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genomic gains

Friday 29 August 2008

Most recurrent genomic gains probably contribute to tumorigenesis by enhancing the activity of specific genes in the affected chromosomal regions.

Types

- large-scale genomic gains
- focal genomic gains

Large-Scale Genomic Gains

Genomic gains commonly arise from chromosomal nondisjunction or unbalanced translocations, which cause complete or partial chromosomal trisomies, or from amplification events affecting DNA segments of different size.

Numerous examples of large-scale genomic gains are associated with specific types of cancer. Since such aberrations involve multiple genes, the identification of their functionally relevant targets has proved to be difficult.

One way to "filter" the genes within regions of DNA copy-number gain is to identify those that are also altered at the RNA or protein level, assuming that genes whose increased dosage translates into increased expression are most likely to be involved in malignant transformation.

This strategy has uncovered new oncogenes in malignant melanoma (MITF and NEDD9 on bands 3p14.2-p14.1 and 6p25-p24, respectively)58,59 and hepatocellular carcinoma (YAP1 and BIRC2 on bands 11q13 and 11q22, respectively) and has identified candidate breast-cancer genes.

Focal Genomic Gains

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.

Therapeutics

Some of these genes encode proteins that can be specifically targeted by new anticancer agents. One example, which occurs in approximately 30% of women with breast cancer, is amplification of the gene on band 17q21.1 that encodes the ERBB2 receptor tyrosine kinase.

The resulting overexpression of ERBB2 represents a target for the monoclonal antibody trastuzumab; the combination of trastuzumab with chemotherapy reduces the rate of death from breast cancer in both the adjuvant and metastatic settings.

See also

- genomic losses

References

- Fröhling S, Döhner H. Chromosomal abnormalities in cancer. N Engl J Med. 2008 Aug 14;359(7):722-34. PMID: #18703475#