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).
Cancer Genomics Program, Hutchison-MRC Research Centre, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Huai-En
HE
Huang
Suet-Feung
SF
Chin
Christophe
C
Ginestier
Valérie-Jeanne
VJ
Bardou
José
J
Adélaïde
N Gopalakrishna
NG
Iyer
Maria J
MJ
Garcia
Jessica C
JC
Pole
Grace M
GM
Callagy
Stephen M
SM
Hewitt
William J
WJ
Gullick
Jocelyne
J
Jacquemier
Carlos
C
Caldas
Max
M
Chaffanet
Daniel
D
Birnbaum
Paul A W
PA
Edwards
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