Does chromosome 17 centromere copy number predict polysomy in breast cancer? A fluorescence in situ hybridization and microarray‐based CGH analysis

Abstract

Approximately 8% of breast cancers show increased copy numbers of chromosome 17 centromere (CEP17) by fluorescence in situ hybridization (FISH) (ie average CEP17 >3.0 per nucleus). Currently, this pattern is believed to represent polysomy of chromosome 17. HER2-amplified cancers have been shown to harbour complex patterns of genetic aberrations of chromosome 17, in particular involving its long arm. We hypothesized that aberrant copy numbers of CEP17 in FISH assays may not necessarily represent true chromosome 17 polysomy. Eighteen randomly selected CEP17 polysomic cases and a control group of ten CEP17 disomic cases, as defined by dual-colour FISH, were studied by microarray-based comparative genomic hybridization (aCGH), which was performed on microdissected samples using a 32K tiling-path bacterial artificial chromosome microarray platform. Additional FISH probes were employed for SMS (17p11.2) and RARA (17q21.2) genes, as references for chromosome 17 copy number. Microarray-based comparative genomic hybridization revealed that 11 out of the 18 polysomic cases harboured gains of 17q with involvement of the centromere, one displayed 17q gain sparing the centromeric region, and only one could be defined as polysomic. The remaining five cases displayed amplification of the centromeric region. Among these, one case, showing score 2+ by immunohistochemistry and 8.5 HER2 mean copy number, was classified as not amplified by HER2 /CEP17 ratio and as amplified by HER2 /SMS ratio. Our results suggest that true chromosome 17 polysomy is likely to be a rare event in breast cancer and that CEP17 copy number greater than 3.0 in FISH analysis is frequently related to gain or amplification of the centromeric region. Larger studies investigating the genetic profiles of CEP17 polysomic cases are warranted.

Absence of chromosome 17 polysomy in breast cancer: analysis by CEP17 chromogenic in situ hybridization and multiplex ligation-dependent probe amplification

“…Our results are consistent, however, with recent data from two studies using array CGH on breast tumors, which also suggest that polysomy of chromosome 17 is a rare event in breast cancer [26,27]. Although extensive prognostic testing should be performed before drawing definite conclusions on the value of CEP17 in HER2 scoring, evidence from our study and other studies is mounting and at least raise questions concerning the proper selection of patients for trastuzumab/lapatinib therapy based on HER2 scoring with CEP17 correction.…”

Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers

“…FISH assays for assessing HER2 gene amplification were performed for IHC equivocal (score 2+) cases, as previously reported [19].…”

Assessment of HER2 gene status in breast carcinomas with polysomy of chromosome 17

“…This finding has been reported by others. 14,26 Interestingly, CEP17 copy number may have a predictive therapeutic value; increased CEP17 copy number appears to be a predictive marker for anthracycline-based chemotherapy in breast cancer. 27,28 Similar to gains in CEP17 copy number as seen on FISH testing, deletions of the CEP17 copy number do not necessarily correlate with deletion of the entire chromosome.…”

“…However, it is important to recognize that an increase in CEP17 signals does not necessarily represent a true polysomy (ie, gain of the entire chromosome), but rather may represent a focal pericentromeric gain or a partial polysomy. 12,14 We have investigated the effect of increased CEP17 signal number on the interpretation of FISH results in breast cancers diagnosed at our institution. We confirm that increased CEP17 signals may lead to discordant interpretations between the HER2/CEP17 ratio and absolute HER2 gene copy number in a significant proportion of cases.…”