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Keywords | Hereditary | tricarboxylic acid cycle | fumarase | succinate dehydrogenase |<br />
renal | paraganglioma | leiomyoma |<br />
TCAC in <strong>Cancer</strong><br />
Defects in the Tricarboxylic<br />
Acid (Krebs) Cycle<br />
Summary<br />
For this project, top European cancer research groups<br />
working on the association between defects in the tricarboxylic<br />
acid cycle (TCAC) and cancer form a consortium<br />
to profoundly characterise the human phenotypes to enable<br />
identifi cation and effi cient cancer prevention, and to<br />
unravel the underlying molecular mechanisms. Recent<br />
breakthrough fi ndings by the consortium participants and<br />
others have shown that defects in at least four TCAC genes<br />
– fumarate hydratase (FH, fumarase), and succinate dehydrogenase<br />
(SDH) B, C, and D – can confer susceptibility<br />
to cancer. We shall take these studies forward by characterising<br />
the natural history of the syndromes in large<br />
European materials.<br />
Simultaneously, we shall perform functional studies to elucidate<br />
the cellular events induced by these defects by<br />
systematic biology approaches including functional studies<br />
in cell lines, model organisms, and transcription profi ling of<br />
TCAC defi cient and profi cient tumours and models.<br />
TCAC defect-associated expression patterns will be utilised<br />
to examine other cancer types for such defects. We have<br />
evidence that modifying genes play a key role in TCAC<br />
defect-associated tumourigenesis and candidate regions<br />
have been identifi ed. Following gene identifi cation, the<br />
possible role of these modifi ers in low penetrance cancer<br />
predisposition in the general population will be examined.<br />
The rationale to form this consortium is simple and strong.<br />
The consortium brings together the key European cancer<br />
researchers studying TCAC-associated tumourigenesis.<br />
Studying the tumourigenic eff ects of FH and the diff erent<br />
units of SDH separately would be ineff ective, and formation<br />
of the consortium will ensure that Europe will maintain the<br />
initiative in this new and exciting fi eld of research. The deliverables<br />
arising from the work packages will contribute to<br />
the common goals; prevention of TCAC-associated cancers<br />
and learning the lessons these lesions can teach to cancer<br />
research.<br />
BIOLOGY 77<br />
Aim<br />
The two key tasks to achieve this project’s objective are:<br />
• characterising the natural history and prevalence of<br />
TCAC-defi cient cancers;<br />
• unravelling the molecular mechanisms driving TCACassociated<br />
tumourigenesis.<br />
Expected results<br />
The impact of the proposed research is two-fold. First, it provides<br />
a basis for cancer detection, prevention and treatment<br />
in high-risk individuals with TCAC defects. The discoveries by<br />
us and others linking TCAC defects to a high risk of tumours<br />
are so recent that even the very basic data on the natural history<br />
of the respective syndromes is missing and, without this<br />
knowledge, evidence-based measures to fi ght this novel<br />
tumour type cannot be developed. Second, the proposed<br />
research will create data on the frequency of TCAC-defi cient<br />
hereditary and sporadic cancers, and will characterise the<br />
molecular mechanisms underlying their genesis. This will be<br />
a major advancement for cancer research in general.<br />
Potential applications<br />
This project will create data for management of TCACdefi<br />
cient tumours.<br />
Diagnosis<br />
• Improved molecular diagnosis of hereditary susceptibility.<br />
• Classifi cation of tumours.<br />
Also, it will create an expression profi le-based classifi er for<br />
TCAC defi cient cancers.<br />
Management<br />
• Hereditary susceptibility: it goes without saying that an<br />
exact diagnosis of the syndromes involved is a very signifi<br />
cant factor in improving the management of the<br />
patient, and the relatives. Appropriate follow-up strategies<br />
and much more accurate genetic counselling on<br />
cancer risk will become available.<br />
• TCAC-defi cient tumours: whether hereditary or sporadic,<br />
TCAC-defi cient tumours are likely to display special<br />
biological properties which are relevant for clinical management,<br />
including response to drug treatment. We<br />
anticipate that the more detailed molecular classifi cation<br />
of tumours provided by eff orts of this proposal will<br />
considerably improve the standard care of such lesions.
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