We are delighted to award the 2020 BTF Research Award to Professor Márta Korbonits, William Harvey Research Institute, Queen Mary University of London, for her project: 

A novel genetic cause of medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a rare but aggressive form of thyroid cancer. In about a quarter of all cases, MTC affects more than one person in the same family. Most of these patients have a genetic abnormality – mutation – in a portion of the DNA called the RET gene which predisposes them to develop MTC. Genetic testing is very important for these patients, as family members who have inherited the mutation need to be monitored closely so that the cancer can be recognized early and treated successfully. Moreover, in families with specific types of mutation, MTC can present at an early age. In this case, children who inherited the mutation require surgery to remove the thyroid gland during the first few years of life in order to prevent the development and spread of the cancer. In some families, however, the cause of MTC is still unknown and, as a consequence, it is not possible to identify other family members who are at risk of developing the disease.

As a research group with extensive experience in defining the genetic causes of tumours arising from the endocrine glands, we have been studying the DNA of members of two families with MTC and, using advanced techniques, we have been able to identify a novel genetic mutation as the cause of their disease. We have obtained DNA from six other MTC families with unknown genetic cause and 75 patients who developed MTC without other affected family members. We plan to test the DNA of these patients to see if they have abnormalities in the novel gene we identified. We will look at the level of the protein linked to this gene in their tumour samples as we think this will help to identify those patients having more aggressive forms of cancer and that should be monitored more closely. We will alter this gene in cells we are growing in our laboratory to study their behaviour and understand the mechanisms how the mutation we discovered causes the disease. We will inject these mutated cells under the skin of mice to study their growth and how they respond to medications aimed at treating MTC.

Our findings are highly significant, as the discovery of a novel mutation causing this aggressive form of cancer will allow us to understand previously unknown mechanisms explaining how this disease occurs. This can translate into novel treatment options for patients with MTC. Moreover, we will be able to identify children in the two original families who have inherited the mutation and who will be treated promptly so that they will have a high chance of being cancer-free. If mutations are found in other patients, their children and relatives will also directly benefit from the results of our research. Therefore, our study will have direct immediate impact on patients in the UK and world wide both at the diagnostic and at the therapeutic level. 

How the BTF Research Award made a difference

Medullary thyroid cancer (MTC) is a relatively rare but aggressive type of thyroid cancer which is frequently genetically determined and therefore runs in families. Most of these familial tumours are known to be related to mutations of a gene called RET, which has allowed clinicians to diagnose these tumours early in family members, and thus assist in prophylactic surgery to avoid the development of the cancer, especially in young children. However, some familial MTC does not appear to involve RET, and we have used our BTF Research Award to identify a wholly new gene mutation in families who develop MTC without RET mutations. The grant has also allowed us to explore the nature of this gene, its possible involvement in known proliferative pathways, and to develop stable cell lines which allow us to study its mechanism of action.

From the patients’ viewpoint, we can now use this information to demonstrate which family members in such families are likely to develop MTC, and hence we can offer surveillance and early operation to avoid cancer development. This will also help to exclude family members who are not at risk.

In the longer term, understanding the mechanism for tumour development in these patients may lead the way to find novel medical therapies for both these families, and quite possibly for the larger group of patients with sporadic MTC. This is an exciting and fast-developing area of research which has direct implications for patient care, and would not have been possible but for the BTF grant.

Professor Márta Korbonits

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