We congratulate our three Research Award winners for 2021.
- Dr Kate Lines (Oxford) – recipient of the John Pettit Award for MEN1 Research
- Dr Cynthia Andoniadou (London)
- Dr Cristina Ronchi (Birmingham)
Below are the lay summaries of their research proposals and we look forward to hearing how they get on in 12 months’ time when they submit their final reports.
Dr Kate Lines (Oxford) – recipient of the John Pettit Award for MEN1 Research
Identification of genetic regions that can bind the MEN1 promoter and modulate menin expression in MEN1 patients (£9,950)
Multiple endocrine neoplasia type 1 (MEN1) is an inherited disease in which patients develop multiple tumours. It is most commonly caused by mutations in the MEN1 gene. In up to 10-30% of patients however a mutation cannot be found. If a mutation is not identified then it is more difficult to predict the outcome for the patient, and screening of additional family members cannot be undertaken. In this study we have identified a family that have MEN1, but we could not detect any MEN1 mutation. Analysis of the parathyroid tumours from 4 members of this family, however showed they are all negative for menin expression, the protein that is made from the MEN1 gene. This therefore indicates that this family has a mutation that affects the MEN1 gene, but is not located within its immediate DNA sequence. DNA exists in a 3D structure, and therefore it is possible that when this structure is formed a different part of the DNA code can bind to the region of the MEN1 gene and affect its activity. This is what we propose to study within this project. We plan to undertake experiments to find all the DNA regions that can interact with the MEN1 gene. Once we have found these we will then look to see if mutations in these regions are present in the MEN1 patient family, as well as an additional 20 MEN1 patients we have available. Finally, we will confirm whether any mutations we find can affect the levels of menin. Therefore, this study will help inform on the DNA regions that should be examined in MEN1 patients to confirm their diagnosis.
Dr Cynthia Andoniadou (London)
Using transcriptomic data to predict metastatic potential of inherited phaeochromocytoma/paraganglioma with a focus on non-SDHB related disease (£10,000)
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours that can be benign or metastatic. Up to four out of ten patients with metastatic disease do not survive to 5 years, and even the majority of benign tumours are associated with severe symptoms as they secrete high levels of hormones that lead to hypertension, arrhythmia and stroke. These tumours are unpredictable and there is currently no way to determine which will behave aggressively and which will remain benign, even in patients that carry the identical genetic mutations that are responsible for their tumours.
Our project aims to exploit a powerful technique termed RNA-sequencing, which allows us to look at thousands of genes at once in an unbiased manner, and determine which are active in the tumours. Using this technique, we will analyse 10 archived tumours with known genetic mutations, and compare those that have behaved aggressively and metastasised to ones that have remained benign. In this way we can determine differences in gene expression within the tumours, as this is likely to have consequences on tumour behaviour. This research will not only allow us to understand tumour behaviour and pinpoint causative factors for aggressive and metastatic disease; it also has the potential to open up new avenues for treatment. The data generated will act as a valuable resource both for larger-scale studies in future as well as for researchers worldwide studying different aspects of PPGL disease. Dr Andoniadou is the 2022 recipient of the Starling Medal from the Society for Endocrinology.
Dr Cristina Ronchi (Birmingham)
Targeted DNA sequencing of circulating cell-free DNA for prognosis and surveillance of adrenocortical carcinoma (£9,645)
Tumours of the adrenal gland are very frequent in the general population with a prevalence of 2-3% and are mostly harmless. In the rare case that they are cancerous, known as adrenocortical carcinoma (ACC), they are highly aggressive. About half of the patients who have an ACC removed see the tumour return within 2 years, and the majority die within 5 years of diagnosis. Recent developments in genetics, biochemistry, and imaging techniques have set new standards for the diagnosis and treatment of ACC. Nevertheless, there are still critical unmet clinical needs for patients with ACC:
• No markers are available that can help to predict clinical outcomes at the time of the diagnosis
• Follow-up requires frequent imaging that is expensive, results in increased radiation exposure and cannot always answer diagnostic questions.
In my research, I aim to address these needs and to improve the clinical outcome of patients with ACC through the establishment of tailored medical management for individual patients. In the last 2 years, I developed a method for the evaluation of small fragments of genetic information (=DNA) released from tumour cells into the blood. Now, I intend to investigate a larger cohort of patients – before and after surgery – to further validate the clinical utility of this method. Specifically, I will collect blood samples from new patients with ACC. The levels of the DNA fragments will be correlated with clinical data and standard radiological imaging reports (i.e. tumour load and disease progression) and, eventually, specific alterations will be investigated in DNA fragments. The results will be analysed in order to identify markers that could 1. Better predict the clinical course of ACC patients, 2. Recognize disease relapses and/or progression and 3. Monitor the response to therapy earlier and better than standard imaging. The same gene panel will also allow us to identify those patients that might benefit in the near future from innovative anti-cancer drugs.
This method might represent a cheap and quick alternative that could simultaneously better distinguish patients with a good or bad prognosis as well as improve the monitoring of the disease. Due to the rarity of ACC and generally low circulating quantities of these DNA fragments, no studies were able to demonstrate the clinical utility of this method until now. I have access to one of largest series of well-characterized ACC patients in the UK and to cutting-edge technologies, and I have longstanding expertise in genetic studies of adrenal tumours. This makes me ideally suited to perform these analyses. This study will serve to underpin further recruitment of samples within the UK and Europe and major funding applications.