Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer: Beyond the Abstract

Hepatocellular carcinomas (HCCs) have been known to have a high degree of heterogeneity and aneuploidy, which are obstacles to designing therapies. Contemporary targeted therapies may be rendered ineffective against cancers with high heterogeneity. In fact, all stages combined, the 5-year survival rate for HCCs is approximately 15-17%, a frustrating low rate. 

The increasing number of cancer analysis data with next generation sequencing (NGS) enables researchers to better understand cancers; from the mechanism of carcinogenesis, frequently mutated genes, evolution, to potential weaknesses that can be exploited clinically for cancer prevention and therapy. 

We have been investigating “genomic instability and cancer” issue. In this review, based on contemporary NGS data for HCCs, we listed frequently mutated genes in HCCs, described the functions of affected genes and pathways, and discussed the underlying mechanism of heterogeneity in HCCs. Although the number of mutations with high penetration (<10%) was limited, many frequently mutated genes in HCCs have functions to prevent genomic instability (both Chromosome instability and Microsatellite instability). Notably, the pathway analysis suggested that oxidative stress management may be critical to prevent the accumulation of DNA damage and further mutations. Therefore, to prevent or delay HCC development, we suggested; 1) to attenuate Wnt and/or EGFR signaling, 2) to reduce Reactive Oxygen Species through anti-oxidant supplementation, and 3) to reduce DNA damage by controlling exposure to DNA-damaging agents or other DNA-damaging events, such as inflammation or alcohol consumption.

As exemplified in this work, advances in -omics-based tumor analysis and understanding should help developing effective countermeasures for HCCs and other cancers.
Written by: Hiroshi Y. Yamada, Ph.D.

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