Intrapatient genomic divergence across multiple primary tumors in young Korean patients.

Abstract

Purpose: Multiple primary tumors arising in the same individual pose challenges for precision oncology, particularly in the context of hereditary cancer syndromes such as Lynch syndrome. While these tumors may originate from a shared germline predisposition, it remains unclear whether they also share somatic alterations that could be therapeutically exploited. This study aimed to characterize the extent of somatic genomic overlap between synchronous or metachronous gastric and colorectal cancers within young Korean patients.

Methods: Nineteen patients diagnosed with both gastric and colorectal cancers before age 55 underwent whole exome sequencing of formalin-fixed paraffin-embedded tumor tissues. Microsatellite instability (MSI) status was determined, and germline mismatch repair (MMR) variants were assessed to identify Lynch syndrome cases. Somatic mutations, mutational signatures, and copy number alterations were analyzed to quantify intertumoral genomic similarity within individual patients.

Results: Among the 37 tumors analyzed, 36.8% of gastric and 44.4% of colorectal cancers were MSI-high. Germline pathogenic MMR variants were identified in seven patients. Despite shared hypermutated phenotypes, the proportion of overlapping somatic mutations between paired tumors was consistently low (< 5%). Mutational signatures varied by MSI status and included SBS1/5 (aging) and SBS15 (MMR deficiency). Notably, one non-Lynch patient exhibited MYC amplification in both tumors, confirmed by fluorescence in situ hybridization.

Conclusion: Even in patients with shared germline predisposition, primary tumors arising in different organs demonstrate substantial genomic divergence. These findings suggest that organ-specific selective pressures drive independent tumor evolution, underscoring the need for individualized molecular profiling and therapeutic targeting in cases of multiple primary cancers.