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Chronic inflammation and chromosome aneuploidy are major traits of primary liver cancer (PLC), which represent the second most common cause of cancer-related death worldwide. Increased cancer fitness and aggressiveness of PLC may be achieved by enhancing tumoral genomic complexity that alters tumor biology. Here, we developed a scoring method, namely functional genomic complexity (FGC), to determine the degree of molecular heterogeneity among 580 liver tumors with diverse ethnicities and etiologies by assessing integrated genomic and transcriptomic data. We found that tumors with higher FGC scores are associated with chromosome instability and TP53 mutations, and a worse prognosis, while tumors with lower FGC scores have elevated infiltrating lymphocytes and a better prognosis. These results indicate that FGC scores may serve as a surrogate to define genomic heterogeneity of PLC …