focal genomic gains
Friday 29 August 2008
Gains affecting small genomic regions or even single genes have been described less frequently than large gains.
However, it is now possible to identify focal gains by scanning cancer genomes for variations in DNA copy numbers with new high-resolution methods, such as comparative genomic hybridization (CGH) and single-nucleotide polymorphism (SNP) genotyping.
Array-based CGH and SNP genotyping analyses, for example, have shown amplification of a small segment of band 6q25.1 containing the gene encoding estrogen receptor 1 (ESR1) in a subgroup of women with breast cancer, although additional studies will be required to determine the exact frequency of these amplifications as well as their clinical ramifications.
These amplifications correlate with increased ESR1 protein levels, and preliminary clinical data suggest that ESR1 amplification is associated with increased sensitivity to tamoxifen.
The power of high-resolution SNP arrays to identify focal genomic gains is also illustrated by a recent study that revealed amplification of a 480-kb interval on band 14q13, comprising two known genes, in approximately 12% of patients with non–small-cell lung cancer.
Subsequent functional studies identified the NKX2-1 gene, which encodes a lung-specific transcription factor, as an oncogene that may be involved in this focal event.
The analysis of genes that are recurrently amplified in tumors can also reveal alternative pathogenetic mechanisms that can be exploited therapeutically, as exemplified by the identification of point mutations in the catalytic domain of the EGFR receptor tyrosine kinase in patients with non–small-cell lung cancer that are associated with responsiveness to the kinase inhibitors gefitinib and erlotinib.
By contrast, genomic gains can also underlie acquired resistance to targeted cancer therapy, as exemplified by the recent discovery that amplification and overexpression of the gene encoding the MET receptor tyrosine kinase on band 7q31 can restore aberrant signal transduction downstream of mutant EGFR in non–small-cell lung cancer cells treated with an EGFR inhibitor.
Fröhling S, Döhner H.Chromosomal abnormalities in cancer. N Engl J Med. 2008 Aug 14;359(7):722-34. PMID: 18703475