Researchers in Japan, led by Dr. Hideyuki Saya at Fujita Health University, have uncovered key insights into colorectal cancers (CRC) with high tumor mutation burden (TMB) that lack mutations in common driver oncogenes like APC, TP53, KRAS, and PIK3CA. Their study, published in Cancer Science, analyzed tumors from 150 CRC patients using targeted exome sequencing to identify alternative molecular pathways, particularly in TMB-high tumors.
Of the 14 tumors classified as TMB-high, 12 were located in the right colon and frequently carried BRAF mutations and microsatellite instability (MSI-high)—features associated with the serrated pathway of carcinogenesis. These tumors also showed frequent mutations in DNA repair genes, such as ATM, POLE, MSH2, and MSH6, which may occur early in cancer development and contribute to tumor progression through non-canonical pathways.
Importantly, these TMB-high tumors still exhibited alterations in genes related to canonical signaling pathways, including RTK-RAS, PI3K, and NOTCH, despite lacking mutations in the major oncogenes. The findings highlight site-specific and mutation-driven heterogeneity in CRC and suggest that personalized treatments, especially targeted therapies and immunotherapies, could be more effective for these subtypes. The team aims to integrate their in-house genomic analysis system into standard CRC diagnostics to support precision oncology.
Source:
https://www.genengnews.com/topics/cancer/exploring-the-mutational-landscape-of-colorectal-cancer/
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