Oncomere discoveries open new avenues in cancer research

The junk DNA revolution has thrown up yet another neologism for cancer geneticists to add to their spellcheckers: 'oncomere'.

An oncomere ('onco' = cancer, 'mere' = a boundary) is a chromosomal locus harbouring a cluster of mini-genes coding for microRNAs, with a vital crucial role in protecting cells against cancer.

At last week's Lorne Genome Conference, University of North Carolina molecular biologist Dr Scott Hammond described his research team's discovery of a micromere the long arm of chromosome 13, that appears to resolve a long-standing conundrum about the genesis of many common blood cancers.

Loss of heterozygosity -- the loss of a chromosomal segment along with one copy of all its embedded genes -- is a common feature of cancerous cells and tissues.

Cancer geneticists have recognised for a long time that many leukaemias and lymphomas are associated with a deletion of the chromosomal locus 13q31 and that patients with such deletions sometimes have poor prognosis.

Hammond told the conference that repeated genomic trawls in the 13q31 region located only two open reading frames (ORFs) in the region. One comes from a gene, GPC5, but the encoded protein had no obvious role in regulating the cell proliferation or apoptosis -- programmed cell death -- if cells lost one copy of the gene.

The other ORF, designated C13orf25, codes for a messenger-like RNA that is not translated into a protein. It is an oncomere: its RNA is post-transcriptionally cleaved to form seven fragments less than 22 nucleic acids in length: the signature of a microRNA.

MicroRNAs, or miRNAs, regulate genes through a number of mechanisms, including induction of RNA-induced gene 'knockdown'. Any double-stranded RNA molecule that induces gene-knockdown must be shorter than 23 bases, or it will induce the cell's interferon-based anti-viral defensive systems.

Hammond's team has been using miRNA microarrays to isolate miRNAs, and then using sequence homologies to track them to their chromosomal loci -- and their specific oncomeres. To date, 300 microRNAs have been identified in humans, but Hammond said the eventual number is likely to exceed 1000.

GPC5 is an innocent bystander and has been exonerated of any involvement in tumorigenesis. The real agent provocateur in the 13q region turns out to be the C13orf25 oncomere.

Hammond told the Lorne conference that when cancerous cells are analysed for microRNAs, their patterns of expression are radically different from those of the healthy progenitor tissues or organs.

Indeed, cancerous cells that appear very diverse to a histologist peering down a microscope bear an uncanny resemblance to each other at the microRNA level. Cancerous cells express fewer microarrays than their healthy progenitors, and the basic complement is uncannily similar in the majority of cancers.

And it is no accident, Hammond said, that the small, basic complement of miRNAs expressed by many cancerous tissues and organs bears a close resemblance to those expressed by embryonic stem cells, emphasising that cancerous cells are very stem-like in their behaviour. They are immortalised, and refuse to die on reaching their normal use-by date.

Hammond said oncomeres and their embedded microRNAs have opened up a new line of inquiry into the origins and mechanisms involved in cancer -- and may also be useful as diagnostics and therapeutic targets in future.