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Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers.

Vermeij J, Teugels E, Bourgain C, Xiangming J, in 't Veld P, Ghislain V, Neyns B, De Grève J - BMC Cancer (2008)

Bottom Line: An integrated analysis of both genes could help define the proportion of patients that would potentially benefit from targeted therapies.HER2-neu expression was found in 35%, with a 2/3+ staining in 18%.High polysomy of the EGFR gene was observed in 13% of the invasive epthelial cancers and amplification of the HER2-neu gene was found in 10% and correlated with a high expression level by immunohistochemistry.Mutations within the tyrosine kinase domain were not found in the entire TK domain of both genes, but have been found in very rare cases by others.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory for Molecular Oncology, Universitair Ziekenhuis, Vrije Universiteit Brussel, 1090 Brussels, Belgium. joanna.vermeij@zna.be

ABSTRACT

Background: The status of the EGFR and HER2-neu genes has not been fully defined in ovarian cancer. An integrated analysis of both genes could help define the proportion of patients that would potentially benefit from targeted therapies.

Methods: We determined the tumour mutation status of the entire tyrosine kinase (TK) domain of the EGFR and HER2-neu genes in a cohort of 52 patients with invasive epithelial ovarian cancer as well as the gene copy number and protein expression of both genes in 31 of these patients by DGGE and direct sequecing, immunohistochemistry and Fluorescent in Situ Hybridisation (FISH).

Results: The EGFR was expressed in 59% of the cases, with a 2+/3+ staining intensity in 38%. HER2-neu expression was found in 35%, with a 2/3+ staining in 18%. No mutations were found in exons 18-24 of the TK domains of EGFR and HER2-neu. High polysomy of the EGFR gene was observed in 13% of the invasive epthelial cancers and amplification of the HER2-neu gene was found in 10% and correlated with a high expression level by immunohistochemistry.Mutations within the tyrosine kinase domain were not found in the entire TK domain of both genes, but have been found in very rare cases by others.

Conclusion: Genomic alteration of the HER2-neu and EGFR genes is frequent (25%) in ovarian cancer. EGFR/HER2-neu targeted therapies should be investigated prospectively and specifically in that subset of patients.

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Immunohistochemical and FISH analysis of EGFR and HER2-neu on ovarian tumours. A-C : Immunohistochemistry for EGFR and HER2-neu protein expression on paraffin sections from ovarian tumours (all 400× magnification). Examples of an EGFR score 0 (A), EGFR 3+ overexpression (B) and HER2-neu 3+ overexpression (C). D-F : Fluorescence in situ hybridisation for the EGFR and HER2-neu gene on frozen sections from ovarian tumours (all 630× magnification). Examples of a tumour without EGFR amplification (D), a tumour showing polysomy 7 (E) and a tumour with HER2-neu amplification showing clusters of multiple gene copies (F).
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Figure 1: Immunohistochemical and FISH analysis of EGFR and HER2-neu on ovarian tumours. A-C : Immunohistochemistry for EGFR and HER2-neu protein expression on paraffin sections from ovarian tumours (all 400× magnification). Examples of an EGFR score 0 (A), EGFR 3+ overexpression (B) and HER2-neu 3+ overexpression (C). D-F : Fluorescence in situ hybridisation for the EGFR and HER2-neu gene on frozen sections from ovarian tumours (all 630× magnification). Examples of a tumour without EGFR amplification (D), a tumour showing polysomy 7 (E) and a tumour with HER2-neu amplification showing clusters of multiple gene copies (F).

Mentions: EGFR immunostaining could be performed in adequately preserved samples from 31 patients. Positivity was found in 20/31 invasive epithelial cancers (64.5%) of which 13 (42 %) had an intensity of ≥ 2 (Table 3). FISH analysis for EGFR could be interpreted in 27 invasive epithelial cancers. No gene amplification was found in any of the samples. In 4 cases (13%) an increased number of EGFR copies (≥ 4 per nucleus) was detected in the presence of polysomy for chromosome 7. Such cases were defined as "high polysomy" as previously reported in NSCLC [14]. Immunohistochemistry on these polysomy cases yielded variable results one case being 0, one case 1+ and two cases 2+ for EGFR, giving no indication for a correlation with the gene copy number (Fig 1).


Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers.

Vermeij J, Teugels E, Bourgain C, Xiangming J, in 't Veld P, Ghislain V, Neyns B, De Grève J - BMC Cancer (2008)

Immunohistochemical and FISH analysis of EGFR and HER2-neu on ovarian tumours. A-C : Immunohistochemistry for EGFR and HER2-neu protein expression on paraffin sections from ovarian tumours (all 400× magnification). Examples of an EGFR score 0 (A), EGFR 3+ overexpression (B) and HER2-neu 3+ overexpression (C). D-F : Fluorescence in situ hybridisation for the EGFR and HER2-neu gene on frozen sections from ovarian tumours (all 630× magnification). Examples of a tumour without EGFR amplification (D), a tumour showing polysomy 7 (E) and a tumour with HER2-neu amplification showing clusters of multiple gene copies (F).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2266762&req=5

Figure 1: Immunohistochemical and FISH analysis of EGFR and HER2-neu on ovarian tumours. A-C : Immunohistochemistry for EGFR and HER2-neu protein expression on paraffin sections from ovarian tumours (all 400× magnification). Examples of an EGFR score 0 (A), EGFR 3+ overexpression (B) and HER2-neu 3+ overexpression (C). D-F : Fluorescence in situ hybridisation for the EGFR and HER2-neu gene on frozen sections from ovarian tumours (all 630× magnification). Examples of a tumour without EGFR amplification (D), a tumour showing polysomy 7 (E) and a tumour with HER2-neu amplification showing clusters of multiple gene copies (F).
Mentions: EGFR immunostaining could be performed in adequately preserved samples from 31 patients. Positivity was found in 20/31 invasive epithelial cancers (64.5%) of which 13 (42 %) had an intensity of ≥ 2 (Table 3). FISH analysis for EGFR could be interpreted in 27 invasive epithelial cancers. No gene amplification was found in any of the samples. In 4 cases (13%) an increased number of EGFR copies (≥ 4 per nucleus) was detected in the presence of polysomy for chromosome 7. Such cases were defined as "high polysomy" as previously reported in NSCLC [14]. Immunohistochemistry on these polysomy cases yielded variable results one case being 0, one case 1+ and two cases 2+ for EGFR, giving no indication for a correlation with the gene copy number (Fig 1).

Bottom Line: An integrated analysis of both genes could help define the proportion of patients that would potentially benefit from targeted therapies.HER2-neu expression was found in 35%, with a 2/3+ staining in 18%.High polysomy of the EGFR gene was observed in 13% of the invasive epthelial cancers and amplification of the HER2-neu gene was found in 10% and correlated with a high expression level by immunohistochemistry.Mutations within the tyrosine kinase domain were not found in the entire TK domain of both genes, but have been found in very rare cases by others.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory for Molecular Oncology, Universitair Ziekenhuis, Vrije Universiteit Brussel, 1090 Brussels, Belgium. joanna.vermeij@zna.be

ABSTRACT

Background: The status of the EGFR and HER2-neu genes has not been fully defined in ovarian cancer. An integrated analysis of both genes could help define the proportion of patients that would potentially benefit from targeted therapies.

Methods: We determined the tumour mutation status of the entire tyrosine kinase (TK) domain of the EGFR and HER2-neu genes in a cohort of 52 patients with invasive epithelial ovarian cancer as well as the gene copy number and protein expression of both genes in 31 of these patients by DGGE and direct sequecing, immunohistochemistry and Fluorescent in Situ Hybridisation (FISH).

Results: The EGFR was expressed in 59% of the cases, with a 2+/3+ staining intensity in 38%. HER2-neu expression was found in 35%, with a 2/3+ staining in 18%. No mutations were found in exons 18-24 of the TK domains of EGFR and HER2-neu. High polysomy of the EGFR gene was observed in 13% of the invasive epthelial cancers and amplification of the HER2-neu gene was found in 10% and correlated with a high expression level by immunohistochemistry.Mutations within the tyrosine kinase domain were not found in the entire TK domain of both genes, but have been found in very rare cases by others.

Conclusion: Genomic alteration of the HER2-neu and EGFR genes is frequent (25%) in ovarian cancer. EGFR/HER2-neu targeted therapies should be investigated prospectively and specifically in that subset of patients.

Show MeSH
Related in: MedlinePlus