Genomic Copy Number Analysis of HER2-Equivocal Breast Cancers.
OBJECTIVE
Guidelines for HER2 testing define an equivocal range for HER2 using two approved testing methods, immunohistochemistry (IHC) and in situ hybridization (ISH). We investigated genome-wide copy number alterations in this subgroup.


METHODS
Ten breast cancers with equivocal HER2 status by both IHC and ISH were analyzed by single-nucleotide polymorphism cytogenomic microarray (SNP array). DNA ploidy analysis by flow cytometry was performed on nine cases with sufficient material remaining.


RESULTS
SNP array analysis showed uniform gain of chromosome 17 (polysomy) in one case and segmental copy number gains encompassing HER2 and the centromere in five other cases. Flow cytometry revealed hyperdiploidy in six cases, all but one of which also had HER2 gains on SNP array. Although there was no evidence of HER2 amplification by SNP array, six cases showed amplification of other genomic regions, including known oncogenes in four cases.


CONCLUSIONS
A combination of hyperdiploidy and segmental copy number gains contributes to HER2 ISH-equivocal results in most breast cancers. Cases in which HER2 copy number gain is not corroborated by genomic analysis suggest the presence of other contributing variables influencing ISH results. Genomic copy number analysis also implicates non-HER2 oncogenic drivers in many cases that are HER2 equivocal.
From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN geiersbach.katherine@mayo.edu.
Katherine B
KB
Geiersbach
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT.
Carlynn
C
Willmore-Payne
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT.
Alexandra V
AV
Pasi
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT.
Christian N
CN
Paxton
Huntsman Cancer Institute.
Theresa L
TL
Werner
Department of Pathology, University of Utah, Salt Lake City.
Xinjie
X
Xu
Department of Pathology, University of Utah, Salt Lake City.
Carl T
CT
Wittwer
Department of Pathology, University of Utah, Salt Lake City.
H Evin
HE
Gulbahce
Department of Pathology, University of Utah, Salt Lake City.
Erinn
E
Downs-Kelly
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology; D002886:Chromosomes, Human, Pair 17; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D005434:Flow Cytometry; D005784:Gene Amplification; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
Breast cancer; Genetics; HER2