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      FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis

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          Abstract

          Background

          The amplicon on 8p11.2 is reported to be found in up to 10% of breast carcinomas. It has been demonstrated recently that this amplicon has four separate cores. The second core encompasses important oncogene candidates, including the fibroblast growth factor receptor 1 ( FGFR1) gene. Recent studies have demonstrated that specific FGFR1 amplification correlates with gene expression and that FGFR1 activity is required for the survival of a FGFR1 amplified breast cancer cell line.

          Methods

          FGFR1 amplification was analysed in tissue microarrays comprising a cohort of 880 unselected breast tumours by means of chromogenic in situ hybridisation using inhouse-generated FGFR1-specific probes. Chromogenic in situ hybridisation signals were counted in a minimum 30 morphologically unequivocal neoplastic cells. Amplification was defined as >5 signals per nucleus in more than 50% of cancer cells or when large gene copy clusters were seen.

          Results

          FGFR1 amplification was observed in 8.7% of the tumours and was significantly more prevalent in patients >50 years of age and in tumours that lacked HER2 expression. No association was found with other histological parameters. Survival analysis revealed FGFR1 amplification as an independent prognostic factor for overall survival in the whole cohort. Subgroup analysis demonstrated that the independent prognostic impact of FGFR1 amplification was only seen in patients with oestrogen-receptor-positive tumours, where FGFR1 amplification was the strongest independent predictor of poor outcome.

          Conclusion

          Given that up to 8.7% of all breast cancers harbour FGFR1 amplification and that this amplification is an independent predictor of overall survival, further studies analysing the FGFR1 as a potential therapeutic target for breast cancer patients are warranted.

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          High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses.

          Douglas MacMillan, R W Blamey, E Paish … (2005)
          Recent studies on gene molecular profiling using cDNA microarray in a relatively small series of breast cancer have identified biologically distinct groups with apparent clinical and prognostic relevance. The validation of such new taxonomies should be confirmed on larger series of cases prior to acceptance in clinical practice. The development of tissue microarray (TMA) technology provides methodology for high-throughput concomitant analyses of multiple proteins on large numbers of archival tumour samples. In our study, we have used immunohistochemistry techniques applied to TMA preparations of 1,076 cases of invasive breast cancer to study the combined protein expression profiles of a large panel of well-characterized commercially available biomarkers related to epithelial cell lineage, differentiation, hormone and growth factor receptors and gene products known to be altered in some forms of breast cancer. Using hierarchical clustering methodology, 5 groups with distinct patterns of protein expression were identified. A sixth group of only 4 cases was also identified but deemed too small for further detailed assessment. Further analysis of these clusters was performed using multiple layer perceptron (MLP)-artificial neural network (ANN) with a back propagation algorithm to identify key biomarkers driving the membership of each group. We have identified 2 large groups by their expression of luminal epithelial cell phenotypic characteristics, hormone receptors positivity, absence of basal epithelial phenotype characteristics and lack of c-erbB-2 protein overexpression. Two additional groups were characterized by high c-erbB-2 positivity and negative or weak hormone receptors expression but showed differences in MUC1 and E-cadherin expression. The final group was characterized by strong basal epithelial characteristics, p53 positivity, absent hormone receptors and weak to low luminal epithelial cytokeratin expression. In addition, we have identified significant differences between clusters identified in this series with respect to established prognostic factors including tumour grade, size and histologic tumour type as well as differences in patient outcomes. The different protein expression profiles identified in our study confirm the biologic heterogeneity of breast cancer and demonstrate the clinical relevance of classification in this manner. These observations could form the basis of revision of existing traditional classification systems for breast cancer.
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            Expression of luminal and basal cytokeratins in human breast carcinoma.

            David Ellis, R W Blamey, El-Sayed Mahdy … (2004)
            We have examined basal and luminal cell cytokeratin expression in 1944 cases of invasive breast carcinoma, using tissue microarray (TMA) technology, to determine the frequency of expression of each cytokeratin subtype, their relationships and prognostic relevance, if any. Expression was determined by immunocytochemistry staining using antibodies to the luminal cytokeratins (CKs) 7/8, 18 and 19 and the basal markers CK 5/6 and CK 14. Additionally, assessment of alpha-smooth muscle actin (SMA) and oestrogen receptor status (ER) was performed. The vast majority of the cases showed positivity for CK 7/8, 18 and 19 indicating a differentiated glandular phenotype, a finding associated with good prognosis, ER positivity and older patient age. In contrast, basal marker expression was significantly related to poor prognosis, ER negativity and younger patient age. Multivariate analysis showed that CK 5/6 was an independent indicator for relapse free interval. We were able to subgroup the cases into four distinct phenotype categories (pure luminal, mixed luminal/basal, pure basal and null), which had significant differences in relation to the biological features and the clinical course of the disease. Tumours classified as expressing a basal phenotype (the combined luminal plus basal and the pure basal) were in a poor prognostic subgroup, typically ER negative in most cases. These findings provide further evidence that breast cancer has distinct differentiation subclasses that have both biological and clinical relevance. Copyright 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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              The Nottingham Prognostic Index in primary breast cancer.

              Robert Elston, David Ellis, H Galea … (1991)
              In 1982 we constructed a prognostic index for patients with primary, operable breast cancer. This index was based on a retrospective analysis of 9 factors in 387 patients. Only 3 of the factors (tumour size, stage of disease, and tumour grade) remained significant on multivariate analysis. The index was subsequently validated in a prospective study of 320 patients. We now present the results of applying this prognostic index to all of the first 1,629 patients in our series of operable breast cancer up to the age of 70. We have used the index to define three subsets of patients with different chances of dying from breast cancer: 1) good prognosis, comprising 29% of patients with 80% 15-year survival; 2) moderate prognosis, 54% of patients with 42% 15-year survival; 3) poor prognosis, 17% of patients with 13% 15-year survival. The 15-year survival of an age-matched female population was 83%.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Breast Cancer Res
                Title: Breast Cancer Research
                Publisher: BioMed Central (London )
                ISSN (Print): 1465-5411
                ISSN (Electronic): 1465-542X
                Publication date (Print): 2007
                Publication date (Electronic): 30 March 2007
                Volume: 9
                Issue: 2
                Page: R23
                Affiliations
                [1 ]Department of Histopathology, School of Molecular Medical Sciences, A Floor, West Block, Queen's Medical Centre, Nottingham University Hospitals Trust and University of Nottingham, Nottingham, NG7 2UH, UK
                [2 ]The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK
                [3 ]Division of Epidemiology and Public Health, School of Community Health Sciences, Queen's Medical Centre, Nottingham University Hospitals Trust and University of Nottingham, Nottingham, NG7 2UH, UK
                Article
                Publisher ID: bcr1665
                DOI: 10.1186/bcr1665
                PMC ID: 1868920
                PubMed ID: 17397528
                SO-VID: dc2acfa9-f22b-44b3-bc94-454d68185610
                Copyright © Copyright © 2007 Elsheikh et al., licensee BioMed Central Ltd.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 1 December 2006
                Date revision requested : 9 February 2007
                Date revision received : 12 March 2007
                Date accepted : 30 March 2007
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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