A recurrent chromosome breakpoint in breast cancer at the NRG1/neuregulin 1/heregulin gene.
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).
Huang
Huai-En
HE
Cancer Genomics Program, Hutchison-MRC Research Centre, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Chin
Suet-Feung
SF
Ginestier
Christophe
C
Bardou
Valérie-Jeanne
VJ
Adélaïde
José
J
Iyer
N Gopalakrishna
NG
Garcia
Maria J
MJ
Pole
Jessica C
JC
Callagy
Grace M
GM
Hewitt
Stephen M
SM
Gullick
William J
WJ
Jacquemier
Jocelyne
J
Caldas
Carlos
C
Chaffanet
Max
M
Birnbaum
Daniel
D
Edwards
Paul A W
PA
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D044584:Carcinoma, Ductal / Q000235:genetics / Q000378:metabolism; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D020890:Neuregulin-1 / Q000096:biosynthesis / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D016612:Paraffin Embedding
D020890:Neuregulin-1