Diagnostics & Imaging Week Correspondent

LONDON — A new sequencing strategy eventually will make it possible to trawl through the genomes of many different types of cancer looking for places where genetic changes have taken place.

Although the new technology, called massively parallel sequencing, is currently in its infancy, future developments will allow researchers to compare and contrast the genetic idiosyncrasies of hundreds if not thousands of samples from a range of tumors.

The ultimate goal will be to identify places in the genomes of cancers where stretches of DNA have been deleted, inserted, turned back to front, or broken and become reattached to different chromosomes.

Andrew Futreal, co-director of the Cancer Genome Project at the Wellcome Trust Sanger Institute in Hinxton, UK, told Diagnostics & Imaging Week's sister publication BioWorld International: "We will be able to find out just how messed up cancer genomes are, and in how many different ways they can be messed up. If we begin to see a breakpoint that recurs in multiple samples of breast cancer, for example, this might suggest that this event is important in the genesis of that cancer. Such rearrangements can turn out to be incredibly important for the biology of the disease, and will ultimately allow scientists to think about ways of exploiting such genetic abnormalities in order to benefit patients therapeutically."

Precedents already exist for successful therapeutic strategies that target such genetic flaws. For example, in chronic myeloid leukemia, two genes called BCR and ABL are fused together by a chromosomal translocation. The resulting protein has a tyrosine kinase function, which is inhibited by the anti-leukemia drug Gleevec.

Scientists are keen to use similar approaches to treat other cancers, arguing that therapies directed at the unusual "fusion protein" that results from a chromosomal translocation would be highly specific because it would be present only in the cancer cells.

Until recently, most of the known genetic rearrangements directly involved in cancer were those present in leukemias and lymphomas.

Although solid tumors were known to have a multitude of rearrangements, their genomes are vastly more complicated, and there was no good way of pulling those rearrangements out using conventional approaches.

Futreal, together with Michael Stratton, also co-director of the Cancer Genome Project, and colleagues therefore hit upon a new strategy, which has been called massively parallel sequencing.

An account of their recent work appears in Nature Genetics, in a paper titled: "Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing."

The technology involves breaking up the genome of a cancer cell, at random, into millions of fragments of DNA of a certain length for example, 400 base pairs. The next step is to sequence short lengths from each end of the fragments.

Once these sequences are available, the researchers align them against the reference human genome sequence.

Futreal said: "If these sequences go back exactly where they should for example, they are on chromosome 1 and exactly 400 base pairs apart, in the correct orientation then that tells us that this bit of the genome that we have sampled is normal."

If, however, the ends of the 400 base-pair fragment end up 2 megabases apart, then that suggests there has been an insertion of DNA in the cancer genome, or if they are now only 50 base pairs apart, that will suggest that there has been a deletion from the cancer genome.

"There are also more complicated outcomes," Futreal said. "If one of the two ends is on chromosome 1, but the other matches up with the sequence on chromosome 15, that tells us that chromosomes 1 and 15 have broken and joined to each other in the cancer genome."

As the researchers report in Nature Genetics, that approach allowed them to identify more than 100 genetic rearrangements in the cancers of two individuals with lung cancer.

They then validated their findings with the new technique, using conventional Sanger sequencing.

"We would now like to extend the analysis to many different types of cancer," Futreal said. "What we have done so far is just the baby steps' of this technology. It can be made faster and much more efficient. The ultimate goal is to sequence the genomes of lots and lots of different cancers."

The differences in genetic architecture that will be observed, he predicted, will shed light on the biology of different cancers, and that in turn hopefully will lead to new therapeutic strategies.