Shaping of tumor and drug-resistant genomes by instability and selection

Tumors with defects in mismatch repair (MMR) show fewer chromosomal changes by cytogenetic analyses than most solid tumors, suggesting that a greater proportion of the alterations required for malignancy occur in genes with nucleotide sequences susceptible to errors normally corrected by MMR. Here, we used genome-wide microarray comparative genomic hybridization to carry out a higher resolution evaluation of the effect of MMR competence on genomic alterations occurring in 20 cell lines and to determine if characteristic aberrations arise in MMR-proficient and -deficient HCT116 cells undergoing selection for methotrexate resistance. We observed different spectra of aberrations in MMR-proficient compared to -deficient cell lines, as well as among cell lines with different types of MMR-deficiency. We also observed different genetic routes to drug resistance. Resistant MMR-deficient cells most frequently displayed no copy number alterations (16/29 cell pools), whereas all MMR-proficient cells had unique abnormalities involving chromosome 5, including amplicons centered on the target gene, DHFR and/or a neighboring novel locus (7/13 pools). These observations support the concept that tumor genomes are shaped by selection for alterations that promote survival and growth advantage, as well as by the particular dysfunctions in genes responsible for maintenance of genetic integrity.