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A Recurrent Chromosome Breakpoint in Breast Cancer at the NRG1/Neuregulin 1/Heregulin Gene

¹ Cancer Genomics Program, Hutchison-MRC Research Centre, Departments of Pathology and Oncology, University of Cambridge, Cambridge, United Kingdom; ² Molecular Oncology and Medical Oncology Departments, Marseille Cancer Research Institute, Institut National de la Santé et de la Recherche Médicale and Institut Paoli-Calmettes, Marseille, France; ³ Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Advanced Technology Center, Bethesda, Maryland; and ⁴ Department of Biosciences, University of Kent, Canterbury, Kent, United Kingdom

Most studies of genomic rearrangements in common cancers have focused on regional gains and losses, but some rearrangements may break within specific genes. We previously reported that five breast cancer cell lines have chromosome translocations that break in the NRG1 gene and that could cause abnormal NRG1 expression. NRG1 encodes the Neuregulins 1 (formerly the Heregulins), ligands for members of the ErbB/epidermal growth factor-receptor family, which includes ErbB2/HER2. We have now screened for breaks at NRG1 in paraffin sections of breast tumors. Tissue microarrays were screened by fluorescence in situ hybridization, with hybridization probes proximal and distal to the expected breakpoints. This screen detects breaks but does not distinguish between translocation or deletion breakpoints. The screen was validated with array-comparative genomic hybridization on a custom 8p12 high-density genomic array to detect a lower copy number of the sequences that were lost distal to the breaks. We also precisely mapped the breaks in five tumors with different hybridization probes. Breaks in NRG1 were detected in 6% (19 of 323) of breast cancers and in some lung and ovarian cancers. In an unselected series of 213 cases with follow-up, breast cancers where the break was detected tended to be high-grade (65% grade III compared with 28% of negative cases). They were, like breast tumors in general, mainly ErbB2 low (11 of 13 were low) and estrogen receptor positive (11 of 13 positive).

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