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| Status |
Public on May 09, 2022 |
| Title |
Clinical associations of ESR2 (estrogen receptor beta; ERβ) expression across thousands of primary breast tumors |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
PURPOSE: 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.
METHODS: 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 (Sweden Cancerome Analysis Network—Breast [SCAN-B], ClinicalTrials.gov identifier: NCT02306096). Spearman rank correlation was used to determine correlations between expression of ESR1 and ESR2. Kruskal-Wallis non-parametric test and Wilcoxon rank sum test were used to compare and plot expression of the ESR1 and ESR2 genes in various clinical groups such as PAM50 subtype and age groups in both the SCAN-B and TCGA cohorts. Transformed ESR2 expression data was divided into tertiles, with the first tertile defined as ESR2-high, and the bottom two tertiles at ESR2-low. Mann Whitney U test and Fisher’s exact test were used to evaluate significant differences in the clinicopathological variables for the ESR2-high and ESR2-low groups. Survival analysis was performed by Kaplan-Meier and Cox regression survival analyses that included a median follow-up of 6.2 years (IQR = 2.2).
RESULTS: Using RNA-seq data, we found that 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, size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors.
CONCLUSIONS: 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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| Overall design |
Illumina paired-end RNA-sequencing and expression estimation using StringTie, were performed for the SCAN-B 3,207 BC cohort. Hormone receptor positive early breast tumors were defined as cases expressing estrogen (ERα) or progesterone (PR) receptors using an immunohistochemical staining cutoff ≥ 10% of neoplastic/BC cells as indicated by Swedish guidelines and HER2 status was assessed according to standard recommendations. Molecular subtyping was performed using the PAM50 gene list. Clinical/medical records were retrieved from the Swedish National Cancer Registry (NKBC).
Due to the patient consent, Swedish law, the potential that the sequencing data contains personally-identifiable information and hereditary mutations, and the right to privacy, the submitter cannot make available the raw sequence data in a public repository.
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| Contributor(s) |
Dalal H, Dahlgren M, Gladchuk S, Brueffer C, Gruvberger-Saal SK, Saal LH |
| Citation(s) |
35304506 |
| Submission date |
May 04, 2022 |
| Last update date |
May 09, 2022 |
| Contact name |
Lao H Saal |
| E-mail(s) |
lao.saal@med.lu.se
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| Organization name |
Lund University
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| Department |
Department of Oncology and Pathology
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| Lab |
Translational Oncogenomics Unit
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| Street address |
Scheelevägen 2, MV404B2
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| City |
Lund |
| ZIP/Postal code |
22391 |
| Country |
Sweden |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (3207)
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| Relations |
| BioProject |
PRJNA834993 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE202203_RawCounts_gene_3207.tsv.gz |
204.3 Mb |
(ftp)(http) |
TSV |
| GSE202203_TPM_Raw_gene_3207.tsv.gz |
401.9 Mb |
(ftp)(http) |
TSV |
| GSE202203_UCSC_hg38_knownGenes_22sep2014.gtf.gz |
19.8 Mb |
(ftp)(http) |
GTF |
| Processed data are available on Series record |
| Raw data not provided for this record |
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