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tumoral genomic losses resulting in allelic insufficiency

Friday 29 August 2008

Chromosomal deletions can cause tumorigenesis by inactivation of a single allele.

Since such haplo-insufficient tumor-suppressor genes cannot be identified through analysis of the remaining allele, alternative approaches are required to assess the consequences of monoallelic deletion.

An example is a recent study in which graded down-regulation of multiple candidate genes by RNA interference was used to identify RPS14 as a causal gene for the 5q minus syndrome, a subtype of the myelodysplastic syndrome characterized by a 1.5-Mb commonly deleted region on chromosome band 5q32.

Notably, patients with the 5q minus syndrome are highly responsive to the thalidomide derivative lenalidomide, although the mechanisms through which lenalidomide restores normal erythropoiesis remain unknown.

Monoallelic deletions can completely inactivate tumor-suppressor genes that are located on the X chromosome because humans carry only one functional copy of all X-linked genes.

This mechanism was documented in a recent study that identified small deletions of band Xq11.1, targeting the FAM123B tumor-suppressor gene, in 21.6% of patients with sporadic Wilms’ tumors.

DNA sequence analysis subsequently identified additional patients with inactivating FAM123B mutations, again highlighting the potential of chromosomal imbalances for guiding the discovery of alternative genetic changes with similar functional consequences.

References

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