Evaluating sources of intrachromosomal instability in sporadic cancer genomes

Genomic instability is one of the hallmarks of tumorigenesis, although it is still disputed if this process acts as a progression facilitator, or is a secondary consequence of malignancy. Intrachromosomal genomic instability has been detected in the pre-malignant aberrant crypts of the colon, supporting the model that instability is an early step in the progression to malignancy in sporadic colorectal tumors and is therefore most likely a facilitator of tumorigenesis. Intrachromosomal genomic instability was quantified using Inter-(Simple Sequence Repeat) PCR analysis on paired tumor and normal DNA samples of breast, thyroid, and colorectal cancers, ultimately quantifying similar overall levels of instability. We assessed the correlations between K-ras and GSTM1 mutations and a tumor's level of genomic instability. A significant association was found between tumors with a GSTM1-null status and elevated inter-(simple sequence repeat) FCR instability, while a weak correlation was observed between mutant K-ras and inter-(simple sequence repeat) PCR genomic instability.; Colorectal tumors were analyzed using comparative genomic hybridization BAC microarrays. There is a three BAC-clone region on chromosome 9 that contains the c-ABL gene, where copy number alteration is associated with genome-wide aCGH copy number loss. There is a highly significant interaction between that region of chromosome 9 and chromosome 22q11-13, another region whose loss is associated with genome-wide deletion. Additional regions of interest include the telomeric end of chromosome 14 whose loss is associated with genome-wide copy number losses, and regions on chromosome l, 2, 3, 7, and 13 whose amplification is associated with genome-wide copy number gains.