Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer.

INTRODUCTION: Colorectal cancer (CRC) tumor DNA is characterized by chromosomal damage termed chromosomal instability (CIN) and excessively shortened telomeres. Up to 80% of CRC is microsatellite stable (MSS) and is historically considered to be chromosomally unstable (CIN+). However, tumor phenotyping depicts some MSS CRC with little or no genetic changes, thus being chromosomally stable (CIN-). MSS CIN- tumors have not been assessed for telomere attrition. EXPERIMENTAL DESIGN: MSS rectal cancers from patients ≤50 years old with Stage II (B2 or higher) or Stage III disease were assessed for CIN, telomere length and telomere maintenance mechanism (telomerase activation [TA]; alternative lengthening of telomeres [ALT]). Relative telomere length was measured by qPCR in somatic epithelial and cancer DNA. TA was measured with the TRAPeze assay, and tumors were evaluated for the presence of C-circles indicative of ALT. p53 mutation status was assessed in all available samples. DNA copy number changes were evaluated with Spectral Genomics aCGH. RESULTS: Tumors were classified as chromosomally stable (CIN-) and chromosomally instable (CIN+) by degree of DNA copy number changes. CIN- tumors (35%; n=6) had fewer copy number changes (<17% of their clones with DNA copy number changes) than CIN+ tumors (65%; n=13) which had high levels of copy number changes in 20% to 49% of clones. Telomere lengths were longer in CIN- compared to CIN+ tumors (p=0.0066) and in those in which telomerase was not activated (p=0.004). Tumors exhibiting activation of telomerase had shorter tumor telomeres (p=0.0040); and tended to be CIN+ (p=0.0949). CONCLUSIONS: MSS rectal cancer appears to represent a heterogeneous group of tumors that may be categorized both on the basis of CIN status and telomere maintenance mechanism. MSS CIN- rectal cancers appear to have longer telomeres than those of MSS CIN+ rectal cancers and to utilize ALT rather than activation of telomerase.

Prostate cancer cells use genetic and epigenetic mechanisms for progression to androgen independence.

Studies on the genetic basis of prostate cancer (PCa) have lead to mixed results with the only consensus being that PCa is a complex disease. Our goal was to gain insight into potential events involved in the acquisition of the androgen-refractory phenotype in PCa cells regardless of DNA-change dependence. To this end, we examined two LNCaP PCa cell line models of progression-one developed in vivo and one developed in vitro-using molecular cytogenetic and microarray gene expression analyses and extended this investigation of specific events into PCa tumors. The chromosomal changes observed in both in vivo and in vitro androgen-independent cell lines are similar to those seen in PCa during tumor progression. Correspondingly, gene expression analysis showed significant heterogeneity in the genes expressed among androgen-independent cells, but with some common gene expression changes that correlated with the acquired androgen-independent phenotype. Thus, growth conditions under which the cells progress appeared to impact the mechanisms used for progression, albeit within tumor-type-specific pathways. Our findings suggest that a dynamic and adaptable combination of epigenetic and DNA-change-dependent events can be used by PCa cells for the acquisition of the androgen-independent phenotype. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.