Introduction Most familial MTC is caused by a germline mutation of the RET proto-oncogene. Rare families exist with predisposition to MTC in whom no RET mutation has been identified. Identification of novel candidate genes within such families may inform the molecular behaviour of more common, sporadic disease. Whole exome sequencing (WES) enables all protein coding regions of the genome to be sequenced in parallel; a novel paradigm for MTC gene discovery. Methods Patients with MTC were recruited through internationally developed collaborations. WES was completed in three generations of the index family. Germline and tumour DNA were analysed for conformational mutations. In vitro functional analysis of candidate gens was completed to unpick biological pathways. Results Over 20,000 mutations were screened. A frameshift mutation in the oestrogen receptor 2 gene (ESR2) has been identified with familial segregation. Further alterations in ESR2 have been identified in germline DNA from a patient with young onset sporadic disease and tumour DNA from sporadic MTC. The functional protein of the ESR2 gene binds to a response element in the upstream pathway of the RET gene, controlling transcription. In-vitro studies show that ESR2 mutants lead to null proteins and up-regulation or RET at mRNA and protein levels. Further, loss of ESR2 protein is observed in patients with germline ESR2 mutations. Conclusions This study establishes a novel method of gene predisposition identification in the context of MTC. As well as the potential for a genetic test, and as a prognostic biomarker, the on-going functional work may elucidate targets for novel therapies that may include pre-existing anti-oestrogen.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:669107 |
| Date | January 2015 |
| Creators | Smith, Joel Anthony |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/6314/ |
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