The last decade has brought to light the importance of gene copy number changes in a wide variety of human diseases. Understanding in detail of how changes in copy number of individual genes or large chromosomal regions enhance or perhaps suppress disease is a critical challenge. With an ever more detailed view of the human genome, its variations in the normal population and in disease prone families, we will be able to learn which copy number changes don’t matter and allow us to focus on those that impact function.
A particularly exciting future direction is the pursuit of gene copy number changes in developing therapies. The realization that CNVs contribute to difficult to treat diseases, such as neurological and psychiatric disorders brings with it the possibility of targeting the gene products amplified/deleted in particular disorders. For example duplication of AUTS4
, a gene encoding the GABAA
receptor subunit, has been associated with autism spectrum disorder (Zhang et al., 2009
). Autistic individual with this CNV may benefit from compounds that downregulate GABAA
receptor function. CNVs causing disruptions of MYT1L
have been seen in patients with Schizophrenia. Crohn’s disease, a bowl inflammatory disease, is linked to copy number reduction of HBD2
. Compounds that increase the function of the remaining copy or inhibit the function of negative regulators of the pathways that these genes function in may have a significant therapeutic index.
Cancer is the prime example in which gene amplifications and deletions have been shown to drive disease (Gordon et al., 2012
). Therapies where overexpressed or amplified oncogenic drivers are targeted have been developed. The gene encoding EGFR is amplified in non-small-cell lung cancer. Small molecules such as gefitinib or erlotinib have been applied to inhibit EGFR with success (Carling, 2004
; Paez et al., 2004
, which encodes the EGFR receptor HER2, is amplified in ~30% of primary breast cancers (Slamon et al., 1987
). Trastuzumab, an anti-HER2 antibody, has been used in the therapy of HER2
amplified breast cancers with great success (Baselga et al., 1998
). These successes raise the exciting possibility that targeting amplified disease drivers provides opportunities for therapy in cancer, psychiatric disorders and autoimmune diseases, where effective treatments are scarce.
Whether large-scale gene copy number changes as are the cause of Down syndrome or as occur in cancer can be targeted in therapy remains to be determined. In Down syndrome, gene dosage changes of many different genes contribute to the associated phenotypes, making the development of therapeutics a challenge. The identification of individual genes responsible for specific phenotypes could enable the development of therapeutics that target specific aspects of the condition. For example, individuals with Down syndrome could benefit from therapies that lower APP protein levels, to prevent early onset Alzheimer’s disease; the development of which has, unfortunately, failed so far.
In cancer, the situation is even more complex. In this disease, the contribution of gene dosage changes of many genes is augmented by the variability of an ever-changing genetic make-up. Many cancers do however harbor specific aneuploidies that could be targeted in therapy. For example, trisomy 8 is frequently observed in patients with AML and associated with poor survival when present together with other genetic aberrations (Wolman et al., 2002
). Drugs that target cells with amplified chromosome 8 may aid in the treatment of AML. Genomic instability in cancers also leads to loss of many genomic regions. These genetic lesions could provide additional therapeutic targets (Nijhawan et al., 2012
). The general stress phenotypes associated with aneuploidy could also be explored in cancer treatment. The advantage of such compounds is that they would show efficacy against a broad spectrum of cancers. Compounds that preferentially inhibit the proliferation of aneuploid cell lines have been shown to exist and appear to exaggerate the general stress phenotypes associated with whole chromosome copy number changes (Tang et al., 2011
). These compounds included AICAR, an agonist of the stress activated AMP kinase and the Hsp90 inhibitor 17-AAG (Tang et al., 2011
). Thus targeting the general stresses associated with aneuploidy could be developed as cancer drug targets. It is worth noting that Hsp90 inhibitors such as 17-AAG, displaye anti-tumor efficacy in HER2/ErbB2-positive breast cancer and are currently in phase II and III clinical trails. The proteasome inhibitor bortezomib is used in the treatment of multiple myeloma (Richardson et al., 2005
). Other inhibitors of the ubiquitin-proteasome system such as highly specific inhibitors of the proteasome-associated deubiquitinating enzyme Usp14 (Lee et al., 2010
) could also show efficacy against aneuploid cells and thus could be used in the treatment of aneuploid cancers. We note that, compounds that target aneuploid cells may be especially effective when combined with chemotherapeutics that increase chromosome mis-segregation such as Taxol.
Changes in gene copy number, large and small in scale, contribute to population diversity and are significant contributors to disease. Understanding their cost and benefits will provide critical insights into evolution and diseases.