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Title: Chromosome aberrations targeting the NRG1 gene in cancer
Author: Huang, H. E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2004
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Thirty-four breast and nine pancreatic cancer cell lines were surveyed for alterations of the NRG1 gene by fluorescence in situ hybridization (FISH). A recent chromosome translocation breakpoint that targets the NRG1 gene was found in five breast and two pancreatic lines. High-resolution mapping by two-colour FISH showed that the breakpoints were clustered in a 1.1 Mb interval within NRG1. RT-PCR showed an extensive complexity of NRG1 transcripts in the translocation-positive lines, suggesting that expression of the ligand is a consequence of these structural arrangements. This study was extended to primary tumour material to confirm the presence and prevalence of NRG1 translocation in uncultured cancer cells. I designed a FISH strategy (using a custom FISH probe-the Neuprobe), which was used in a high-throughput manner on archival paraffin embedded material in the form of tissue microarrays (TMAs).A survey of 339 primary breast carcinomas identified a disruption targeting NRG1 in approximately 6% of all cases examined. The common abnormality seen was a deletion in the 5’ end of the gene, often accompanied by amplification of the 3’ end. Genomic alteration of NRG1 was associated with ectopic expression of NRG1 α and β isoforms. Fine mapping confirmed that these breakpoints cluster within the same region seen in cell lines. These results were independently validated by array-based CGH, using a custom made array with overlapping BACS spanning 8p12. NRG1 translocation was associated with high-grade tumours, low HER2 expression, and high expression levels of FGFR1, TACC (both in close genomic proximity to NRG1). A further survey of 242 primary ovarian tumours identified the same abnormality in 10% of tumours.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available