Choi Yoon Young
Department of Surgery, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea.
Korean J Clin Oncol. 2025 Aug;21(2):90-97. doi: 10.14216/kjco.25359. Epub 2025 Aug 31.
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.
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.
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.
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.
同一个体出现的多个原发性肿瘤对精准肿瘤学构成挑战，尤其是在林奇综合征等遗传性癌症综合征的背景下。虽然这些肿瘤可能源于共同的种系易感性，但它们是否也共享可用于治疗的体细胞改变仍不清楚。本研究旨在描述年轻韩国患者中同步或异时性胃癌和结直肠癌之间体细胞基因组重叠的程度。
19例在55岁之前被诊断为胃癌和结直肠癌的患者接受了福尔马林固定石蜡包埋肿瘤组织的全外显子测序。确定微卫星不稳定性（MSI）状态，并评估种系错配修复（MMR）变异以识别林奇综合征病例。分析体细胞突变、突变特征和拷贝数改变，以量化个体患者肿瘤间的基因组相似性。
在分析的37个肿瘤中，36.8%的胃癌和44.4%的结直肠癌为MSI高。在7例患者中鉴定出种系致病性MMR变异。尽管存在共同的高突变表型，但配对肿瘤之间重叠体细胞突变的比例始终较低（<5%）。突变特征因MSI状态而异，包括SBS1/5（衰老）和SBS15（MMR缺陷）。值得注意的是，一名非林奇综合征患者的两个肿瘤均表现出MYC扩增，经荧光原位杂交证实。
即使在具有共同种系易感性的患者中，不同器官出现的原发性肿瘤也表现出显著的基因组差异。这些发现表明器官特异性选择压力驱动独立的肿瘤进化，强调在多原发性癌症病例中进行个体化分子分析和治疗靶向的必要性。
