Annual research report: chromosome 1p and 19q deletion analysis

	2006	2005	Press Release

Progress report, May 2005
Implementation and audit of chromosome 1p and 19q deletion analysis for guiding the treatment of patients with malignant brain tumours

Background
Analysis of blood and tumour tissue from patients undergoing neurosurgery for brain tumours has now been established at Frenchay and Southmead Hospitals for almost three years. The service was initiated by a student attachment, and subsequently secured by the generous support of Hammer Out. This extra test allows us to ensure that all patients with tumours likely to show sensitivity to PCV chemotherapy are offered this treatment. No patient is denied a trial of PCV at the time of relapse, but we discourage early use if the chance of benefit is low. The test therefore helps us to optimise patients’ quality as well as quantity of life.

Clinical Practice
Fresh tissue is taken at the time of tumour surgery whenever possible (i.e. provided that it is technically feasible to resect enough of the tumours without exposing the patient to increased risk). When a tumour is confirmed, a blood sample is sent, usually during oncology consultation. Most patients then commence radiotherapy, during the course of which the chromosome analysis if performed (see below) and the results made available during. Some patients, e.g. those with lowergrade tumours, do not require radiotherapy, and they attend clinic to hear the results and discuss the
benefits of chemotherapy. Patients with 1p 19q deletions are offered chemotherapy routinely.

Analysis
We now routinely compare the DNA in the tumour with that in the blood, to look for loss of markers at 4 separate loci on each of the two chromosomes of interest (1p, the short arm of chromosome 1, and 19q, the long arm of chromosome 19). We have found that in all patients at least one of these loci is 'informative' (i.e. the length of the segment of DNA on the maternally inherited copy of the chromosome differs slightly from that on the paternally inherited copy). Because of their different lengths, the two copies separate when they are passed through a polyacrylamide gel and this allows us to see whether one or other of the copies that is present in the blood is missing from the tumour (i.e. we perform a 'loss-of-heterozygosity' assay).

Results
Since the service started, almost 100 samples have been analysed. At the time of writing, 26 patients are known to have had positive results, with deletions of either 1p, 19q or both. Deletion of 19q alone is less predictive of benefit from chemotherapy but we are keen to analyse this group also when more results are available. Data regarding outcomes are presently incomplete as many patients are still receiving treatment. It is however already evident that presence of these deletions does confer an advantage in terms of response and survival. Patients with 1p deletions have the best outlook, with several of our patients achieving durable remissions. All patients with deletions identified since commencement of the Hammer Out service are alive and well, having had chemotherapy offered as part of treatment, albeit in conjunction with continued care and other therapies.

Improving the service
As with all developments, there has been a learning curve, but this service is now well established. To improve further, in the future:

1. Occasional patients are referred out of our area (because neurosurgery covers a different catchment area from oncology) and in future, we need to establish a clear channel to ensure that any positive results are communicated to distant clinicians.
2. We should like to analyse the patients with 19q deletions only, particularly to establish whether responses are more frequent with PCV or temozolomide chemotherapy.
3. We plan to start testing tumour tissue for the status of another gene MGMT also. This predicts for specific sensitivity to temozolomide chemotherapy. The reults will have implications for many patients with glioblastomas, and will help to make a case for appropriate individuals to be offered temozolomide during and after radiotherapy as part of their initial treatment.

Acknowledgement
The staff involved in this work remain extremely grateful to Hammer Out for their continued support of this project. We are proud to be one of very few centres able to offer this routinely.

Kirsten Hopkins and Seth Love