancer. Consequently, identifying these pathogenic variants through early screening is vital for effective prevention.
The study, published in Clinical Gastroenterology and Hepatology, identified 24 pathogenic variants in HCRC-related genes among 5.2% of Taiwanese CRC patients, a figure that rises to 8.2% in early-onset cases. These HCRC patients also exhibited significantly higher rates of other familial cancers. The research highlighted several noteworthy novel variants, such as a variant in the POLD1 gene. This case was particularly striking, as the carrier was only 26 years old, with a large 11 cm tumor and an extremely high tumor mutational burden.
However, the researchers believe many population-specific pathogenic variants remain hidden among the 1,915 "Variants of Uncertain Significance" identified in the study. After using the Taiwan Biobank to filter out variants common in Taiwan, the team focused on the remaining rare variants, and 25.5% were previously undocumented. They also analyzed tumor mutational characteristics to confirm if a detected variant was the likely "driver" of the cancer. By integrating age and family history data, they identified an additional 41 candidate pathogenic variants.
Ultimately, these findings advance the understanding of genetic risk within the Taiwanese HCRC population. By highlighting the unique genetic landscape of local patients, the study underscores the urgent need to expand genomic databases to include more Asian-specific variants, ensuring that precision medicine is more accurate and effective for all populations.
Maximizing clinical impact through bioinformatics
Yi-Chen Huang, the study's first author and a researcher at NTU, highlighted the broader implications of the findings. "Moving forward, we are working to characterize these candidate pathogenic variants by predicting changes in protein structure and integrating multi-omics data, with the goal of maximizing their clinical impact through bioinformatics," says Huang.
"This study identifies germline risk factors that enable earlier detection and precision care in CRC, while helping to close the gap in defining germline risk in Asian populations, particularly in early-onset CRC, which is rapidly increasing in Taiwan," says co-corresponding author Han-Mo Chiu, professor of internal medicine, division of gastroenterology and hepatology, NTU.
Provided by National Taiwan University