Extensive genetic heterogeneity within tumor accompanied by little expression divergence and their functional implications

The intratumor heterogeneity has been widely observed in various types of cancers from the perspective of the morphological or phenotypic profiles of cancer cells, introducing significant challenges in designing effective treatment strategies. The recent high-resolution genome-wide studies have revealed genetic diversity resulting from clonal evolution within individual cancers. In general, how much the genetic heterogeneity among subclones contributes to phenotypic differences of cancer cells remains unexamined, because majority of mutations are not likely to be essential for phenotypic variations during the clone evolution. In this study, we performed a comprehensive genome-wide analysis of the heterogeneity within the tumor from a hepatocellular carcinoma (HCC) patient. Variations among multiple-regional small sections of the tumor were investigated at both genomic DNA and transcriptome level. Although startling intratumor genetic heterogeneity in SNVs and chromosomal alterations is observed, the tumor shows rather homogeneous at gene expression level. The transcriptional homogeneity is common in different cancer types, supported by the analysis of the published gene expression data. It implies that the existence of large intratumor genetic heterogeneity is not necessary to result in the differences in gene expression and signaling pathways between subclones, leading to phenotypic differences of cancer cells within a tumor.