No Strong Association Between HER-2/neu Protein Overexpression and Gene Amplification in High-grade Invasive Urothelial Carcinomas

Caner, Vildan; Türk, Nilay Şen; Düzcan, Füsun; Şatıroğlu-Tufan, N. Lale; Kelten, Esra Canan; Zencir, Sevil; Dodurga, Yavuz; Bağcı, Hüseyin; Duzcan, Suleyman Ender

doi:10.1007/s12253-008-9027-y

Cited by 54 publications

(48 citation statements)

References 19 publications

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“…Consistent with other published studies of HER2 immunohistochemical staining in urothelial carcinoma, 9,[12][13]15,20 we considered carcinomas positive if they exhibited 2 þ or 3 þ immunostaining.…”

Section: Immunohistochemistrymentioning

confidence: 67%

“…37 As a result, studies have often found a 100% correlation between HER2 protein expression and aneusomy of chromosome 17. 12,30 However, the finding of HER2 gene amplification in a large proportion of our micropapillary carcinoma cases suggests an additional mechanism for HER2 protein expression in this urothelial carcinoma variant and suggests the potential relevance of HER2 in micropapillary carcinoma biology and therapy.…”

Section: Discussionmentioning

confidence: 79%

“…Previous analysis of HER2 gene amplification in conventional urothelial carcinoma found that gene amplification was present in only 10-11% of metastatic and non-metastatic lesions 9 and HER2 protein expression in only 30-36% of cases. Overall, there does not seem to be a strong association between HER2 protein expression and gene amplification in conventional urothelial carcinoma, 12 which is perhaps explained by the relative paucity of gene amplification found in conventional urothelial carcinoma specimens, ranging from only 5.1 to 22.2%. 12,[16][17][18] Sauter et al 35 found that even when urothelial carcinomas show HER2 amplification, there is extreme heterogeneity in the amount of amplification per cell, with areas of amplification 'clustering' together and the fraction of amplified cells ranging from 18-94% within tumors.…”

Section: Discussionmentioning

confidence: 90%

“…29 The HER2 protein is considered to have a significant role in bladder cancer outcomes, with HER2 protein expression reported in up to 31-65.5% of samples. 12,16,30 Furthermore, HER2 protein expression seems to correlate with tumor stage, tumor grade, [30][31][32] and poor prognosis. [30][31][32][33][34] One study found that the 5-year disease-free survival rate decreased from 48.5% in HER2-negative patients to 9.7% in those who were HER2 positive.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9] HER2 is normally responsible for regulating cell proliferation and survival. 9,10 Its overexpression results in increased vascular endothelial growth factor production and thus angiogenesis, 11 as well as increased cell proliferation and decreased cell-cell adhesion by activation of the ras/mitogen-activated protein kinase pathway, 11,12 which are important factors in oncogenesis and tumor progression. [8][9][10] HER2 protein overexpression has been most extensively researched in breast cancer, in which it occurs in B20% of primary invasive carcinomas 13 and portends a poor prognosis with decreased disease-free and overall survival.…”

mentioning

confidence: 99%

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HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

et al. 2011

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Human epidermal growth factor receptor-2 (HER2) is a well-recognized growth-promoting factor in cancer, although its application to urothelial carcinoma has been limited because of a low frequency of gene amplification. We evaluated HER2 protein expression and gene amplification in micropapillary carcinoma, a rare but highly aggressive variant of urothelial carcinoma by dual-color in situ hybridization. Gene amplification was defined by a HER2:CHR17 ratio of Z2.2; low and high levels of amplification were further defined as o2.5 and Z2.5, respectively. Immunohistochemistry was used to determine HER2 protein expression using the American Society of Clinical Oncology/College of American Pathologists Guidelines of HER2 staining. Protein expression, gene amplification, and chromosome 17 aneusomy were compared by Jonchkeere-Terpstra and Cochran-Armitage trend tests. In all, 19 of the 20 micropapillary carcinoma samples yielded usable dual-color in situ hybridization and immunohistochemistry results for evaluation. Overall, 68% (n ¼ 13) demonstrated HER2 protein expression of 2 þ to 3 þ staining. Gene amplification was present in 42% of samples (n ¼ 8), with 100% correlation with 2 þ and 3 þ protein expression. Gene amplification and protein expression were significantly associated (P ¼ 0.01). Overall, 53% of samples (n ¼ 10) had aneusomy of chromosome 17. Chromosome 17 aneusomy was present in approximately half of the samples evaluated, suggesting inherent genomic instability in this variant of urothelial carcinoma. However, increased HER2:CHR17 ratios demonstrate increased HER2 expression due to amplification in the majority of micropapillary carcinomas. These results suggest that HER2-targeted therapy may be successful on the genomic level in patients with this disease.

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Section: Immunohistochemistrymentioning

confidence: 67%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

et al. 2011

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HER2 as a target in invasive urothelial carcinoma

et al. 2015

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We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum-based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of ≥2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival. ERBB2 mutation was determined by hotspot sequencing. mRNA expression was assessed using NanoString counting. Association of overall survival (OS) and HER2 status was assessed by a Cox regression model. NIH-3T3 cells containing HER2 V777L were assessed for growth, invasion, and HER2 kinase activation. In all, 22% of Spanish and 4% of Greek cohorts had 3+ HER2 staining by IHC. FISH amplification was identified in 20% of Spanish and 4% of Greek cohorts. Kappa coefficient between FISH and IHC was 0.47. HER2 status was not associated with OS in univariate (Spanish P = 0.34; Greek P = 0.11) or multivariate (Spanish P = 0.49; Greek P = 0.12) analysis. HER2-positive tumors expressed higher levels of HER2 mRNA than HER2-negative tumors (P < 0.001). HER2 mutations (V777L and L755S) were identified in two (2%) patients. In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and HER2 kinase constitutive activation. In summary, HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. HER2 positivity rates can differ between different populations. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC.

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Overexpression of PTK6 (breast tumor kinase) protein—a prognostic factor for long-term breast cancer survival—is not due to gene amplification

et al. 2009

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In a previous retrospective study, we demonstrated the prognostic value of protein tyrosine kinase 6 (PTK6) protein expression in breast carcinomas. Here, we analyzed PTK6 gene amplification using fluorescence in situ hybridization technique in a cohort of 426 invasive breast carcinomas and compared it with PTK6 expression level as well as with the clinical outcome of patients. Forty-five percent of tumors show increased PTK6 gene copy numbers when compared to normal tissue. Most of these, however, were related to chromosome 20 polysomy (30%), while gene amplification accounted for only 15%. Only "low level" amplification of the PTK6 gene, with up to eight signals per nucleus, was found. The PTK6 cytogenetic status (normal, gene amplification, polysomy 20) was not associated with histopathological parameters or with the protein expression of HER receptors. No statistical association was identified between PTK6 gene status and expression level. Further, the PTK6 gene status does not influence the disease-free survival of patients at > or = 240 months. Based on these results, we state that the PTK6 overexpression is not essentially attributed to gene amplification, and the PTK6 protein expression-but not gene status-is of prognostic value in breast carcinomas. PTK6 protein overexpression may result from polysomy 20 in a minority of the tumors. In a marked proportion of tumors, however, the overexpression is likely to be caused by posttranscriptional regulation mechanisms.

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No Strong Association Between HER-2/neu Protein Overexpression and Gene Amplification in High-grade Invasive Urothelial Carcinomas

Cited by 54 publications

References 19 publications

HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization

HER2 as a target in invasive urothelial carcinoma

Overexpression of PTK6 (breast tumor kinase) protein—a prognostic factor for long-term breast cancer survival—is not due to gene amplification

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