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| 2. |
- Cirenajwis, Helena, et al.
(författare)
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Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
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| 4. |
- Dahlgren, Malin, et al.
(författare)
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CITED1 as a marker of favourable outcome in anti-endocrine treated, estrogen-receptor positive, lymph-node negative breast cancer.
- 2023
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Ingår i: BMC Research Notes. - 1756-0500. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate CITED1 as a potential biomarker of anti-endocrine response and breast cancer recurrence, given its previously determined role in mediating estrogen-dependant transcription. The study is a continuation of earlier work establishing the role of CITED1 in mammary gland development.Results: CITED1 mRNA is associated with estrogen-receptor positivity and selectively expressed in the GOBO dataset of cell lines and tumours representing the luminal-molecular subtype. In patients treated with tamoxifen, higher CITED1 correlated with better outcome, suggesting a role in anti-estrogen response. The effect was particularly evident in the subset of estrogen-receptor positive, lymph-node negative (ER+/LN-) patients although noticeable divergence of the groups was apparent only after five years. Tissue microarray (TMA) analysis further validated the association of CITED1 protein, by immunohistochemistry, with favourable outcome in ER+, tamoxifen-treated patients. Although we also found a favourable response to anti-endocrine treatment in a larger TCGA dataset, the tamoxifen-specific effect was not replicated. Finally, MCF7 cells overexpressing CITED1 showed selective amplification of AREG but not TGFα suggesting that maintenance of specific ERα-CITED1 mediated transcription is important for the long-term response to anti-endocrine therapy. These findings together confirm the proposed mechanism of action of CITED1 and support its potential use as a prognostic biomarker.
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| 5. |
- Dahlgren, Malin, et al.
(författare)
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Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer
- 2021
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Ingår i: JNCI Cancer Spectrum. - : Oxford University Press (OUP). - 2515-5091. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses. We identified ESR1 resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of ESR1 mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test P < .001 and P = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors. These population-based results indicate that ESR1 mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor ESR1 screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.
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| 6. |
- Dalal, Hina, et al.
(författare)
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Clinical associations of ESR2 (estrogen receptor beta) expression across thousands of primary breast tumors
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression. To add further clarity to ESR2 in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n = 3207) from the SCAN-B study. RNA-seq shows ESR2 is expressed at low levels overall with a slight inverse correlation to ESR1 expression (Spearman R = -0.18, p = 2.2e-16), and highest ESR2 expression in the basal- and normal-like PAM50 subtypes. ESR2-high tumors had favorable overall survival (p = 0.006), particularly in subgroups receiving endocrine therapy (p = 0.03) and in triple-negative breast cancer (p = 0.01). These results were generally robust in multivariable analyses accounting for patient age, tumor size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors. Taken together, our results indicate that ESR2 is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.
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| 7. |
- Gruvberger, Sofia, et al.
(författare)
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Estrogen receptor beta expression is associated with tamoxifen response in ER alpha-negative breast carcinoma
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:7, s. 1987-1994
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Endocrine therapies, such as tamoxifen, are commonly given to most patients with estrogen receptor (ERalpha)-positive breast carcinoma but are not indicated for persons with ERalpha-negative cancer. The factors responsible for response to tamoxifen in 5% to 10% of patients with ERalpha-negative tumors are not clear. The aim of the present study was to elucidate the biology and prognostic role of the second ER, ERbeta, in patients treated with adjuvant tamoxifen.EXPERIMENTAL DESIGN: We investigated ERbeta by immunohistochemistry in 353 stage II primary breast tumors from patients treated with 2 years adjuvant tamoxifen, and generated gene expression profiles for a representative subset of 88 tumors.RESULTS: ERbeta was associated with increased survival (distant disease-free survival, P = 0.01; overall survival, P = 0.22), and in particular within ERalpha-negative patients (P = 0.003; P = 0.04), but not in the ERalpha-positive subgroup (P = 0.49; P = 0.88). Lack of ERbeta conferred early relapse (hazard ratio, 14; 95% confidence interval, 1.8-106; P = 0.01) within the ERalpha-negative subgroup even after adjustment for other markers. ERalpha was an independent marker only within the ERbeta-negative tumors (hazard ratio, 0.44; 95% confidence interval, 0.21-0.89; P = 0.02). An ERbeta gene expression profile was identified and was markedly different from the ERalpha signature.CONCLUSION: Expression of ERbeta is an independent marker for favorable prognosis after adjuvant tamoxifen treatment in ERalpha-negative breast cancer patients and involves a gene expression program distinct from ERalpha. These results may be highly clinically significant, because in the United States alone, approximately 10,000 women are diagnosed annually with ERalpha-negative/ERbeta-positive breast carcinoma and may benefit from adjuvant tamoxifen.
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| 8. |
- Gruvberger, Sofia, et al.
(författare)
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Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns
- 2001
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Ingår i: Cancer Research. - 1538-7445. ; 61:16, s. 5979-5984
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the phenotype associated with estrogen receptor alpha (ER) expression in breast carcinoma, gene expression profiles of 58 node-negative breast carcinomas discordant for ER status were determined using DNA microarray technology. Using artificial neural networks as well as standard hierarchical clustering techniques, the tumors could be classified according to ER status, and a list of genes which discriminate tumors according to ER status was generated. The artificial neural networks could accurately predict ER status even when excluding top discriminator genes, including ER itself. By reference to the serial analysis of gene expression database, we found that only a small proportion of the 100 most important ER discriminator genes were also regulated by estradiol in MCF-7 cells. The results provide evidence that ER+ and ER- tumors display remarkably different gene-expression phenotypes not solely explained by differences in estrogen responsiveness.
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| 9. |
- Harbst, Katja, et al.
(författare)
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Molecular and genetic diversity in the metastatic process of melanoma.
- 2014
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 233:1, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk.
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| 10. |
- Holm, Karolina, et al.
(författare)
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Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes
- 2012
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Ingår i: Molecular Oncology. - : Elsevier. - 1574-7891 .- 1878-0261. ; 6:5, s. 494-506
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Tidskriftsartikel (refereegranskat)abstract
- Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and Well-characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal-like, luminal A, luminal B, HER2-enriched and normal-like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2-/Ki67low, ER+/HER2-/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal-like, triple negative and HER2-enriched tumors, and high H3K27me3 in luminal A, HER2-enriched and normal-like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal-like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease-free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer.
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