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

Moelans, Cathy B.; Weger, Roel A. de; Diest, Paul J. van

doi:10.1007/s10549-009-0539-2

Cited by 105 publications

(87 citation statements)

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“…[25][26][27] In our opinion, it would be better to use the term disorder (instead of the usual term polysomy) to define FISH-detected copy number alterations of Cep17, since recent studies, performed by microarray-based comparative genomic hybridization, 15 have confirmed that ''true'' polysomy is a rare event in breast cancer, frequently mimicked by Cep17 amplification. Also, Moelans et al, 18 in their extensive analysis investigating the frequency of polysomy 17 and its association with HER2/neu amplification (by Cep17 chromogenic in situ hybridization and by copy number analysis of a set of 17 genes along chromosome 17, using multiplex ligation-dependent probe amplification), concluded that true polysomy of chromosome 17, either of the whole chromosome, or the short or the long arm, is very rare. Chromosome 17 usually shows a complex pattern of gains and losses, rather unrelated to the copy number status of the centromere; consequently, correction with Cep17 probes may provide misleading false-negative HER2/neu amplification results.…”

Section: Discussionmentioning

confidence: 99%

“…2,13 The reported incidence of chromosome 17 polysomy, as estimated by FISH, ranges from 5% to 50%. 11,14 However, recent validation studies performed via comparative genomic hybridization [15][16][17][18] have shown that ''true'' polysomy is a rare event and that Cep17 amplification can mimic the presence of multiple copies of chromosome 17, leading to an overestimation of the incidence of Chr17 polysomy. Therefore, Cep17 amplifi-cation represents an important source of inaccuracy in FISH testing for HER2/neu amplification.…”

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confidence: 99%

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Centromere 17 Copy Number Alteration: Negative Prognostic Factor in Invasive Breast Cancer?

Petroni

Addati²,

Mattioli³

et al. 2012

Archives of Pathology &Amp; Laboratory Medicine

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N Context.-Chromosome 17 polysomy has been identified in 5% to 50% of invasive breast cancers; even though a relationship with human epidermal growth factor receptor 2 (HER2/neu) status has been reported, other studies have shown that coincident centromere 17 (Cep17) amplification may be the cause of an overestimation of chromosome 17 polysomy in fluorescence in situ hybridization (FISH) testing.Objective.-To evaluate polysomy/amplification of Cep17 in invasive breast cancer with relation to proliferative activity (Ki-67), estrogen receptor, progesterone receptor, and HER2/neu status, in an attempt to identify a subgroup of patients with a worse prognosis.Design.-A total of 647 cases of invasive ductal breast cancer were collected and subjected to FISH analysis for HER2/neu gene and centromere 17 alteration, HercepTest for HER2/neu protein expression, and routine immunohistochemistry for Ki-67 and hormone receptor status.Results.-Copy number gain of Cep17 was observed in 27.3% of cases. Within this group, HER2/neu gene amplification was detected in 14.1% of cases, whereas HER2/neu expression was scored 3+ in 20.1% of cases; about half of the HER2/neu overexpressing cases (9.8%) did not show amplification by FISH. Moreover, 69% of polysomic cases showed high Ki-67 index.Conclusions.- (1) Centromere 17-altered cases are frequently HER2/neu overexpressing but not amplified, resulting in HercepTest/FISH disagreement; (2) HER2/neu amplification is seen at a higher incidence in cases without Cep17 copy number alterations, which are therefore not necessarily due to chromosome 17 disorder; (3) proliferation index is significantly higher in aneusomic tumors. These data suggest that the presence of Cep17 alterations could identify a subset of breast cancers with more aggressive biological and clinical behavior, which may show nonresponsiveness to conventional therapy independently of HER2/neu amplification status.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Centromere 17 Copy Number Alteration: Negative Prognostic Factor in Invasive Breast Cancer?

Petroni

Addati²,

Mattioli³

et al. 2012

Archives of Pathology &Amp; Laboratory Medicine

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“…17 Similarly, MLPA analysis of 17 chromosome 17 loci identified no cases of true polysomy among 111 breast cancers, although 19% had shown CEP17 increases by CISH. 60 Molecular karyotyping studies have confirmed the rarity of true polysomy 17 in breast cancer. For example, Marchiò et al 62 used array-comparative genomic hybridization (aCGH) to make a detailed assessment of chromosome 17 status in 18 breast tumors with apparent polysomy 17 (CEP17 Z3).…”

Section: Polysomy 17 and Response To Anti-her2 Therapymentioning

confidence: 94%

“…However, concurrent evaluation of several chromosome 17 genes using multiple-probe FISH or multiplex ligation-dependent probe amplification (MLPA) suggests that focal amplifications encompassing the centromere are the usual reason for high-level increases in CEP17 signals. 17,60,61 Of 171 breast tumors with apparent polysomy (CEP17 42.6), only 24 cases (14%) showed the equivalent increases in copy numbers of CEP17, HER2, SMS, RARA, and TP53 that would result from whole chromosomal gains. 17 Similarly, MLPA analysis of 17 chromosome 17 loci identified no cases of true polysomy among 111 breast cancers, although 19% had shown CEP17 increases by CISH.…”

Section: Polysomy 17 and Response To Anti-her2 Therapymentioning

confidence: 99%

HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity

Hanna

Rüschoff²,

Bilous³

et al. 2014

Modern Pathology

251

201

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Trastuzumab-containing therapy is a standard of care for patients with HER2 þ breast cancer. HER2 status is routinely assigned using in situ hybridization to assess HER2 gene amplification, but interpretation of in situ hybridization results may be challenging in tumors with chromosome 17 polysomy or intratumoral genetic heterogeneity. Apparent chromosome 17 polysomy, defined by increased chromosome enumeration probe 17 (CEP17) signal number, is a common genetic aberration in breast cancer and represents an alternative mechanism for increasing HER2 copy number. Some studies have linked elevated CEP17 count ('polysomy') with adverse clinicopathologic features and HER2 overexpression, although there are numerous discrepancies in the literature. There is evidence that elevated CEP17 ('polysomy') count might account for trastuzumab response in tumors with normal HER2:CEP17 ratios. Nonetheless, recent studies establish that apparent 'polysomy' (CEP17 increase) is usually related to focal pericentromeric gains rather than true polysomy. Assigning HER2 status may also be complex where multiple cell subclones with distinct HER2 amplification characteristics coexist within the same tumor. Such genetic heterogeneity affects up to 40% of breast cancers when assessed according to a College of American Pathologists guideline, although other definitions have been proposed. Recent data have associated heterogeneity with unfavorable clinicopathologic variables and poor prognosis. Genetically heterogeneous tumors harboring HER2-amplified subclones have the potential to benefit from trastuzumab, but this has yet to be evaluated in clinical studies. In this review, we discuss the implications of apparent polysomy 17 and genetic heterogeneity for assigning HER2 status in clinical practice. Among our recommendations, we support the use of mean HER2 copy number rather than HER2:CEP17 ratio to define HER2 positivity in cases where coamplification of the centromere might mask HER2 amplification. We also highlight a need to harmonize in situ hybridization scoring methodology to support accurate HER2 status determination, particularly where there is evidence of heterogeneity.

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“…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.…”

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

Vranić

Teruya

Repertinger

et al. 2010

Cancer

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BACKGROUND:The current study was performed to determine the impact of polysomy 17 on the interpretation of HER2 testing of invasive breast carcinomas using fluorescent in situ hybridization methods. Current American Society of Clinical Oncology/College of American Pathologists guidelines define HER2-positive tumors as those with >6 HER2 genes per nucleus or those with HER2/CEP17 (chromosome 17) ratio >2.2. These guidelines are potentially contradictory in tumors with polysomy of chromosome 17. METHODS: Seventy-two breast carcinoma cases with reported polysomy of chromosome 17 (3 CEP17 signals on average) by fluorescent in situ hybridization were identified, and the corresponding HER2 immunohistochemistry was obtained. The HER2 status of the archived samples was reviewed, and the tumors were recategorized according to the 2007 American Society of Clinical Oncology/College of American Pathologists guidelines. RESULTS: The average CEP17 copy number for the group was 4.5 (range, 3.0-10.4). Thirty-three (45.8%) cases had >6 copies of HER2 per nucleus. Twenty-one cases (29.2%) qualified as HER2 gene amplified using the HER2/CEP17 ratio (>2.2) guideline. All these cases had >6 HER2 signals, which represented 63.6% of all cases with >6 HER2 signals. HER2 protein expression showed significant positive correlations with both HER2 gene copy number and HER2/CEP17 ratio (P < .01, r s ¼ 0.56 and 0.64, respectively). CONCLUSIONS: Increased CEP17 signals detected in invasive breast carcinomas may lead to discordant interpretation of gene amplification in a significant proportion of the cases, depending on which criterion (ratio vs absolute number) is used for interpretation. However, increased gene dosage (>6 HER2 genes or HER2/CEP17 ratio >2.2), regardless of the evaluation method, is positively correlated with HER2 protein expression. Cancer 2011;117:48-53.

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

Abstract: Amplification of the HER2 gene, present in 15-30% of breast carcinomas, correlates with poor outcome and is an indication for treatment with trastuzumab.

Cited by 105 publications

References 22 publications

Centromere 17 Copy Number Alteration: Negative Prognostic Factor in Invasive Breast Cancer?

Centromere 17 Copy Number Alteration: Negative Prognostic Factor in Invasive Breast Cancer?

HER2 in situ hybridization in breast cancer: clinical implications of polysomy 17 and genetic heterogeneity

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

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