| 1. |
- Bergqvist, Jenny, et al.
(author)
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Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome
- 2007
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In: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 18:5, s. 845-850
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Journal article (peer-reviewed)abstract
- BACKGROUND: Our aim was to use quantitative real-time PCR (Q-PCR) and RNA expression profiles (RNA-EPs) to investigate HER2 status in relation to outcome. PATIENTS AND METHODS: Cut-off levels for Q-PCR and RNA-EP were established in relation to immunohistochemistry (IHC) validated by FISH in a test set of frozen tissue samples from 40 primary breast cancers. The HER2 status was subsequently studied in another validation set of 306 tumors, where Q-PCR and RNA-EP results were compared with previously carried out IHC that we had validated by chromogenic in situ hybridization (CISH). RESULTS: Q-PCR and RNA-EP offered similar sensitivity (90% versus 77%), specificity (93% versus 95%), and negative (99% versus 98%) and positive (63% versus 61%) predictive values for HER2 determinations. Analyses of relapse-free survival (RFS) and overall survival on the basis of 5 and 10 years of follow-up indicated equivalent hazard ratios for all three techniques. In contrast to IHC/CISH, both Q-PCR and RNA-EP analyses of HER2 also gave statistically significant results regarding RFS and breast cancer-corrected survival after 10 years of follow-up. CONCLUSION: The use of RNA-EP and Q-PCR to analyze HER2 in frozen and formalin-fixed breast cancer samples may be an alternate approach to IHC in combination with FISH/CISH.
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| 2. |
- Lindahl, Thomas, et al.
(author)
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Overexpression of cyclin E protein is associated with specific mutation types in the p53 gene and poor survival in human breast cancer.
- 2004
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In: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 25:3, s. 375-80
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Journal article (peer-reviewed)abstract
- Cyclin E is one of the key regulators of the G(1)/S transition in the cell cycle. Overexpression of cyclin E has been observed in several malignancies and is associated with high proliferation, aberrant expression of other cell cycle regulators and chromosomal instability in vitro. To explore potential associations between cyclin E deregulation and inactivation of the p53 tumor suppressor gene in human breast cancer, we investigated the immunohistochemical expression of cyclin E in paraffin embedded breast cancers from 270 women with known p53 status by cDNA based sequencing of the p53 gene. The breast cancers were divided into three subgroups according to the percentage of cyclin E-positive cells. One hundred and seventy-one patients (63%) had low cyclin E, 72 (27%) medium and 27 (10%) had high cyclin E content. Fifty-six percent (15/27) of the breast cancers with high cyclin E had p53 gene mutations, compared with 14% (24/171) of those with low cyclin E content (P < 0.0001). In p53 mutated breast cancers high cyclin E content was associated with insertions, deletions and nonsense point mutations in the p53 tumor suppressor gene, whereas low cyclin E was linked to p53 missense point mutations. We also observed statistically significant associations between a high cyclin E content and aneuploidy, high S phase, larger tumor size, estrogen receptor negativity, presence of axillary node metastases and high tumor grade. High cyclin E content was associated with poor overall survival in univariate and multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.3-4.5). In summary, our findings demonstrate that overexpression of cyclin E is associated with an aggressive tumor phenotype and specific types of p53 mutations.
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| 3. |
- Pawitan, Yudi, et al.
(author)
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Gene expression profiling spares early breast cancer patients from adjuvant therapy : derived and validated in two population-based cohorts
- 2005
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In: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 7:6, s. R953-64
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Adjuvant breast cancer therapy significantly improves survival, but overtreatment and undertreatment are major problems. Breast cancer expression profiling has so far mainly been used to identify women with a poor prognosis as candidates for adjuvant therapy but without demonstrated value for therapy prediction. METHODS: We obtained the gene expression profiles of 159 population-derived breast cancer patients, and used hierarchical clustering to identify the signature associated with prognosis and impact of adjuvant therapies, defined as distant metastasis or death within 5 years. Independent datasets of 76 treated population-derived Swedish patients, 135 untreated population-derived Swedish patients and 78 Dutch patients were used for validation. The inclusion and exclusion criteria for the studies of population-derived Swedish patients were defined. RESULTS: Among the 159 patients, a subset of 64 genes was found to give an optimal separation of patients with good and poor outcomes. Hierarchical clustering revealed three subgroups: patients who did well with therapy, patients who did well without therapy, and patients that failed to benefit from given therapy. The expression profile gave significantly better prognostication (odds ratio, 4.19; P = 0.007) (breast cancer end-points odds ratio, 10.64) compared with the Elston-Ellis histological grading (odds ratio of grade 2 vs 1 and grade 3 vs 1, 2.81 and 3.32 respectively; P = 0.24 and 0.16), tumor stage (odds ratio of stage 2 vs 1 and stage 3 vs 1, 1.11 and 1.28; P = 0.83 and 0.68) and age (odds ratio, 0.11; P = 0.55). The risk groups were consistent and validated in the independent Swedish and Dutch data sets used with 211 and 78 patients, respectively. CONCLUSION: We have identified discriminatory gene expression signatures working both on untreated and systematically treated primary breast cancer patients with the potential to spare them from adjuvant therapy.
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| 5. |
- Wennmalm, Kristian, et al.
(author)
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Gene expression in 16q is associated with survival and differs between Sørlie breast cancer subtypes
- 2007
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In: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 46:1, s. 87-97
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Journal article (peer-reviewed)abstract
- We have investigated the relationship between gene expression and chromosomal positions in 402 breast cancer patients. Using an overrepresentation approach based on Fisher's exact test, we identified disproportionate contributions of specific chromosomal positions to genes associated with survival. Our major finding is that the gene expression in the long arm of chromosome 16 stands out in its relationship to survival. This arm contributes 36 (18%) and 55 (11%) genes to lists negatively associated with recurrence-free survival (set to sizes 200 and 500). This is a highly disproportionate contribution from the 313 (2%) genes in this arm represented on the used Affymetrix U133A and B microarray platforms (Bonferroni corrected Fisher test: P < 2.2 x 10(-16)). We also demonstrate differential expression in 16q across tumor subtypes, which suggests that the ERBB2, basal, and luminal B tumors progress along a high grade-poor prognosis path, while luminal A and normal-like tumors progress along a low grade-good prognosis path, in accordance with a previously proposed model of tumor progression. We conclude that important biological information can be extracted from gene expression data in breast cancer by studying non-random connections between chromosomal positions and gene expression. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
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