Genetic Instability and Disease Prognostication

Abstract

Genetic instability is a striking feature of human cancers, with an impact on the genesis, progression and prognosis. The clinical importance of genomic instability and aneuploidy is underscored by its association with poor patient outcome in multiple cancer types, including breast and colon cancer. Interestingly, there is growing evidence that prognostic gene expression signatures simply reflect the degree of genomic instability. Additionally, also the proteome is affected by aneuploidy and has therefore become a powerful tool to screen for new targets for therapy, diagnosis and prognostication. In this context, the chapter presents the impact of genomic instability on disease prognostication occurring in human cancers.

Keywords: Cancer; Genetic instability; Genomics; Prognosis; Proteomics.

Fig. 1

a HDAC2 and TXNL1 immunohistochemical detection in colorectal cancer specimens based on a tissue microarray. Image examples are given at 800-fold magnification. b Tissue-microarray-based immunohistochemical evaluation of HDAC2 and TXNL1 comparing diploid versus aneuploid colorectal carcinoma specimens. Immunoreactivity was scored with “0” showing no positivity, “1” presenting up to 20 % immunopositive cells, “2” up to 50 %, and “3” above 50 % stained cells. Bar plots of the TMA analysis confirmed HDAC2 and TXNL1 as significantly (asterisk) differentially expressed proteins between diploid and aneuploid tumors. Figure adapted from Gemoll et al. (2011)

Fig. 2

Applying the 12-gene genomic instability signature for prediction of disease-free and overall survival in independent datasets using Kaplan-Meier analyses. The curves in red reflect carcinoma patients harboring the genomically stable signature, the curves in green represent patients with the one implying genomic instability. For all three examples, statistically significant association of genomic instability with shorter disease-free and overall survival was observed. Figure adapted from Habermann et al. (2011a, b)