Active Cancer Genetics & Molecular Biology

Understanding how an SLC30A9 gene deletion causes familial medullary thyroid carcinoma

Funder AMS (part of Academy)
Recipient organisation Queen Mary University of London
Funding £30K
Period Sept 2025 — Aug 2027

In plain English

AI plain-English summary

A single DNA deletion in the SLC30A9 gene is causing medullary thyroid carcinoma in two families who carry none of the usual cancer-driving mutations. Most inherited cases of this rare thyroid cancer are caused by mutations in the RET gene, but roughly 25% of familial cases have no known genetic cause. The researcher has identified a deletion in SLC30A9 that appears to force the cell's protein-making machinery to restart at a later point, producing a shortened, potentially cancer-causing protein. This fills a gap in understanding why some families develop the disease despite having normal RET genes. If the work succeeds, it will provide the proof-of-concept needed to offer genetic testing and prospective screening for affected families. It could also reveal SLC30A9 as a previously unknown player in cancer, potentially leading to new therapeutic targets for the sporadic form of the disease. Beyond cancer, the project will shed light on translation reinitiation—a poorly understood mechanism by which cells produce truncated proteins—and how it can cause human disease. This is primarily fundamental science, but understanding this overlooked process could eventually explain other genetic disorders where standard mutation screens come up empty.

View original technical description
Medullary thyroid carcinoma (MTC) can arise in a familial setting in 25% of cases, generally as a result of a RET gene mutation. I have studied two related families with >20 cases of RET mutation-negative MTC over several different generations and identified a unique intragenic deletion in the SLC30A9 gene as the cause of their disease. Preliminary data suggest that the deletion results in translation reinitiation and my hypothesis is that the resulting truncated protein has oncogenic properties. Firstly, I aim to assess the role of SLC30A9 mutations in other families with the same phenotype and in patients with sporadic MTC which I have already recruited into the study. Secondly, I aim to characterise the mechanisms leading to tumour development by using MTC cells stably expressing wild-type and mutant SLC30A9, specifically looking at their oncogenic properties in vitro and in vivo using nude mice. Given previous evidence showing a role of SLC30A9 as a transcriptional co-regulator, I will study the transcriptome of these cells to gain insights into the causative mechanisms and affected pathways. This research will have significant implications for affected patients, as it will provide the proof-of-concept for genetic testing and prospective screening. It will also uncover a previously unknown role of SLC30A9 in cancer and may result in novel therapeutic targets for patients with the sporadic form of the disease. Lastly, it will provide novel insights into the role of translation reinitiation, an often overlooked and poorly understood mechanism, in causing human disease.

View the original record at the funder ↗

Researchers

Donato Iacovazzo (EPMC Awardee)

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Original classification

Starter Grant for Clinical Lecturers

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