Unstable genomes elevate transcriptome dynamics

• Published in: International journal of cancer Vol. 134; no. 9; pp. 2074 - 2087
• Main Authors: Stevens, Joshua B., Liu, Guo, Abdallah, Batoul Y., Horne, Steven D., Ye, Karen J., Bremer, Steven W., Ye, Christine J., Krawetz, Stephen A., Heng, Henry H.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 01.05.2014; Wiley Subscription Services, Inc
• Subjects: Biological and medical sciences; Cancer; cancer evolution; CCAs; Cell Transformation, Neoplastic - genetics; Chromosomal Instability - genetics; clonal chromosome aberrations; Evolution, Molecular; Gene expression; Gene Expression Profiling; genome chaos; Genome, Human - genetics; Genomes; Humans; Karyotype; karyotypic heterogeneity; Medical research; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); NCCAs; non‐clonal chromosome aberrations; Oligonucleotide Array Sequence Analysis; Transcriptome - genetics; transcriptome dynamics; Tumors; Chromosomal aberration; Chaos; transcriptome dynamics; Transcriptome; clonal chromosome aberrations; NCCAs; Malignant tumor; cancer evolution; CCAs; Heterogeneity; Cancerology; genome chaos; Dynamics; karyotypic heterogeneity; Cytogenetics; non-clonal chromosome aberrations; Evolution; Instability; Genome; Karyotype; Cancer
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28531

The challenge of identifying common expression signatures in cancer is well known, however the reason behind this is largely unclear. Traditionally variation in expression signatures has been attributed to technological problems, however recent evidence suggests that chromosome instability (CIN) and resultant karyotypic heterogeneity may be a large contributing factor. Using a well‐defined model of immortalization, we systematically compared the pattern of genome alteration and expression dynamics during somatic evolution. Co‐measurement of global gene expression and karyotypic alteration throughout the immortalization process reveals that karyotype changes influence gene expression as major structural and numerical karyotypic alterations result in large gene expression deviation. Replicate samples from stages with stable genomes are more similar to each other than are replicate samples with karyotypic heterogeneity. Karyotypic and gene expression change during immortalization is dynamic as each stage of progression has a unique expression pattern. This was further verified by comparing global expression in two replicates grown in one flask with known karyotypes. Replicates with higher karyotypic instability were found to be less similar than replicates with stable karyotypes. This data illustrates the karyotype, transcriptome, and transcriptome determined pathways are in constant flux during somatic cellular evolution (particularly during the macroevolutionary phase) and this flux is an inextricable feature of CIN and essential for cancer formation. The findings presented here underscore the importance of understanding the evolutionary process of cancer in order to design improved treatment modalities. What's new? Karyotypic alteration is a driving force of cancer evolution, but its effects on the transcriptome are not well understood. In the present study, the pattern of genome alteration and expression dynamics during somatic evolution was interrogated using an immortalization model. The model revealed that major karyotypic alterations, such as structural or numerical changes, result in significant deviations in gene expression, suggesting that karyotype changes influence gene expression. The data further indicates that karyotype and transcriptome pathways are in constant flux during somatic cellular evolution and that this flux is essential for cancer formation.