NRG1 gene rearrangements in clinical breast cancer: identification of an adjacent novel amplicon associated with poor prognosis.
Rearrangements of the neuregulin (NRG1) gene have been implicated in breast carcinoma oncogenesis. To determine the frequency and clinical significance of NRG1 aberrations in clinical breast tumors, a breast cancer tissue microarray was screened for NRG1 aberrations by fluorescent in situ hybridization (FISH) using a two-color split-apart probe combination flanking the NRG1 gene. Rearrangements of NRG1 were identified in 17/382 cases by FISH, and bacterial artificial chromosome array comparative genomic hybridization was applied to five of these cases to further map the chromosome 8p abnormalities. In all five cases, there was a novel amplicon centromeric to NRG1 with a minimum common region of amplification encompassing two genes, SPFH2 and FLJ14299. Subsequent FISH analysis for the novel amplicon revealed that it was present in 63/262 cases. Abnormalities of NRG1 did not correlate with patient outcome, but the novel amplicon was associated with poor prognosis in univariate analysis, and in multivariate analysis was of prognostic significance independent of nodal status, tumor grade, estrogen receptor status, and human epidermal growth factor receptor (HER)2 overexpression. Of the two genes in the novel amplicon, expression of SPFH2 correlated most significantly with amplification. This amplicon may emerge as a result of breakpoints and chromosomal rearrangements within the NRG1 locus.
Prentice
Leah M
LM
Department of Pathology and Prostate Centre, Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, Canada V6H 3Z6.
Shadeo
Ashleen
A
Lestou
Valia S
VS
Miller
Melinda A
MA
deLeeuw
Ronald J
RJ
Makretsov
Nikita
N
Turbin
Dmitry
D
Brown
Lindsay A
LA
Macpherson
Nicol
N
Yorida
Erika
E
Cheang
Maggie C U
MC
Bentley
John
J
Chia
Stephen
S
Nielsen
Torsten O
TO
Gilks
C Blake
CB
Lam
Wan
W
Huntsman
David G
DG
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D046228:Microarray Analysis; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D066247:Receptor, ErbB-4; D015996:Survival Rate; D016335:Zinc Fingers
D004273:DNA, Neoplasm; D066246:ErbB Receptors; D020890:Neuregulin-1; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human