Paterson Institute for Cancer Research SCIENTIFIC REPORT 2005

ACADEMIC RADIATION ONCOLOGY:
TRANSLATIONAL RADIOGENOMICS
immunohistochemistry. This work is part of an
international collaboration involving Professor Jens
Overgaard’s group in Aarhus, Dr Jim Raleigh in
North Carolina and a group in Vancouver. Staining
and scoring of the sections was recently completed
and over the past year we have finished updating the
clinical database. The relationship between
pimonidazole staining and radiotherapy outcome is
currently being explored.
Changes in plasma TGFß1 are prognostic for
radiation morbidity in patients with head and
neck cancer
Another biological feature important in determining
how a patient responds to radiotherapy is their
intrinsic sensitivity to radiation. Some patients are
inherently radiosensitive and likely to develop
severe long-term complications, which may not
become apparent for several months or even years
following treatment. The small numbers of
patients who develop severe late radiation toxicity
limit the total curative doses that can be safely
administered to all patients. The ability to predict
patients predisposed to developing toxicity early has
potential for allowing safe dose-escalation in others
to increase their chance of a cure. The
Translational Radiogenomics group is interested in
not only hypoxia but also methods for measuring
normal tissue radiosensitivity. Transforming
growth factor-β1 (TGFβ1) is implicated in the
development of radiation-induced fibrosis and a
study in patients with lung cancer showed changes
in TGFβ1 predicted the likelihood of acute toxicity
following radiotherapy. A prospective study was
initiated, therefore, in 1999 to measure changes in
plasma TGFβ1 during radiotherapy in patients with
head and neck cancer. Analysis of the results in the
past year (Christine Clinton) showed that changes in
TGFβ1 – end to pre-treatment ratio of less than
one, with an elevated end of treatment TGFβ1 level
- correlated with both acute and late radiation toxicity.
Radiogenomics: assessment of polymorphisms
for predicting the effects of radiotherapy
(RAPPER)
Current thinking is that an individual’s intrinsic
radiosensitivity is determined by polymorphic
sequence variation in a large number of genes. The
availability of a reference sequence of the human
genome is raising the possibility of genotyping
studies looking at variations in a large number of
genes, i.e. those involved in DNA damage recognition
and repair, proliferation, apoptosis and
cytokine response to cellular damage. In order to
have sufficient statistical power to find meaningful
correlations, these studies require large numbers of
patients. Following a successful grant application to
the Cancer Research UK Translational Research in
Clinical Trials Committee, we obtained funding for
RAPPER. The study is being co-ordinated by our
group (Rebecca Elliot) and involves collaboration
with Drs Neil Burnet and Alison Dunning in
Cambridge, along with numerous Clinical
Oncologists locally and around the UK. The study
has a planned accrual of up to 3000 patients with
breast, prostate or gynaecological cancer. Patients
will have received radiotherapy with curative intent
and have detailed late effect data. Blood samples
will be taken and analysed for single nucleotide
polymorphisms in candidate genes in Cambridge at
the end of the project. With the appointment of
Teresa Bailey in October we are now looking forward
to banking our first blood samples.
Figure 2: HIF-1α expression was not observed in normal gastric mucosa. Low and weak HIF-1α expression was observed in
mucosa infected with H. pylori and increased in percentage and intensity with the sequence of H. pylori associated gastritis, intestinal
metaplasia, dysplasia and intestinal type adenocarcinoma (left to right).
P A T E R S O N I N S T I T U T E S C I E N T I F I C R E P O R T 2 0 0 5
Figure 1:
Dendogram
of 59 head
and neck
cancers
clustered
using a
knowledgeb
a s e d
derived
hypoxia
Publications listed
on page 62
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